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Elite controllers (EC), a small subset of the HIV-positive population (
Dalbavancin is a novel lipoglycopeptide with potent activity against several gram-positive pathogens, an excellent safety profile and a long elimination half-life.
In this case series observed at the University Hospital of Vienna between 2015 and 2017, all adult patients with gram-positive infections who received at least one dosage of dalbavancin were screened (n = 118). A total of 72 patients were included in the final analysis. The number of included patients stratified by the source of infection was: skin and soft tissue infection (SSTI) (n = 26), osteomyelitis (n = 20), spondylodiscitis (n = 14), acute septic arthritis (n = 4) and prosthetic joint infection (n = 8).
In 46 patients (64%), clinical cure was detected at the end of dalbavancin therapy without additional antibiotic therapy. Of the 26 patients who received additional antibiotic therapy other than dalbavancin, 15 patients (21%) showed no clinical improvement under dalbavancin therapy, four patients (5%) had side effects (nausea n = 1, exanthema n = 2, hyperglycemia n = 1), and in seven patients (10%) clinical improvement under dalbavancin therapy was detected but antibiotic therapy was de-escalated to an oral drug.
We demonstrated high clinical effectiveness of dalbavancin for acute gram-positive infections primarily acute SSTI, acute septic arthritis, acute osteomyelitis and spondylodiscitis. In patients with biofilm-associated infection (chronic infection or joint prosthesis), source control was absolutely necessary for treatment success.
Isnard S, Ramendra R, Dupuy F, et al.
AbstractBackgroundRegenerating islet-derived protein-3α (REG3α) is an antimicrobial peptide secreted by intestinal Paneth cells. Circulating REG3α has been identified as a gut damage marker in inflammatory bowel diseases. People with HIV (PWH) on antiretroviral therapy (ART) present with an abnormal intestinal landscape leading to microbial translocation, persistent inflammation and development of non-AIDS co-morbidities. Herein, we assessed REG3α as a marker of gut damage in PWH.MethodsPlasma from 169 adult PWH, including 30 elite controllers (ECs), and 30 HIV-uninfected controls were assessed. REG3α plasma levels were compared with HIV disease progression, epithelial gut damage, microbial translocation and immune activation markers.ResultsCross-sectionally, REG3α levels were elevated in untreated and ART-treated PWH compared with controls. ECs also had elevated REG3α levels compared to controls. Longitudinally, REG3α levels increased in PWH without ART and decreased in those who initiated ART. REG3α levels were inversely associated with CD4 T-cell count and CD4/CD8 ratio, while positively correlated with HIV viral load in untreated participants, and with fungal products translocation and inflammatory markers in all PWH.ConclusionPlasma REG3α levels were elevated in PWH, including ECs. The gut inflammatory marker REG3 may be used to evaluate therapeutic interventions and predict non-AIDS co-morbidities risks in PWH.
Coagulase-negative Staphylococci (CoNS) have emerged as a major causative agent of blood-stream infections (BSI). Linezolid (LZD) is currently used for treating glycopeptide and methicillin-resistant staphylococci. It is important to understand the resistance mechanism and probable transmission of LZD resistant (LR) CoNS within the hospital.
Clinically significant LRCoNS from patients with BSI were characterized using MALDI-TOF and 16S rRNA gene sequence analysis. Antimicrobial susceptibility and MIC of vancomycin and LZD were determined. LZD resistance mechanisms using PCR for the cfr gene and mutation in the V domain of the 23S rRNA gene were studied.
The MIC of LZD ranged from 8 to 32 μg/ml. LR was observed in three different CoNS species from diverse locations within the hospital. The cfr gene was identified in all the isolates. Sequence analysis of V domain region of 23S rRNA gene confirmed mutation in single copy among 12/15 isolates with novel mutations: G2614 T and C2384T. All infections were nosocomially acquired and LZD resistance was emerging in the absence of prior LZD use. Horizontal spread of resistant isolates and cfr gene among diverse species were the probable mechanisms of transmission.
The study highlights the novel mutations associated with LRCoNS and the importance of surveillance & transmission pathway within the hospital. It also systematically discusses the published information on LRCoNS.
Swidergall M, Khalaji M, Solis N, et al.
AbstractBackgroundCandidalysin is a cytolytic peptide toxin secreted by Candida albicans hyphae and has significantly advanced our understanding of fungal pathogenesis. Candidalysin is critical for mucosal C albicans infections and is known to activate epithelial cells to induce downstream innate immune responses that are associated with protection or immunopathology during oral or vaginal infections. Furthermore, candidalysin activates the NLRP3 inflammasome and causes cytolysis in mononuclear phagocytes. However, the role of candidalysin in driving systemic infections is unknown.MethodsIn this study, using candidalysin-producing and candidalysin-deficient C albicans strains, we show that candidalysin activates mitogen-activated protein kinase (MAPK) signaling and chemokine secretion in endothelial cells in vitro.ResultsCandidalysin induces immune activation and neutrophil recruitment in vivo, and it promotes mortality in zebrafish and murine models of systemic fungal infection.ConclusionsThe data demonstrate a key role for candidalysin in neutrophil recruitment and fungal virulence during disseminated systemic C albicans infections.
Brejt, Josef A.; Golightly, Linnie M.
Purpose of review
Malaria threatens the lives of over 200 million individuals with the disease each year. Plasmodium falciparum is the predominant cause of severe malaria which may be lethal and result in neurocognitive sequelae despite appropriate treatment. We review recent advances regarding the pathophysiology of severe malaria and treatment recommendations for severe disease in the United States.
Infected red blood cell (iRBC) sequestration in microvascular beds is a critical factor in the development of severe malaria syndromes. Interactions between iRBC variant adhesive peptides and the endothelial protein C receptor (EPCR) result in perturbations of coagulation and cytopreservation pathways. Alterations in the protein C/EPCR axis are implicated in cerebral malaria, respiratory distress, and anemia. Brain MRIs reveal the posterior reversible encephalopathy syndrome in cerebral malaria patients. Transcriptomic analysis reveals commonalities in disease pathogenesis in children and adults despite differences in clinical presentation. US guidelines for severe malaria treatment currently recommend intravenous artesunate including in pregnant women and children.
Despite advances in our understanding of malarial pathogenesis much remains unknown. Antimalarial agents eradicate parasites but no treatments are available to prevent or ameliorate severe malaria or prevent disease sequelae. Further study is needed to develop effective adjunctive therapies.
Correspondence to Linnie M. Golightly, Weill Cornell Medicine, 1300 York Ave., A421, New York, NY 10065, USA. Tel.: +1 (212) 746 7602;. e-mail: email@example.com
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
Pepper, Dominique J.; Sun, Junfeng; Cui, Xizhong; Welsh, Judith; Natanson, Charles; Eichacker, Peter Q.
To address three controversial components in the Centers for Medicare and Medicaid Service’s sepsis bundle for performance measure (SEP-1): antibiotics within 3 hours, a 30 mL/kg fluid infusion for all hypotensive patients, and repeat lactate measurements within 6 hours if initially elevated. We hypothesized that antibiotic- and fluid-focused bundles like SEP-1 would probably show benefit, but evidence supporting specific antibiotic timing, fluid dosing, or serial lactate requirements would not be concordant. Therefore, we performed a meta-analysis of studies of sepsis bundles like SEP-1.
PubMed, Embase, ClinicalTrials.gov through March 15, 2018.
Studies comparing survival in septic adults receiving versus not receiving antibiotic- and fluid-focused bundles.
Two investigators (D.J.P., P.Q.E.).
Seventeen observational studies (11,303 controls and 4,977 bundle subjects) met inclusion criteria. Bundles were associated with increased odds ratios of survival (odds ratio [95% CI]) in 15 studies with substantial heterogeneity (I2 = 61%; p < 0.01). Survival benefits were consistent in the five largest (1,697–12,486 patients per study) (1.20 [1.11–1.30]; I2 = 0%) and six medium-sized studies (167–1,029) (2.03 [1.52–2.71]; I2 = 8%) but not the six smallest (64–137) (1.25 [0.42–3.66]; I2 = 57%). Bundles were associated with similarly increased survival benefits whether requiring antibiotics within 1 hour (n = 7 studies) versus 3 hours (n = 8) versus no specified time (n = 2); or 30 mL/kg fluid (n = 7) versus another volume (≥ 2 L, n = 1; ≥ 20 mL/kg, n = 2; 1.5–2 L or 500 mL, n = 1 each; none specified, n = 4) (p = 0.19 for each comparison). In the only study employing serial lactate measurements, survival was not increased versus others. No study had a low risk of bias or assessed potential adverse bundle effects.
Available studies support the notion that antibiotic- and fluid-focused sepsis bundles like SEP-1 improve survival but do not demonstrate the superiority of any specific antibiotic time or fluid volume or of serial lactate measurements. Until strong reproducible evidence demonstrates the safety and benefit of any fixed requirement for these interventions, the present findings support the revision of SEP-1 to allow flexibility in treatment according to physician judgment.
