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Ma, J., Guo, F., Jin, Z., Geng, M., Ju, M., Ravichandran, A., Orugunty, R., Smith, L., Zhu, G., Zhang, H.
Novel antiparasitic activity was observed for the antifungal occidiofungin. It efficaciously and irreversibly inhibited the zoonotic enteric parasite Cryptosporidium parvum in vitro with limited cytotoxicity (EC50 = 120 nM vs. TC50 = 988 nM), and its treatment disrupted the parasite morphology. Besides expanded activity spectrum, occidiofungin as a glycolipopeptide is characterized by poor absorbability and its ability to retain in gastrointestinal tract, making it worth to also investigate its potential activities on other enteric parasites.
Marion Mathelié-Guinlet, Abir T. Asmar, Jean-François Collet, Yves F. Dufrêne
The bacterial cell envelope plays essential roles in controlling cell shape, division, pathogenicity, and resistance against external stresses. In Escherichia coli, peptidoglycan (PG) has long been thought to be the primary component that conveys mechanical strength to the envelope. But a recent publication demonstrates the key contribution of the lipoprotein Lpp in defining the stiffness of the cell envelope and its sensitivity to drugs.
LaVergne S, Sakabe S, Kanneh L, et al.
AbstractBackgroundEbola virus disease has killed thousands of West and Central Africans over the past several decades. Many who survive the acute disease later suffer from post Ebola syndrome (PES), a constellation of symptoms whose causative pathogenesis is unclear.MethodsWe investigated Ebola virus (EBOV)-specific CD8+ and CD4+ T cell responses in 37 Sierra Leonean EBOV disease survivors with (N=19) and without sequelae (N=18) of arthralgia and ocular symptoms. Peripheral blood mononuclear cells were infected with recombinant vesicular stomatitis virus encoding EBOV antigens. We also studied the presence of EBOV-specific IgG, antinuclear antibodies, anti-cyclic citrullinated peptide antibodies, rheumatoid factor, complement levels, and cytokine levels in these two groups.ResultsSurvivors with sequelae had a significantly higher EBOV-specific CD8+ and CD4+ T cell response. No differences in EBOV-specific IgG, antinuclear antibody, or anti-cyclic citrullinated peptide antibody levels were found. Survivors with sequelae showed significantly higher rheumatoid factor levels.ConclusionEEBOV-specific CD8+ and CD4+ T cell responses were significantly higher in Ebola survivors with PES. These findings suggest that pathogenesis may occur as an immune mediated disease via virus-specific T cell immune response or that persistent antigen exposure leads to increased and sustained T cell responses.
Wang, X., Rockey, D. D., Dolan, B. P.
Chlamydia bacteria are obligate intracellular pathogens which can cause a variety of disease in humans and other vertebrate animals. To successfully complete their life cycle, Chlamydia must evade both intracellular innate immune responses as well as adaptive cytotoxic T cell responses. Here we report on the role of the chlamydial lipooligosaccharide (LOS) in evading the immune response. Chlamydia infection is known to block the induction of apoptosis. However, when LOS synthesis was inhibited during C. trachomatis infection, HeLa cells regained susceptibility to apoptosis induction following staurosporine treatment. Additionally, the delivery of purified LOS to the cytosol of cells increased the levels of the anti-apoptotic protein survivin. An increase in survivin levels was also detected following C. trachomatis infection, which was reversed by blocking LOS synthesis. Interestingly, while intracellular delivery of LPS derived from E. coli was toxic to cells, LOS from C. trachomatis did not induce any appreciably cell death, suggesting that it does not activate pyroptosis. Chlamydial LOS was also a poor stimulator of maturation of bone marrow-derived dendritic cells when compared to E. coli LPS. Previous work from our group indicated that LOS-synthesis during infection was necessary to alter host cell antigen presentation. However, direct delivery of LOS to cells in the absence of infection did not alter antigenic peptide presentation. Taken together these data suggest that chlamydial LOS, which is remarkably conserved across the Chlamydia genus, may act both directly and indirectly to evade the innate and adaptive immune responses of the host.