The National Institutes of Health had no role in study design or data collection, analysis, or interpretation.
Drs. Pepper and Eichacker had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis, including and especially any adverse effects, and drafted the article. Dr. Pepper, Dr. Sun, Ms. Welsh, and Drs. Cui, Natanson, and Eichacker contributed substantially to the study design, data analysis, and interpretation, and approve the final version to be published. Dr. Sun, Ms. Welsh, and Drs. Cui and Natanson revised the article critically for important intellectual content.
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal).
Supported, in part, by National Institutes of Health intramural funding.
Drs. Pepper, Sun, Cui, Natanson, and Eichacker received support for article research from the National Institutes of Health. Drs. Pepper, Sun, and Cui, Ms. Welsh, and Dr. Eichacker disclosed government work.
Clinical Trial Registration numbers: International Prospective Register of Systematic Reviews (PROSPERO) 2017: CRD42017080258.
For information regarding this article, E-mail: firstname.lastname@example.org
Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
Volk C, Burgdorf S, Edwardson G, et al.
AbstractIntroductionPatient IL-1β and IL-10 responses early in the course of Staphylococcus aureus bacteremia (SaB) are associated with bacteremia duration and mortality. We hypothesized that these responses vary depending on choice of antimicrobial therapy, with particular interest in knowing whether the superior performance of -lactams may be linked to key cytokine signaling pathways.MethodsThree medical centers included 59 patients with SaB (47 MRSA, 12 MSSA) from 2015-2017. In the first 48 h, patients were treated with either a β-lactam (n=24), including oxacillin, cefazolin, or ceftaroline, or a glyco-/lipopeptide (n=35), i.e. vancomycin or daptomycin (VAN/DAP). Patient sera from days 1, 3 and 7 were assayed for IL-1β and IL-10 by ELISA and compared using Mann-Whitney U.ResultsOn day 1 of presentation, IL-10 was elevated in patients with outcomes of mortality (P=0.008) and persistent bacteremia (P=0.034), while no difference occurred in IL-1β. Regarding treatment groups, IL-1β and IL-10 was similar at presentation prior to receiving an antibiotic. Patients treated with β-lactam had higher IL-1β on day 3 (median +5.6 pg/mL; P=0.007) and day 7 (+10.9 pg/ml; P=0.016). Ex vivo, the addition of IL-1 receptor antagonist anakinra to whole blood reduced staphylococcal killing, supporting a functional significance of the host IL-1β response in SaB clearance. β-lactam treated patients had sharper declines in IL-10 than VAN/DAP treated patients at days 3 and 7.
Ascher, Simon B.; Scherzer, Rebecca; Nishtala, Arvind; Jotwani, Vasantha; Grunfeld, Carl; Parikh, Chirag R.; Ng, Derek; Wang, Ruibin; Palella, Frank J.; Shlipak, Michael G.; Estrella, Michelle M.
Chronic kidney disease (CKD) occurs commonly among HIV-infected persons. Statins may delay CKD onset and progression via their cholesterol-lowering and pleiotropic effects.
Among 850 HIV-infected men from the Multicenter AIDS Cohort Study with stored urine samples (2009-2011), we evaluated cross-sectional associations of statin use with urine biomarkers of kidney damage (albumin-to-creatinine ratio [ACR], alpha-1-microglobulin, interleukin-18, kidney injury molecule-1, and procollagen type III N-terminal propeptide) using multivariable linear regression. We evaluated the longitudinal associations of statin use with annual change in estimated glomerular filtration rate by creatinine (eGFR) using linear mixed models, and with incident proteinuria and incident CKD (eGFR
Torrens G, Sánchez-Diener I, Jordana-Lluch E, et al.
AbstractBackgroundSearching for new strategies to defeat Pseudomonas aeruginosa is of paramount importance. Previous works in vitro showed that peptidoglycan recycling blockade disables the AmpC-dependent resistance and enhances the susceptibility against cell-wall targeting immunity. Our objective was to validate these findings in murine models.MethodsWildtype PAO1, the recycling-defective mutants in AmpG and NagZ, the AmpC hyper-producer dacB mutant, and their combinations were used to cause systemic/respiratory infections in mice. Their survival, bacterial burden, inflammation level and effectiveness of ceftazidime or sub-therapeutic colistin to treat the infections were assessed.ResultsThe inactivation of AmpG or NagZ significantly attenuated the virulence, in terms of mice mortality, bacterial load and inflammation. When inactivating these genes in the dacB defective background, the β–lactam resistance phenotype was abolished, disabling the emergence of ceftazidime-resistant mutants, and restoring ceftazidime for treatment. Sub-therapeutic colistin was shown to efficiently clear the infection caused by the recycling-defective strains, likely due to the combined effect with the mice cell-wall targeting immunity.ConclusionsThis study brings us one step closer to new therapies intended to disable P. aeruginosa AmpC-mediated resistance and dampen its virulence, and strongly support the interest of developing efficient AmpG and/or NagZ inhibitors.
Antibiotic resistanceAmpC-type beta-lactamaseantipseudomonal weaponspeptidoglycan recyclingadjuvant strategyin-vivo virulence and resistancevalidation of drug target
A monoclonal antibody that the FDA approved last year to prevent chronic and episodic migraine has now received approval to treat episodic cluster headache in adults. The drug blocks calcitonin gene-related peptide ligand—a potent vasodilator that modulates nociceptive trigeminal neurons involved in the pathophysiology of cluster headaches. Patients can self-inject galcanezumab, marketed as Emgality.
Teasdale, Chloe A.; Yuengling, Katharine A.; Mutiti, Anthony; Arpadi, Stephen; Nxele, Mahlubandile; Pepeta, Lungile; Mogashoa, Mary; Rivadeneira, Emilia D.; Abrams, Elaine J.
We report data from an observational cohort of South African children living with HIV
Romero-Saavedra F, Laverde D, Kalfopoulou E, et al.
AbstractEnterococci have emerged as important nosocomial pathogens due to their resistance against the most commonly used antibiotics. Alternative treatments or prevention options are aimed at polysaccharides and surface-related proteins that play important roles in pathogenesis. Previously, we have shown that two Enterococcus faecium proteins, the secreted antigen A and the peptidyl-prolyl cis-trans isomerase, as well as the Enterococcus faecalis polysaccharide diheteroglycan are able to induce opsonic and cross-protective antibodies. Here, we evaluate the use of glycoconjugates consisting of these proteins and an enterococcal polysaccharide to develop a vaccine with broader strain coverage. Diheteroglycan was conjugated to these two enterococcal proteins. Rabbit sera raised against these glycoconjugates showed IgG titers towards the corresponding conjugate, as well as to the respective protein and carbohydrate antigens. Effective opsonophagocytic killing for the two sera was observed against different E. faecalis and E. faecium strains. ELISA against whole bacterial cells showed immune recognition of the sera towards 22 enterococcal strains. Moreover, sera conferred protection in a mouse infection model against E. faecalis and E. faecium strains. Our results suggest that these glycoconjugates are promising candidates for vaccine formulations with a broader coverage against these nosocomial pathogens and that the evaluated proteins are potential carrier proteins.
Early diagnosis of gastric tuberculosis is often challenging because the disease is very rare and its clinical manifestation is nonspecific and misleading. To raise the awareness and emphasize early diagnosis of gastric tuberculosis, we present a case of gastric tuberculosis secondary to pleural and pulmonary tuberculosis.
A 26-year-old woman complained gastric pain for 1 month but showed no other symptoms, who had no previous exposure to tuberculosis.Gastric stromal tumor was originally suspected. However, the pathology of her gastroscopic biopsy of the gastric lesion showed granulomatous lesions and caseating necrosis. Gene sequencing of the biopsy specimen identified deoxyribonucleic acid fragment of Mycobacterium tuberculosis. Chest computed tomography scan revealed nodular shadows in the lesser curvature soft tissue of the stomach, patchy densities and calcified nodular shadows in the upper right lung, bilateral pleural thickening, and calcified pleural nodules. Thus, the diagnosis was gastric tuberculosis secondary to pulmonary and pleural tuberculosis. The patient was hospitalized and treated with the antituberculosis therapy for 1 week. After discharged from the hospital, the patient continued routine antituberculosis therapy for 18 months and was follow-up was normal.Literature search found 22 cases of gastric tuberculosis reported from 2000 to 2016. Review of the 22 cases suggested that polymerase chain reaction has been increasingly used in the recent years in addition to the conventional histopathological and bacteriological approaches.
Clinical presentation of gastric tuberculosis is not specific.When granuloma or caseation is detected on biopsy in patients who are suspected of having gastric malignancy or acid peptic diseases, polymerase chain reaction for Mycobacterium tuberculosis could be used as an available and sensitive diagnostic test in addition to pathology, acid-fast bacilli smear staining and culture.
A combination of visual and auditory stimulation reduced brain amyloid-β peptide (Aβ) and improved memory in mouse models of Alzheimer disease (AD), according to recent preclinical research.
Ming S, Li M, Wu M, et al.
AbstractImmunosuppression contributes to the mortality of sepsis. However, the underlying mechanism remains unclear. In the present study, we investigated the role of inhibitory receptor immunoglobulin-like transcript 5 (ILT5) in sepsis. We first screened the expression of ILT family members, and found that ILT5 was dramatically up-regulated in the peripheral blood mononuclear cells (PBMCs) from sepsis patients vs healthy donors. Knockdown of ILT5 by siRNA increased bacterial killing and reactive oxygen species (ROS) production in THP-1 and RAW264.7 cells. Moreover, ILT5-expressing monocytes/macrophages exhibited lower expression of antigen-presenting molecules including MHC-II and CD80. In the in vitro co-culture system with monocytes/macrophages, blockage of ILT5 facilitated Th1 proliferation and differentiation of CD4+T cells. Furthermore, in vivo experiment demonstrated that pretreatment with ILT5 blocking peptide improved the survival and pulmonary pathology of septic mice. Together, our study identified ILT5 as an immunosuppressive regulator during sepsis, which may provide potential therapeutic strategy for sepsis.
Malaria represents a worldwide medical emergency affecting mainly poor areas. Plasmodium parasites during blood stages can release kinins to the extracellular space after internalization of host kininogen inside erythrocytes and these released peptides could represent an important mechanism in liver pathophysiology by activation of calcium signaling pathway in endothelial cells of vertebrate host. Receptors (B1 and B2) activated by kinins peptides are important elements for the control of haemodynamics in liver and its physiology. The aim of this study was to identify changes in the liver host responses (i.e. kinin receptors expression and localization) and the effect of ACE inhibition during malaria infection using a murine model.
Balb/C mice infected by Plasmodium chabaudi were treated with captopril, an angiotensin I-converting enzyme (ACE) inhibitor, used alone or in association with the anti-malarial chloroquine in order to study the effect of ACE inhibition on mice survival and the activation of liver responses involving B1R and B2R signaling pathways. The kinin receptors (B1R and B2R) expression and localization was analysed in liver by western blotting and immunolocalization in different conditions.
It was verified that captopril treatment caused host death during the peak of malaria infection (parasitaemia about 45%). B1R expression was stimulated in endothelial cells of sinusoids and other blood vessels of mice liver infected by P. chabaudi. At the same time, it was also demonstrated that B1R knockout mice infected presented a significant reduction of survival. However, the infection did not alter the B2R levels and localization in liver blood vessels.
Thus, it was observed through in vivo studies that the vasodilation induced by plasma ACE inhibition increases mice mortality during P. chabaudi infection. Besides, it was also seen that the anti-malarial chloroquine causes changes in B1R expression in liver, even after days of parasite clearance. The differential expression of B1R and B2R in liver during malaria infection may have an important role in the disease pathophysiology and represents an issue for clinical treatments.
Vivax malaria is the predominant form of malaria outside Africa, affecting about 14 million people worldwide, with about 2.5 billion people exposed. Development of a Plasmodium vivax vaccine is a priority, and merozoite surface protein 7 (MSP-7) has been proposed as a plausible candidate. The P. vivax genome contains 12 MSP-7 genes, which contribute to erythrocyte invasion during blood-stage infection. Previous analysis of MSP-7 sequence diversity suggested that not all paralogs are functionally equivalent. To explore MSP-7 functional diversity, and to identify the best vaccine candidate within the family, MSP-7 expression and antigenicity during bloodstream infections were examined directly from clinical isolates.
Merozoite surface protein 7 gene expression was profiled using RNA-seq data from blood samples isolated from ten human patients with vivax malaria. Differential expression analysis and co-expression cluster analysis were used to relate PvMSP-7 expression to genetic markers of life cycle stage. Plasma from vivax malaria patients was also assayed using a custom peptide microarray to measure antibody responses against the coding regions of 12 MSP-7 paralogs.
Ten patients presented diverse transcriptional profiles that comprised four patient groups. Two MSP-7 paralogs, 7A and 7F, were expressed abundantly in all patients, while other MSP-7 genes were uniformly rare (e.g. 7J). MSP-7H and 7I were significantly more abundant in patient group 4 only, (two patients having experienced longer patency), and were co-expressed with a schizont-stage marker, while negatively associated with liver-stage and gametocyte-stage markers. Screening infections with a PvMSP-7 peptide array identified 13 linear B-cell epitopes in five MSP-7 paralogs that were recognized by plasma from all patients.
These results show that MSP-7 family members vary in expression profile during blood infections; MSP-7A and 7F are expressed throughout the intraerythrocytic development cycle, while expression of other paralogs is focused on the schizont. This may reflect developmental regulation, and potentially functional differentiation, within the gene family. The frequency of B-cell epitopes among paralogs also varies, with MSP-7A and 7L consistently the most immunogenic. Thus, MSP-7 paralogs cannot be assumed to have equal potential as vaccines. This analysis of clinical infections indicates that the most abundant and immunogenic paralog is MSP-7A.
Johnson, Kelly A.; Hessol, Nancy A.; Kohn, Robert; Nguyen, Trang Q.; Mara, Elise S.; Hsu, Ling; Scheer, Susan; Cohen, Stephanie E.
The comparative effectiveness of pre and post-exposure prophylaxis (PrEP and PEP) for men who have sex with men (MSM) is unclear.
We conducted a case-control study of MSM who were initially HIV-uninfected during 9/1/2012 – 6/30/2016 at San Francisco’s only municipal sexually transmitted diseases (STD) clinic.
Each case was matched with up to three controls based on age, baseline visit date, and follow-up time. The primary dependent variable was HIV seroconversion; the primary independent variable was exposure to PrEP, PEP, or neither. Conditional logistic regression was used to calculate odds ratios and 95% confidence intervals.
Of 638 MSM (161 cases, 477 controls), 137 reported ever taking PrEP, 98 reported taking PEP only, and 403 took neither. PrEP takers had more non-HIV STDs during the analysis (72.3% vs. 55.1% vs. 42.4% p
The island of Anjouan (Comoros) is highly endemic for leprosy with an annual incidence of 5–10/10,000. In May/June, 2015 single-dose Rifampicin post-exposure prophylaxis (SDR-PEP) was administered to 269 close contacts of 70 leprosy-patients in four villages as a pilot programmatic intervention. Two years later we revisited the villages for follow-up investigations. The main aim of our study was to quantify spatial associations between reported leprosy cases before and after PEP implementation. A secondary aim was to assess the effect of this single round of SDR-PEP at the individual level.
We conducted door-to-door leprosy screening in all four villages in August/September, 2017. We screened all consenting individuals for leprosy and recorded geographic coordinates of their household. We also recorded whether they had received SDR-PEP and whether they had been diagnosed with leprosy, before or after the 2015 intervention. We fitted a Poisson model with leprosy as outcome and distance to the nearest pre-intervention case and SDR-PEP as predictors.
During the survey we found 114 new cases among 5760 contacts screened (2.0% prevalence), in addition to the 39 cases detected in the two preceding years. We found statistically significant associations of incident leprosy with physical distance to index cases ranging from 2.4 (95% confidence interval (95% CI) 1.5–3.6) for household contacts to 1.8 (95% CI 1.3–2.5) for those living at 1–25 m, compared to individuals living at ≥75 m.
The effect of SDR-PEP appeared protective but did not reach statistical significance due to the low numbers, with an incidence rate ratio (IRR) of 0.6 (95% CI 0.3–1.2) overall, and 0.5 (95% CI 0.2–1.3) when considering only household contacts.
This pilot demonstrated an increased risk of leprosy in contacts beyond the household, therefore a wider circle should be considered for chemoprophylaxis. Baseline surveys and extended contact definitions are essential for improving SDR-PEP effectiveness.
Olbrich A, Wardemann H, Böhm S, et al.
AbstractNeutralizing antibodies can prevent hepatitis C virus (HCV) infection, one of the leading causes of cirrhosis and liver cancer. Here, we characterized the immunoglobulin repertoire of memory B cell antibodies against a linear epitope in the central front layer of HCV envelope (E2) (aa483-499) in patients that were infected in a single-source outbreak. A reverse transcriptase (RT)-PCR based immunoglobulin gene cloning and recombinant expression approach was applied to express monoclonal antibodies from HCV E2-peptide-binding IgG+ memory B cells. We identified highly mutated antibodies with neutralizing effect in vitro against different genotype isolates sharing similar gene features. Our data confirm the importance of VH1-69 usage for neutralizing activity. The data offers a promising basis for vaccine research and the use of anti-E2 antibodies as a mean of passive immunization.