Goodman K, Cosgrove S, Pineles L, et al.
AbstractBackgroundQuantifying the amount and diversity of antibiotic use in United States hospitals assists antibiotic stewardship efforts but is hampered by limited national surveillance. Our study aimed to address this knowledge gap by examining adult antibiotic use across 576 hospitals and nearly 12 million encounters in 2016 – 2017.MethodsWe conducted a retrospective study of patients aged ≥ 18 years discharged from hospitals in the Premier Healthcare Database between January 1, 2016 – December 31, 2017. Using daily antibiotic charge data, we mapped antibiotics to mutually-exclusive classes and to spectrum of activity categories. We evaluated relationships between facility and case-mix characteristics and antibiotic use in negative binomial regression models.ResultsThe study included 11,701,326 admissions, totaling 64,064,632 patient-days, across 576 hospitals. Overall, patients received antibiotics in 65% of hospitalizations, at a crude rate of 870 days of therapy (DOTs) per 1000 patient-days. By class, use was highest among beta-lactam/beta-lactamase inhibitor combinations, third- and fourth-generation cephalosporins, and glycopeptides. Teaching hospitals averaged lower rates of total antibiotic use than non-teaching hospitals (834 versus 957 DOTS per 1000 patient-days; P
He, J., Thomas, M. A., de Anda, J., Lee, M. W., Van Why, E., Simpson, P., Wong, G. C. L., Grayson, M. H., Volkman, B. F., Huppler, A. R.
Candida albicans is a commensal organism that causes life-threatening or life-altering opportunistic infections. Treatment of Candida infections is limited by the paucity of anti-fungal drug classes. Naturally occurring antimicrobial peptides are promising agents for drug development. CCL28 is a CC chemokine that is abundant in saliva and has in vitro antimicrobial activity. In this study, we examine the in vivo Candida killing capacity of CCL28 in oropharyngeal candidiasis (OPC), as well as the spectrum and mechanism of anti-Candida activity. In the mouse model of OPC, application of wild type CCL28 reduces oral fungal burden in severely immunodeficient mice without causing excessive inflammation or altering tissue neutrophil recruitment. CCL28 is effective against multiple clinical strains of C. albicans. Polyamine protein transporters are not required for CCL28 anti-Candida activity. Both structured and unstructured CCL28 proteins show rapid and sustained fungicidal activity that is superior to clinical anti-fungal agents. Application of wild type CCL28 to C. albicans results in membrane disruption as measured by solute movement, enzyme leakage and induction of negative Gaussian curvature on model membranes. Membrane disruption is reduced in CCL28 lacking the functional C-terminal tail. Our results strongly suggest that CCL28 can exert antifungal activity in part via membrane permeation and has potential for development as an anti-Candida therapeutic agent without inflammatory side effects.
Fehling, H., Choy, S. L., Ting, F., Landschulze, D., Bernin, H., Lender, S. C., Mühlenpfordt, M., Bifeld, E., Eick, J., Marggraff, C., Kottmayr, N., Groneberg, M., Hoenow, S., Sellau, J., Clos, J., Meier, C., Lotter, H.
With an estimated number of approximately 1.4 million new cases annually, leishmaniasis belongs to the most important parasitic diseases in the world. Nevertheless, existing drugs against leishmaniasis in general have several drawbacks, urgently necessitating new drug development. A glycolipid molecule of the intestinal protozoan parasite Entamoeba (E.) histolytica and its synthetic analogs previously showed considerable immunotherapeutic effects against Leishmania (L.) major infection. Here, we designed and synthesized a series of new immunostimulatory compounds derived from the phosphatidylinositol-b-anchor (EhPIb) subunit of the native compound and investigated their anti-leishmanial activity in vitro and in vivo in a murine model of cutaneous leishmaniasis. The new synthetic EhPIb analogs showed almost no toxicity in vitro. Treatment with the analogs significantly decreased the parasite load in murine and human macrophages in vitro. In addition, topical application of the EhPIb analog Eh-1 significantly reduced cutaneous lesions in the murine model, correlating with an increase in the production of selected Th1 cytokines. In addition, we could show in in vitro experiments that treatment with Eh-1 led to a decrease in mRNA expression of arginase 1 and IL-4, which are required by the parasites to circumvent their elimination by the immune response.The use of the host-targeting synthetic EhPIb compounds, either alone or in combination therapy with anti-parasitic drugs, shows promise for treating cutaneous leishmaniasis and therefore might improve the current unsatisfactory status of chemotherapy against this infectious disease.