Sagna A, Kassié D, Couvray A, et al.
AbstractBackgroundThe anarchic and poor controlled urbanization led to an increasing risk of mosquito-borne diseases (MBD) in many African cities. Here, we evaluate the spatial heterogeneity of human exposure to both malaria and arbovirus vectors in an urban area of Northern Senegal using antibody-based biomarkers of exposure to Anopheles and Aedes mosquito bites.MethodsA cross-sectional study was undertaken during the rainy season of 2014 in four neighborhoods of the city of Saint-Louis, Northern Senegal. In each neighborhood, dry blood spots were performed in children aged 6-59 months and IgG responses to both gSG6-P1 (Anopheles) and Nterm-34kDa (Aedes) salivary peptides were evaluated as validated biomarkers of respective mosquito bite exposure.ResultsIgG response levels to gSG6-P1 and Nterm-34kDa salivary peptides varied significantly between the four neighborhoods (p
The ability of a malaria antigen to induce effective, long-lasting immune responses is important for the development of a protective malaria vaccine. Plasmodium vivax merozoite surface protein-8 (PvMSP8) has been shown to be immunogenic in natural P. vivax infections and produces both cell-mediated and antibody-mediated immunity. Thus, PvMSP8 has been proposed as a vaccine candidate following fusion with other merozoite antigens in blood stage vaccine design. Here, the long-term responses of antibodies and memory B cells (MBCs) specific to PvMSP8 in individuals were monitored in a longitudinal cohort study.
Both cross-sectional surveys and cohort studies were utilized to explore the persistence of antibody and MBC responses to PvMSP8. Antibody titers were detected in individuals with acute disease and those who recovered from an infection for 4 years. The dominant peptide epitope of PvMSP8 recognized by naturally acquired antibodies was examined to observe the durability of the post-infection antibody response. PvMSP8-specific MBCs were also in subjects 4 years post-infection using an enzyme-linked immunospot assay.
The prevalence of antibodies to PvMSP8 was high during and after infection. The antibody levels in individual responders were monitored for up to 12 months post-infection and showed that most patients maintained their seropositive response. Interestingly, the anti-PvMSP8 antibody responses stably persisted in some patients who had recovered from an infection for 4 years. Positive PvMSP8-specific MBCs were also detected at 4 years post-infection. However, analysis in these individuals showed no correlation with the presence or titer of circulating antibody.
PvMSP8 had the ability to induce a long-term humoral immune response. The antibodies and MBCs specific for this antigen developed and persisted in subjects who acquired a natural P. vivax infection. Inclusion of the PvMSP8 antigen in blood stage vaccine design should be considered.
The increase in drug resistance to affordable antibiotics used to treat Gram positive bacterial infections has complicated the management of enterococcal infections. Resistance to vancomycin, one of the most powerful antibiotics, is of utmost concern as both intrinsic and acquired forms of resistance do occur in enterococci. This cross-sectional study aimed to determine the species, antibiotic susceptibility profiles and vanA/vanB gene frequencies among enterococci isolated from patients at Mulago Hospital in Kampala, Uganda.
Between November 2011 and October 2012, stool, urine, sputum and blood samples, as well as vaginal, endocervical, pus, ear and urethra swabs from 3229 patients were processed for isolation of bacteria, yielding 162 enterococci of which 115 were available for analysis (one isolate per specimen/patient). Species-level confirmation and susceptibility testing were determined with the Phoenix™ AST/ID Automated System, while vanA/vanB gene carriage was determined by PCR.
Species-level identification revealed 72 isolates of E. faecalis, 20 E. gallinarum/casseliflavus, 5 E. faecium, 4 E. raffinosus and 2 isolates each for E. hirae and E. durans. Ten isolates could not be identified to species level. Antibiotic resistance was generally low especially to ampicillin, quinolones, nitrofurantoin, glycopeptides and linezolid, but high for erythromycin and tetracycline. Equally, vanA and vanB gene frequencies were low (i.e. 15.8 and 7.9%, respectively) and detected only in E. casseliflavus/gallinarum species that are intrinsically resistant to vancomycin. Vancomycin resistant isolates of E. faecalis and E. faecium were not detected.
Enterococcus species are frequent in clinical specimens at Mulago Hospital but they are highly susceptible to common antibiotics especially ampicillin. While vancomycin resistant enterococcal (VRE) isolates of E. faecium and E. faecalis are rare in the hospital and frequency of multidrug resistance is low, non-faecium and non-faecalis VRE isolates (i.e. E. gallinarum/casseliflavus) are frequent, some with VanA/VanB (high-level) vancomycin resistance. Therefore, species-level identification of enterococci is necessary in resource limited settings to guide infection control and treatment of enterococcal infections.
Sun, Bing; Fernandes, Nicole; Pulliam, Lynn
To use plasma neuron-derived exosomes (NDE) to detect proteins that diagnose HIV-associated neurocognitive disorders (HAND). To compare NDE cargo from HAND with Alzheimer's disease (AD).
Eighty plasma samples were assayed including men (n=29) and women (n = 51) with and without HAND.
Plasma NDE were isolated by immunoadsorption with neuron specific L1CAM antibody. NDE proteins were quantified by ELISA and proximity extension assays (PEA) for 184 targets.
Neuronal enrichment of NDE was confirmed with elevated synaptophysin and normalized to the exosomal marker, ALG-2-Interacting Protein X (ALIX). NDE from men and women had significant divergent results. High mobility group box 1 (HMGB1) and neurofilament light (NF-L) were significantly increased in NDE from cognitively impaired men and were unchanged in women. NDE from HIV+ men had decreased p-T181-tau, a marker increased in AD, compared to no difference in women. NDE amyloid beta was not increased in cognitive impairment. PEA analysis showed 25 proteins were differentially expressed in HIV infection alone. Seven proteins identified asymptomatic and mild cognitive impairment in HIV+ women. NDE from women had significantly decreased cathepsin S, tau, neuronal cell adhesion molecule and contactin 5 in mild impairment. Twelve proteins were increased in NDE from cognitively impaired men, including carboxypeptidase M, cadherin 3, colony stimulating factor 2 receptor alpha subunit and mesencephalic astrocyte-derived neurotropic factor.
NDE proteins differ in HIV infection alone and cognitive impairment between men and women suggesting mechanistic gender differences associated with HAND. Several NDE targets are different from that reported for AD.
Correspondence to Lynn Pulliam, PhD, Department of Laboratory Medicine, University of California, San Francisco, California and Veterans Affairs Medical Center, 4150 Clement St., San Francisco, CA. Tel: +415 221 4810 X26490; e-mail: email@example.com
Received 21 March, 2019
Revised 16 April, 2019
Accepted 29 April, 2019
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.AIDSonline.com).
Copyright © 2019 Wolters Kluwer Health, Inc.
Whole parasite vaccination is an efficacious strategy to induce sterile immunity and to prevent malaria transmission. Understanding the mechanism and response of immune cells to vaccines plays a critical role in deciphering correlates of protection against infection and disease. Immunoassays, such as ELISpot, are commonly used to assess the immunogenicity of vaccines towards T cells and B cells. To date, these assays only analyse responses to specific antigens since they are based on recombinant parasite-derived proteins or peptides. There is the need for an agnostic approach that allows the evaluation of all sporozoite-associated antigens.
ELISpot plates coated with a defined amount of lysed Plasmodium falciparum sporozoites were used to assess the frequency of sporozoite-specific B cells in peripheral blood mononuclear cells from donors immunized with either a recombinant malaria vaccine or irradiated sporozoites.
This report describes the assay conditions for a specific and sensitive sporozoite-based B cell ELISpot assay. The assay development considers the quality of sporozoite preparation as well as the detection threshold of the frequency of antigen-specific B cells. The assay enables the detection of sporozoite-specific IgM and IgG-producing B cells. Moreover, the assay can detect sporozoite-reactive B cells from subjects that were either vaccinated with the radiation attenuated sporozoite vaccine or a recombinant pre-erythrocytic vaccine.
The newly developed sporozoite-based B cell ELISpot enables the monitoring of changes in the frequency of sporozoite-specific B cells. Applying this assay to assess the potency of vaccination regimens or seasonal changes in B cell populations from subjects residing in malaria-endemic areas will provide an opportunity to gain insight into immune mechanisms involved in protection and/or disease.
Helicobacter pylori (H.pylori) infection is a common medical problem in resource limited areas. The treatment outcome after triple therapy has not been well studied in developing countries and preliminary data suggests a high rate of treatment failure. This study investigated the triple therapy treatment failure rate and associated factors among dyspeptic patients receiving H. pylori first line therapy at a tertiary hospital, Tanzania.