Dousa, K. M., Kurz, S. G., Taracila, M. A., Bonfield, T., Bethel, C. R., Barnes, M. D., Selvaraju, S., Abdelhamed, A. M., Kreiswirth, B. N., Boom, W. H., Kasperbauer, S. H., Daley, C. L., Bonomo, R. A.
Mycobacterium abscessus (Mab) is a highly drug-resistant nontuberculous mycobacteria (NTM). Efforts to discover new treatments for M. abscessus infections are accelerating with a focus on cell wall synthesis proteins (L, D-transpeptidases, LdtMab1-5, and D,D-carboxypeptidase) that are targeted by β-lactam antibiotics. A challenge to this approach is the presence of chromosomally encoded β-lactamase, BlaMab. Using a "mechanism based" approach, we show that a novel ceftaroline-imipenem combination effectively lowered the minimal inhibitory concentrations (MICs) of Mab isolates (MIC50 ≤ 0.25, MIC90 ≤ 0.5). Ceftaroline and imipenem combined with a β-lactamase inhibitor, relebactam or avibactam, demonstrated only a modest effect on susceptibility, compared to each of the beta-lactams alone. In steady state kinetic assays, BlaMab exhibited a lower Ki app (Ki app = 0.30 ± 0.03 μM, avibactam; 136 ± 14 μM, relebactam) and a faster acylation rate for avibactam (k2/K = 3.4 ± 0.4 x 105 M-1s-1, avibactam; 6 ± 0.6 x 102 M-1s-1, relebactam). The kcat/Km was nearly 10-fold lower for ceftaroline fosamil (0.007 ± 0.001 μM-1s-1) compared to imipenem (0.056 ± 0.006 μM-1s-1). Timed mass spectrometry captured complexes of avibactam and BlaMab, LdtMab1, 2, and 4, and D,D-carboxypeptidase, whereas relebactam bound only BlaMab and LdtMab1 and 2. Interestingly, LdtMab1, 2, 4 and 5 and D, D-carboxypeptidase bound only to imipenem when incubated with imipenem and ceftaroline fosamil. We next determined the binding constants of imipenem and ceftaroline fosamil to LdtMab1, 2, 4 and 5 and showed that imipenem bound > 100 fold more avidly than ceftaroline fosamil for LdtMab1 and LdtMab2 (e.g. Ki app or Km LdtMab1 = 0.01 ± 0.01 μM for imipenem vs 0.73 ± 0.08 μM for ceftaroline fosamil). Molecular modelling indicates that LdtMab2 readily accommodates imipenem, but the active site must widen to ≥ 8Å for ceftaroline to enter. Our analysis demonstrates that ceftaroline and imipenem binding to multiple targets (L, D-transpeptidases and D, D-carboxypeptidase) provides mechanistic rationale for the effectiveness of this dual β-lactam combination in Mab infections.
Cai X, Chen J, Hu J, et al.
AbstractSARS-CoV-2, a novel ß-coronavirus, cause severe pneumonia and has spread throughout the globe rapidly. The disease associated with SARS-CoV-2 infection is named COVID-19. To date, real-time RT-PCR is the only test able to confirm this infection. However, the accuracy of RT-PCR depends on several factors; variations in these factors might significantly lower the sensitivity of detection. Here, we developed a peptide-based luminescent immunoassay that detected immunoglobulin G (IgG) and IgM. The assay cut-off value was determined by evaluating the sera from healthy and infected patients for pathogens other than SARS-CoV-2. To evaluate assay performance, we detected IgG and IgM in the sera from confirmed patients. The positive rate of IgG and IgM was 71.4% and 57.2%, respectively. Therefore, combining our immunoassay with real-time RT-PCR might enhance the diagnostic accuracy of COVID-19.