A prospective study in the Gastroenterology unit of the Bugando Medical Centre (BMC) was conducted between October 2015 and May 2017. All dyspeptic patients with stool antigen tests positive for H.pylori were given first line therapy, and stool antigen testing was repeated within 7 days and 5 weeks after completion of the treatment. Biopsies were taken before initiation of therapy and analysed for clarithromycin and quinolone resistance mutations using polymerise chain reaction (PCR) and sequencing. Adherence and other social-demographic characteristics were documented.
A total of 210 patients were enrolled; the median age was 35 years (interquartile range, 27–48). First line treatment failure as defined by positive stool antigen 5 weeks post treatment was observed in 65/210 (31%) of patients. Independent predictors of first line treatment failure were presence of clarithromycin resistance mutations (OR: 23.12, 95% CI (9.38–56.98), P
Mendez, J. M., Kolora, L. D., Lemon, J. S., Dupree, S. L., Keestra-Gounder, A. M.
Nucleotide-binding oligomerization domain 1 (NOD1) is an intracellular pattern-recognition receptor (PRR) responsible for sensing bacterial peptidoglycan fragments. Stimulation of NOD1 leads to a robust innate immune response via activation of the major transcription factor NF-B. In addition to peptidoglycan sensing, NOD1, and the closely related PRR NOD2, have been linked to inflammation by responding to the endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR). Here we show, that differential ER stress induction renders cells more susceptible to a Salmonella Typhimurium infection in a NOD1-dependent manner measured by increased NF-kB activation and cytokine expression. In HeLa57A cells, stably transfected with a NF-B::luciferase reporter, we show that cells undergoing ER stress induced by thapsigargin display a significant increase in NF-B activation in response to NOD1 stimulation by C12-iE-DAP and the S. Typhimurium effector protein SopE. Tunicamycin-induced ER stress had no effect on NOD1 stimulated NF-B activation. We further show that the mouse intestinal epithelial cell line MODE-K and RAW264.7 macrophages are more responsive to Salmonella infection when treated with thapsigargin but not with tunicamycin. These profound differences between thapsigargin and tunicamycin treated cells on inflammation suggest that different components downstream of the UPR contribute to NOD1 activation. We found that the NOD1-induced inflammatory response is dependent on protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) activation in conjunction with stimulation of the inositol triphosphate receptor (IP3R). Together, these results suggest that differential UPR activation makes cells more responsive to bacterial infections in a NOD1-dependent manner.
Zhujun Ao, Lijun Wang, Emelissa J. Mendoza, Keding Cheng, Wenjun Zhu, Eric A. Cohen, Keith Fowke, Xiangguo Qiu, Gary Kobinger, Xiaojian Yao
by Zhujun Ao, Lijun Wang, Emelissa J. Mendoza, Keding Cheng, Wenjun Zhu, Eric A. Cohen, Keith Fowke, Xiangguo Qiu, Gary Kobinger, Xiaojian Yao
The development of an effective vaccine against HIV infection remains a global priority. Dendritic cell (DC)-based HIV immunotherapeutic vaccine is a promising approach which aims at optimizing the HIV-specific immune response using primed DCs to promote and enhance both the cellular and humoral arms of immunity. Since the Ebola virus envelope glycoprotein (EboGP) has strong DC-targeting ability, we investigated whether EboGP is able to direct HIV particles towards DCs efficiently and promote potent HIV-specific immune responses. Our results indicate that the incorporation of EboGP into non-replicating virus-like particles (VLPs) enhances their ability to target human monocyte-derived dendritic cells (MDDCs) and monocyte-derived macrophages (MDMs). Also, a mucin-like domain deleted EboGP (EboGPΔM) can further enhanced the MDDCs and MDMs-targeting ability. Furthermore, we investigated the effect of EboGP on HIV immunogenicity in mice, and the results revealed a significantly stronger HIV-specific humoral immune response when immunized with EboGP-pseudotyped HIV VLPs compared with those immunized with HIV VLPs. Splenocytes harvested from mice immunized with EboGP-pseudotyped HIV VLPs secreted increased levels of macrophage inflammatory proteins-1α (MIP-1α) and IL-4 upon stimulation with HIV Env and/or Gag peptides compared with those harvested from mice immunized with HIV VLPs. Collectively, this study provides evidence for the first time that the incorporation of EboGP in HIV VLPs can facilitate DC and macrophage targeting and induce more potent immune responses against HIV.
Rogovskyy, A. S., Caoili, S. E. C., Ionov, Y., Piontkivska, H., Skums, P., Tsyvina, V., Zelikovsky, A., Waghela, S. D.
Lyme disease (LD), the most prevalent vector-borne illness in the United States and Europe, is caused by Borreliella burgdorferi (Bb). No vaccine is available for humans. Dogmatically, Bb can establish a persistent infection in the mammalian host (e.g., mice) due to a surface antigen, VlsE. This antigenically variable protein allows the spirochete to continually evade borreliacidal antibodies. However, our recent study has shown that the Bb spirochete is effectively cleared by anti-Bb antibodies of New Zealand White rabbits despite the surface expression of VlsE. Besides homologous protection, the rabbit antibodies also cross-protect against heterologous Bb and significantly reduced pathology of LD arthritis in persistently infected mice. Thus, this finding that NZW rabbits develop a unique repertoire of very potent antibodies targeting the protective surface epitopes, despite abundant VlsE, prompted us to identify specificities of the rabbit protective antibodies and their respective targets. By applying subtractive reverse vaccinology, which involved random peptide phage display libraries coupled with the next generation sequencing and our computational algorithms, repertoires of non-protective (early) and protective (late) rabbit antibodies were identified and directly compared. Consequently, putative surface epitopes that are unique to the rabbit protective sera have been mapped. Importantly, the relevance of newly identified protection-associated epitopes for their surface exposure has been strongly supported by prior empirical studies. This study is significant because it now allows us to systematically test the putative epitopes for their protective efficacy with an ultimate goal of selecting the most efficacious targets for development of a long-awaited LD vaccine.
Blais, N., Somers, D., Faubert, D., Labbe, S., Castado, C., Ysebaert, C., Gagnon, L.-P., Champagne, J., Gagne, M., Martin, D.
Non-typeable Haemophilus influenzae (NTHi) is a pathogen known for being a frequent cause of acute otitis media in children and respiratory tract infections in adults with chronic obstructive pulmonary disease. In the present study, a vaccine antigen has been developed based on the fusion of two known NTHi adhesive proteins, Protein E (PE) and pilin subunit (PilA). The quality of the combined antigen was investigated through functional, biophysical and structural analyses. It was shown that PE and PilA individual structures are not modified in the PE-PilA fusion and that PE-PilA assembles as a dimer in solution, reflecting PE dimerization. PE-PilA was found to bind vitronectin in ELISA, as isolated PE does. Disulfide bridges were conserved and homogeneous, which was determined by peptide mapping and Top-down analysis on PE, PilA and PE-PilA molecules. Finally, the PE-PilA crystal showed a PE entity with a 3D-structure similar to that of recently published isolated PE, while the structure of the PilA entity was similar to that of a 3D-model elaborated from two other type 4 pilin subunits.Taken together, our observations suggest that the two tethered proteins behave independently within the chimeric molecule and display structures similar to the respective isolated antigens, which are important characteristics for eliciting an optimal antibody-mediated immunity. PE and PilA can thus be further developed as a single fusion protein in a vaccine perspective, in the knowledge that tethering the two antigens does not perceptibly compromise the structural attributes offered by the individual antigens.
Cuenot, E., Garcia-Garcia, T., Douche, T., Gorgette, O., Courtin, P., Denis-Quanquin, S., Hoys, S., Tremblay, Y. D. N., Matondo, M., Chapot-Chartier, M.-P., Janoir, C., Dupuy, B., Candela, T., Martin-Verstraete, I.
Clostridium difficile is the leading cause of antibiotic-associated diarrhea in adults. During infection, C. difficile must detect the host environment and induce an appropriate survival strategy. Signal transduction networks involving serine/threonine kinases (STKs) play key roles in adaptation, as they regulate numerous physiological processes. PrkC of C. difficile is a STK with two PASTA domains. We showed that PrkC is membrane associated and is found at the septum. We observed that deletion of prkC affects cell morphology with an increase in mean size, cell length heterogeneity, and presence of abnormal septa. When compared with the wild-type strain, a prkC mutant was able to sporulate and germinate but was less motile and formed more biofilm. Moreover, a prkC mutant was more sensitive to antimicrobial compounds that target the cell envelope such as the secondary bile salt deoxycholate, cephalosporins, cationic antimicrobial peptides, and lysozyme. This increased susceptibility was not associated with differences in peptidoglycan or polysaccharide II composition. However, the prkC mutant had less peptidoglycan and released more polysaccharide II into the supernatant. A proteomic analysis showed that the majority of C. difficile proteins associated with the cell wall were less abundant in the prkC mutant compared to the wild-type strain. Finally, in a hamster model of infection the prkC mutant had a colonization delay that did not significantly affect overall virulence.
Consumption of unwashed, raw or unhygienically prepared fruits and vegetables act as potential source for the spread of various parasitic diseases. Moreover, the level of contamination and species of contaminant parasites vary from place to place because of variations in environmental and human factors. Therefore local determination of the level of contamination and associated factors is important for efficient intervention of infections acquired via those food items.
A Cross-sectional study was conducted among purchased vegetables in selected markets of Arba Minch town from January to March, 2018. A structured questionnaire was used to capture data about factors associated with parasitic contamination of vegetables in the marketing phase. Selected vegetables were purchased and processed for examination of parasitic contamination using direct wet mount, iodine wet mount and modified zeihl Neelson staining following standard protocols. All data were analyzed using SPSS version 20.0.
Among 347 vegetable samples examined, 87(25.1%) were contaminated with at least one parasite species. Tomato (35.0%) was the most commonly contaminated vegetable while green pepper (10.6%) was the least contaminated one. Entameoba histolytica/dispar (29, 8.4%) was the commonest parasitic contaminant detected followed by Giardia lamblia (24, 6.9%) and oocyst of Cryptosporidium species (5.8%). Vegetable type (X2 = 13.5; p = 0.009) and source of vegetables (X2 = 24.1; p
Grossman, Mark A.; Hofmann, Christian; Ng, Hwee L.; Yang, Otto O.
To assess whether weakly recognized epitope variants induce anergy in HIV-1-specific CD8+ T lymphocyte (CTL) clones as a mechanism of dysfunction.
HIV-1-specific CTL clones were exposed to suboptimally recognized epitope variants, and screened for anergy and other T cell dysfunction markers, and subsequent capability to kill target cells bearing index epitope.
In addition to the optimally recognized index epitope, two suboptimally recognized epitope variants were selected based on titration curves for killing of peptide-labeled target cells by three HIV-1-specific CTL clones targeting the epitopes SLYNTVATL (Gag 77-85, A*02-restricted), RPAEPVPLQL (Rev 66-75, B*07-restricted), and KRWIIMGLNK (Gag 263-272, B*27-restricted). Consequences of suboptimal stimulation were assessed by cytokine secretion, gene expression, and capacity to kill index epitope-labeled target cells upon rechallenge.
Suboptimal recognition of epitope variants reduced cytokine production by CTL similarly to reduction in killing of target cells. Gene expression profiles after suboptimal stimulation demonstrated no patterns consistent with T cell dysfunction due to anergy, exhaustion, or apoptosis. Pre-exposure of CTL to epitope variants had no discernable impact on their subsequent capacity to kill index epitope-bearing target cells.
Our data explore the hypothesis that poorly recognized epitope variants not only facilitate HIV-1 evasion of CTL recognition, but also induce CTL dysfunction through suboptimal signaling causing anergy. However, the results do not suggest that suboptimal signaling induces anergy (or exhaustion or apoptosis), indicating that the major role of CTL epitope variation is likely viral escape.
Correspondence to Otto O. Yang, Division of Infectious Diseases, BSRB 173, 615 Charles E Young Drive South, Los Angeles, CA, 90095, USA. Tel: +310 794 9491; fax: +310 983 1067; e-mail: firstname.lastname@example.org
Received 18 January, 2019
Revised 10 April, 2019
Accepted 24 April, 2019
Copyright © 2019 Wolters Kluwer Health, Inc.
Huang, Y., Hang, X., Jiang, X., Zeng, L., Jia, J., Xie, Y., Li, F., Bi, H.
Helicobacter pylori is a major global pathogen and its infection represents a key factor in the etiology of various gastric diseases including gastritis, peptic ulcers and gastric carcinoma. The efficacy of current standard treatment for H. pylori infection including two broad-spectrum antibiotics is compromised by toxicity toward gut microbiota and development of drug resistance, which will likely only be resolved through novel and selective antibacterial strategies. Here, we synthesized a small molecule, Zinc linolenate (ZnLla), and investigated its therapeutic potential for the treatment of H. pylori infection. ZnLla showed effective antibacterial activity against standard strains and drug-resistant clinical isolates of H. pylori in vitro with no development of resistance during continuous serial passaging. The mechanisms of ZnLla action against H. pylori involved disruption of bacterial cell membranes and generation of reactive oxygen species. In mouse models of multi-drug resistant H. pylori infection, ZnLla showed comparable and superior in vivo killing efficacy to the triple therapy approach, as a monotherapy and a combined therapy with omeprazole, respectively. Moreover, ZnLla treatment induces negligible toxicity against normal tissues and causes minimal effects on both the diversity and composition of the murine gut microbiota. Thus the high degree of selectivity of ZnLla for H. pylori provides an attractive candidate for novel targeted anti-H. pylori treatment.
Shaba, Frackson; Offorjebe, O. Agatha; Phiri, Khumbo; Lungu, Eric; Kalande, Pericles; Nyirenda, Mike; Hoffman, Risa M.; Gupta, Sundeep; Dovel, Kathryn
Facility-based HIVST offered to outpatients in clinic waiting spaces provides an ideal opportunity to take HIVST to scale in low-resource settings. We explore if outpatients are willing to use HIVST kits in outpatient waiting spaces before they receive routine services in Malawi.
A formative qualitative study was conducted to inform the design of a multi-arm clustered randomized trial. In-depth interviews were conducted with 36 adults ( 15 years) seeking outpatient services at five high-burden health facilities in Central and Southern Malawi. Outpatients were purposively sampled on the day of clinic visit. Before the interview, research staff described a hypothetical facility-based HIVST intervention. Data were analyzed using constant comparison analyses.
The vast majority of respondents believed facility-based HIVST in outpatient waiting spaces was acceptable and desired, especially among men. Participants believed the strategy may decrease potential stigma associated with testing due to an opt-out approach, and may increase clients’ willingness to test again in the near future because it will help overcome fears related to an unknown HIV test result. The strategy was also seen as confidential and convenient. A minority of clients believed private spaces for conducting HIVST in facilities were needed.
Facility-based HIVST in outpatient waiting spaces is acceptable and desired among adult outpatients in Malawi. Notably, few respondents were concerned about lack of privacy.
Address correspondence to: Dr. Kathryn Dovel, Partners in Hope, P.O. Box 302, Lilongwe Malawi. (Email: email@example.com Tel: +(265) 997 64 5317)
Conflicts of Interest and Sources of Funding: There are no conflict of interest.
FUNDING: Supported by the U.S. Agency for International Development (USAID) and the President’s Emergency Plan for AIDS Relief (PEPFAR) under Cooperative Agreement AID-OAA-A-15-00070. OO’s time was supported by the Fogarty International Center of the National Institutes of Health (NIH) under Award Number D43TW009343 and the University of California Global Health Institute (UCGHI). KD’s time was partially funded by the National Institute of Mental Health (NIMH) through T32MH080634-10. KD and RH receive support from the UCLA CFAR grant AI028697 and the UCLA AIDS Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of funders.
Received September 14, 2018
Accepted March 18, 2019
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
This Medical Letter review summarizes the cardiovascular benefits and adverse effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors (empagliflozin, canagliflozin) and glucagon-like peptide 1 (GLP-1) receptor agonists (liraglutide, semaglutide) in patients with type 2 diabetes at risk for cardiovascular disease.
Diaz, Y., Govasli, M. L., Zegeye, E. D., Sommerfelt, H., Steinsland, H., Puntervoll, P.
Infection with enterotoxigenic Escherichia coli (ETEC) is a common cause of childhood diarrhea in low- and middle-income countries, as well as of diarrhea among travelers to these countries. In children, ETEC strains secreting the heat-stable toxin (ST) are the most pathogenic, and there are ongoing efforts to develop vaccines that target ST. One important challenge for ST vaccine development is to construct immunogens that do not elicit antibodies that cross-react with guanylin and uroguanylin, which are endogenous peptides involved in regulating the activity of the guanylate cyclase-C (GC-C) receptor. We immunized mice with both human ST (STh) and porcine ST (STp) chemically coupled to bovine serum albumin, and the resulting sera neutralized the toxic activities of both STh and STp. This suggests that a vaccine based on either ST variant can confer cross-protection. However, several anti-STh and anti-STp sera cross-reacted with the endogenous peptides, suggesting that the ST sequence must be altered to reduce the risk of unwanted cross-reactivity. Epitope mapping of four monoclonal anti-STh and six anti-STp antibodies, all of which neutralized both STh and STp, revealed that most epitopes appear to have at least one amino acid residue shared with guanylin or uroguanylin. Despite this, only one monoclonal antibody displayed demonstrable cross-reactivity to the endogenous peptides, suggesting that targeted mutations of a limited number of ST residues may be sufficient to obtain a safe ST-based vaccine.
Falcipains are major cysteine proteases of Plasmodium falciparum involved in haemoglobin degradation and remain attractive anti-malarial drug targets. Several inhibitors against these proteases have been identified, yet none of them has been approved for malaria treatment. Other Plasmodium species also possess highly homologous proteins to falcipains. For selective therapeutic targeting, identification of sequence and structure differences with homologous human cathepsins is necessary. The substrate processing activity of these proteins is tightly controlled via a prodomain segment occluding the active site which is chopped under low pH conditions exposing the catalytic site. Current work characterizes these proteases to identify residues mediating the prodomain regulatory function for the design of peptide based anti-malarial inhibitors.
Sequence and structure variations between prodomain regions of plasmodial proteins and human cathepsins were determined using in silico approaches. Additionally, evolutionary clustering of these proteins was evaluated using phylogenetic analysis. High quality partial zymogen protein structures were modelled using homology modelling and residue interaction analysis performed between the prodomain segment and mature domain to identify key interacting residues between these two domains. The resulting information was used to determine short peptide sequences which could mimic the inherent regulatory function of the prodomain regions. Through flexible docking, the binding affinity of proposed peptides on the proteins studied was evaluated.
Sequence, evolutionary and motif analyses showed important differences between plasmodial and human proteins. Residue interaction analysis identified important residues crucial for maintaining prodomain integrity across the different proteins as well as the pro-segment responsible for inhibitory mechanism. Binding affinity of suggested peptides was highly dependent on their residue composition and length.
Despite the conserved structural and catalytic mechanism between human cathepsins and plasmodial proteases, current work revealed significant differences between the two protein groups which may provide valuable information for selective anti-malarial inhibitor development. Part of this study aimed to design peptide inhibitors based on endogenous inhibitory portions of protease prodomains as a novel aspect. Even though peptide inhibitors may not be practical solutions to malaria at this stage, the approach followed and results offer a promising means to find new malarial inhibitors.
Gaia Bertoldo, Annalisa Pesce, Angela Pepe, Concetta Paola Pelullo, Gabriella Di Giuseppe, The Collaborative Working Group
by Gaia Bertoldo, Annalisa Pesce, Angela Pepe, Concetta Paola Pelullo, Gabriella Di Giuseppe, The Collaborative Working Group
This cross-sectional study aimed at evaluating the knowledge and attitudes concerning influenza vaccination in Southern Italy, and investigating the potential determinants of vaccine uptake. The sample consisted of 700 adults (mean age 58.7y) with chronic diseases attending four public specialty clinics in Italy. Overall, 64.7% of the participants were aware that influenza can be prevented with vaccines and that patients with chronic diseases are at higher risk of developing severe complications. Less than half of the sample (42.1%) received influenza vaccine in the last season, and 46.9% declared the will to receive influenza vaccination in the next season. The level of awareness was significantly lower among the elderly (> = 65y) and those with a higher self-reported health. A significantly higher likelihood of vaccination was observed among the elderly, the subjects with a higher knowledge about vaccine utility and safety, the participants with chronic respiratory diseases, and those who had taken more drugs. Future education programs and communication strategies are strongly needed in adults with chronic diseases to improve influenza vaccination knowledge and uptake.
McCall, I. C., Shah, N., Govindan, A., Baquero, F., Levin, B. R.
Non-replicating bacteria are known to be (or at least commonly thought to be) refractory to antibiotics to which they are genetically susceptible. Here, we explore the sensitivity to killing by bactericidal antibiotics of three classes of non-replicating populations of planktonic bacteria; (1) stationary phase, when the concentration of resources and/or nutrients are too low to allow for population growth; (2) persisters, minority subpopulations of susceptible bacteria surviving exposure to bactericidal antibiotics; (3) antibiotic-static cells, bacteria exposed to antibiotics that prevent their replication but kill them slowly if at all, the so-called bacteriostatic drugs. Using experimental populations of Staphylococcus aureus Newman and Escherichia coli K12 (MG1655) and respectively 9 and 7 different bactericidal antibiotics, we estimate the rates at which these drugs kill these different types of non-replicating bacteria. Contrary to the common belief that bacteria that are non-replicating are refractory to antibiotic-mediated killing, all three types of non-replicating populations of these Gram-positive and Gram-negative bacteria are consistently killed by aminoglycosides and the peptide antibiotics, daptomycin and colistin, respectively. This result indicates that non-replicating cells, irrespectively of why they do not replicate, have an almost identical response to bactericidal antibiotics. We discuss the implications of these results to our understanding of the mechanisms of action of antibiotics and the possibility of adding a short-course of aminoglycosides or peptide antibiotics to conventional therapy of bacterial infections.
Li L, Wang G, Cheung A, et al.
AbstractBackgroundMgrA is an important global virulence gene regulator in Staphylococcus aureus. In the present study, the role of mgrA in host-pathogen interactions related to virulence was explored in both methicillin-resistant S. aureus (MRSA) and methicillin-susceptible S. aureus (MSSA) strains.MethodsIn vitro susceptibilities to human defense peptides (HDPs), adherence to fibronectin (Fn) and endothelial cells (ECs), ECs damage, -toxin production, the expression of global regulator (e.g., agr RNAIII) and its downstream effectors (e.g., -toxin [hla] and Fn binding protein A [fnbA]), MgrA binding to fnbA promoter and effect on HDP-induced mprF and dltA expression were analyzed. The impact of mgrA on virulence was carried out using a mouse bacteremia model.ResultsmgrA mutants displayed significantly higher susceptibilities to the HDPs which might be related to the less HDP-induced mprF and dltA expression, but decreased Fn and ECs adherence, ECs damage, -toxin production, agr RNAIII, hla and fnbA expression, and attenuated virulence in the bacteremia model as compared to their respective parental and mgrA-complemented strains. Importantly, a direct binding of MgrA protein to fnbA promoter was observed.ConclusionsThese results suggest that mgrA mediates host-pathogen interactions and virulence, and may provide a novel therapeutic target for invasive S. aureus infections.
Su Y, Mattsson E, Singh B, et al.
AbstractLaminin is a well-defined component of the airway basement membrane (BM). Efficient binding of laminin via multiple interactions is important for nontypeable Haemophilusinfluenzae (NTHi) colonization in the airway mucosa. Here we identified elongation factor thermo-unstable (EF-Tu), L-lactate dehydrogenase (LDH), Protein D and peptidoglycan-associated lipoprotein P6 as novel laminin-binding proteins (Lbps) of NTHi. In parallel with other well-studied Lbps (P4, PE, PF and Hap), EF-Tu, LDH, PD and P6 exhibited interactions with laminin, and mediated NTHi laminin-dependent adherence to pulmonary epithelial cell lines. Importantly, the NTHi laminin interactome consisting of the well-studied and novel Lbps recognized laminin LG domains from the subunit α chains of laminin-111 and -332, of which the latter isoform is the main laminin in the airway BM. The NTHi interactome mainly targeted multiple heparin-binding domains of laminin. In conclusion, the NTHi interactome exhibited a high plasticity of interactions with different laminin isoforms via multiple heparin-binding sites.
Kerry Murphy, Marla J. Keller, Kathryn Anastos, Shada Sinclair, J. Cooper Devlin, Qiuhu Shi, Donald R. Hoover, Brian Starkman, Jamie McGillick, Caroline Mullis, Howard Minkoff, Maria Gloria Dominguez-Bello, Betsy C. Herold
by Kerry Murphy, Marla J. Keller, Kathryn Anastos, Shada Sinclair, J. Cooper Devlin, Qiuhu Shi, Donald R. Hoover, Brian Starkman, Jamie McGillick, Caroline Mullis, Howard Minkoff, Maria Gloria Dominguez-Bello, Betsy C. Herold
Background Reproductive aging may impact the vaginal microbiome and genital tract mucosal immune environment and contribute to genital tract health in women living with and at-risk for HIV infection. Methods A cross-sectional study of 102 HIV+ (51 premenopausal, 51 postmenopausal) and 39 HIV-uninfected (HIV-) (20 premenopausal, 19 postmenopausal) women was performed in Bronx and Brooklyn, NY. Cervicovaginal lavage (CVL) was collected for quantification of innate antimicrobial activity against E. coli, HSV-2 and HIV and immune mediators by Luminex and ELISA. Microbiome studies by qPCR and 16S rRNA sequencing were performed on vaginal swabs. Results HIV+ postmenopausal compared to premenopausal participants had lower median E. coli bactericidal activity (41% vs. 62%, p = 0.001), lower median gene copies of Lactobacillus crispatus (p = 0.005) and Lactobacillus iners (p = 0.019), lower proportions of Lactobacillus iners, higher proportions of Gardnerella and Atopobium vaginae and lower levels of human beta defensins (HBD-2, HBD-3) and secretory leukocyte protease inhibitor (SLPI), p
Christopher M. Gentile, Anton V. Borovjagin, Jillian R. Richter, Aditi H. Jani, Hongju Wu, Kurt R. Zinn, Jason M. Warram
by Christopher M. Gentile, Anton V. Borovjagin, Jillian R. Richter, Aditi H. Jani, Hongju Wu, Kurt R. Zinn, Jason M. Warram
Background A major obstacle to using recombinant adenoviral vectors in gene therapy is the natural ability of human adenovirus to activate the classical and alternate complement pathways. These innate immune responses contribute to hepatic adenoviral uptake following systemic delivery and enhance the humoral immune responses associated with adenoviral infection. Methods A recombinant Ad5 vector was genetically modified to display a peptide sequence (“rH17d’”), a known inhibitor of the classical complement pathway. The replication-defective vectors Ad5.HVR2-rH17d’ and Ad5.HVR5-rH17d’ were constructed by engineering the rH17d’ peptide into the hypervariable region (HVR)-2 or HVR5 of their major capsid protein hexon. Control Ad5 vectors were created by incorporation of a 6-histidine (His6)-insert in either HVR2 or HVR5 (Ad5.HVR2-His6 and Ad5.HVR5-His6, respectively). All vectors encoded CMV promoter-controlled firefly luciferase (Luc). The four vectors were evaluated in TIB76 mouse liver cells and immunocompetent mice to compare infectivity and liver sequestration, respectively. Results In vitro studies demonstrated that preincubation of all the Ad5 vectors with fresh serum significantly increased their gene transfer relative to preincubation with PBS except Ad5.HVR5-rH17d’, whose infectivity of liver cells showed no serum-mediated enhancement. In line with that, mice injected with Ad5.HVR2-rH17d’ or Ad5.HVR5-rH17d’ showed significantly lower luciferase expression levels in the liver as compared to the respective control vectors, whereas efficiency of tumor transduction by rH17d’ and His6 vectors following their intratumoral injection was similar. Conclusions Displaying a complement-inhibiting peptide on the Ad5 capsid surface by genetic modification of the hexon protein could be a suitable strategy for reducing Ad5 liver tropism (Ad5 sequestration by liver), which may be applicable to other gene therapy vectors with natural liver tropism.
Hayden C, Hung C, Zhang H, et al.
AbstractCoccidioides is the causative agent of San Joaquin Valley Fever, a fungal disease prevalent in the semi-arid regions of the Americas. Efforts to develop a fungal vaccine over the last two decades were unsuccessful. A candidate antigen, Ag2, is notoriously difficult to express in Escherichia coli, and this study sought to accumulate the antigen at high levels in maize. Transformed maize lines accumulated recombinant Ag2 at levels greater than 1g/kg. Mice immunized with this antigen and challenged with live Coccidioides arthroconidia showed a reduction in the fungal load when Ag2 derived from either E.coli or maize was loaded into glucan chitin particles (GCPs). A fusion of Ag2 to the dendritic cell carrier peptide, DCpep, induced a Th17 response in spleen when orally delivered, indicative of a protective immune response. The maize production platform and the GCP adjuvant system show promise for development of a Coccidioides vaccine, but further testing is needed to fully assess the optimal method of administration.
Ersoy, S. C., Abdelhady, W., Li, L., Chambers, H. F., Xiong, Y. Q., Bayer, A. S.
Endovascular infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are a major healthcare concern, especially infective endocarditis (IE). Standard antimicrobial susceptibility testing (AST) defines most MRSA strains as ‘resistant' to β-lactams, often leading to use of costly and/or toxic treatment regimens. In this investigation, five prototype MRSA strains, representing the range of genotypes in current clinical circulation, were studied. We identified two distinct MRSA phenotypes upon AST using standard media, with or without sodium bicarbonate (NaHCO3) supplementation: one highly susceptible to the anti-staphylococcal β-lactams, oxacillin and cefazolin (‘NaHCO3-responsive’) and one resistant to such agents (‘NaHCO3-nonresponsive’). These phenotypes accurately predicted clearance profiles of MRSA from target tissues in experimental MRSA IE treated with each β-lactam. Mechanistically, NaHCO3 reduced expression of two key genes involved in the MRSA phenotype, mecA and sarA, leading to decreased production of penicillin-binding protein (PBP) 2a (that mediates methicillin resistance), in NaHCO3-responsive (but not in NaHCO3-nonresponsive) strains. Moreover, both cefazolin and oxacillin synergistically killed NaHCO3-responsive strains in the presence of the host defense antimicrobial peptide (LL-37) in NaHCO3-supplemented media. These findings suggest that AST of MRSA strains in NaHCO3-containing media may potentially identify infections caused by NaHCO3-responsive strains that are appropriate for β-lactam therapy.
Raz, A., Serrano, A., Hernandez, A., Euler, C. W., Fischetti, V. A.
Multi-drug resistance (MDR) is rapidly increasing in prevalence among isolates of the opportunistic pathogen Pseudomonas aeruginosa, leaving few treatment options. Phage lysins are cell wall hydrolases that have a demonstrated therapeutic potential against Gram-positive pathogens, however the outer membrane of Gram-negative bacteria prevents most lysins from reaching the peptidoglycan, making them less effective as therapeutics. Nevertheless, a few lysins from gram-negative phage can penetrate the bacterial outer membrane, aided by an amphipathic tail found in the molecule's termini. In this work we took a phylogenetic approach to systematically identify those lysins from P. aeruginosa phage that would be most effective therapeutically. We isolated and performed preliminary characterization of 16 lysins, and chose two lysins, PlyPa03 and PlyPa91, which exhibited >5-log killing activity against P. aeruginosa and other Gram-negative pathogens (particularly Klebsiella and Enterobacter). These lysins showed rapid killing kinetics and were active in the presence of high concentrations of salt and urea and in pH conditions ranging from 5.0 to 10.0. Activity was not inhibited in the presence of the pulmonary surfactant Survanta. While neither enzyme was active in 100% human serum, PlyPa91 retained activity in low serum concentrations. The lysins were effective in the treatment of a P. aeruginosa skin infection in a mouse model, and PlyPa91 protected mice in a lung infection model, making these lysins potential drug candidates for Gram-negative infections of the skin or respiratory mucosa.
Accumulating evidence suggests that infections by herpesviruses might be closely linked to Alzheimer's disease (AD). Pathological hallmarks of AD brains include senile plaques induced by amyloid β peptide (Aβ) in the extracellular space and intracellular neurofibrillary tangles (NFTs) consisting of phosphorylated tau protein. The prevailing hypothesis for the mechanism of AD is amyloid cascade reaction. Recent studies revealed that infections by herpesviruses induce the similar pathological hallmarks of AD, including Aβ production, phosphorylation of tau (P‐tau), oxidative stress, neuroinflammation, etc. Aβ peptide is regarded as one of the antimicrobial peptides, which inhibits HSV‐1 replication. In the elderly, reactivation of herpesviruses might act as an initiator for amyloid cascade reaction in vulnerable individuals, triggering the neurofibrillary formation of phosphorylated tau and inducing oxidative stress and neuroinflammation, which can further contribute to the accumulation of Aβ and P‐tau by impairing mitochondria and autophagosome. Epidemiological studies have shown AD susceptibility genes, such as APOE‐ε4 allele, are highly linked to infections by herpesviruses. Interestingly, anti‐herpesviral therapy significantly reduced the risk of AD in a large population study. Given that herpesviruses are arguably the most prevalent opportunistic pathogens and often reactivate in the elderly, it is reasonable to argue reactivation of herpesviruses might be major culprits for initiating AD in individuals carrying AD susceptibility genes. In this review, we summarize epidemiological and molecular evidence that support for a hypothesis of herpesviral infections and antimicrobial protection in the development of AD, and discuss the implications for future prevention and treatment of the disease.
Retningslinjer til sundhedsprofessionelle vedr. håndtering af infektion med zikavirus (2019)
Antiviral behandling af hiv smittede personer (2019)
Lumbalpunktur af patienter i blodfortyndende behandling (2019)
Reply to Barner and Bruno-Murtha
23.09.2019Clinical Infectious Diseases Advance Access
False-negative Results of Human Immunodeficiency Virus (HIV) Rapid Testing in HIV Controllers
21.09.2019Clinical Infectious Diseases Advance Access
Resistance of Influenza Virus to Antiviral Medications
20.09.2019Clinical Infectious Diseases Advance Access
Oseltamivir resistance in severe influenza A(H1N1)pdm09 pneumonia and acute respiratory distress syndrome: a French multicenter observational cohort study
20.09.2019Clinical Infectious Diseases Advance Access
Baloxavir marboxil in Japanese pediatric patients with influenza: safety and clinical and virologic outcomes
20.09.2019Clinical Infectious Diseases Advance Access
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