Journal of Medical Virology, Accepted Article.
Arenas, I., Ibarra, M. A., Santana, F. L., Villegas, E., Hancock, R. E. W., Corzo, G.
Two non-amidated host defence peptides named Pin2[G] and FA1 were evaluated against three types of pathogenic bacteria; two isolated from diabetic foot ulcer patients, Staphylococcus aureus UPD13 and Pseudomonas aeruginosa UPD3, and another from a commercial collection, Salmonella enterica serovar Typhimurium (ATCC 14028). In vitro experiments showed that the antimicrobial performance of the synthetic peptides, Pin2[G] and FA1, was modest, although FA1 was more effective than Pin2[G]. In contrast Pin2[G] had superior in vivo anti-infective activity to FA1 in rabbit wound infections by the diabetic foot ulcer pathogens S. aureus UPD13 and P. aeruginosa UPD3. Indeed, Pin2[G] reduced bacterial colony counts of both S. aureus UPD13 and P. aeruginosa UPD3 by >100,000-fold after 48-72 h on skin wounds of infected rabbits, while in similar infected wounds, FA1 had no major effects at 72-96 h of treatment. Ceftriaxone was equally effective vs. Pseudomonas but less effective vs. S. aureus infections. Additionally, the two peptides were evaluated in mice against intragastrically inoculated S. enterica ser. Typhimurium (ATCC 14028). Only Pin2[G], at 0.56 mg/kg, was effective in reducing systemic (liver) infection by >67-fold, equivalent to the effect of treatment with levofloxacin. Pin2[G] showed superior immunomodulatory activity in increasing chemokine production by a human bronchial cell line and suppressing poly(IC)-induced pro-inflammatory IL6 production. These data showed that the in vitro antimicrobial activity of these peptides was not correlated with their in vivo anti-infective activity, and suggest that other factors such as immunomodulatory activity were more important.
Puttkammer, Nancy; Parrish, Canada; Desir, Yrvel; Hyppolite, Nathaelf; Wagenaar, Bradley; Joseph, Nadjy; Hall, Lara; Honoré, Jean Guy; Robin, Ermane; Perrin, Georges; François, Kesner
The World Health Organization (WHO) recommends universal antiretroviral therapy (ART) for people living with HIV (PLWH), but evidence about effects of expanded ART access on ART retention in low-resource settings is limited.
Haiti’s Ministry of Health endorsed universal ART for pregnant women in March 2013 (Option B+) and for all PLWH in July 2016. This study included 51,579 ART patients from 2011-17 at 94 hospitals and clinics in Haiti.
This observational, retrospective cohort study described time trends in 6-month ART retention using secondary data, and compared results during three time periods using an interrupted time series (ITS) model: pre-Option B+ (period 1: 1/11-2/13), Option B+ (period 2: 3/13-6/16), and Test and Start (T&S, period 3: 7/16-9/17).
From the pre-Option B+ to the T&S period, the monthly count of new ART patients increased from 366/month to 877/month, and the proportion with same-day ART increased from 6.3% to 42.1% (p
Yves Dauvilliers, Johan Verbraecken, Markku Partinen, Jan Hedner, Tarja Saaresranta, Ognian Georgiev, Rumen Tiholov, Isabelle Lecomte, Renaud Tamisier, Patrick Lévy, Catherine Scart-Gres, Jeanne-Marie Lecomte, Jean-Charles Schwartz, Jean-Louis Pépin
American Journal of Respiratory and Critical Care Medicine, Volume 201, Issue 9, Page 1135-1145, May 1, 2020.
Sheikh,, Zubeda B.; Stretz, Christoph; Maciel, Carolina B.; Dhakar,, Monica B.; Orgass, Hailey; Petroff, Ognen A.; Hirsch, Lawrence J.; Gilmore, Emily J.
To compare electrographic seizures, hyperexcitable patterns, and clinical outcomes in lobar and deep intraparenchymal hemorrhage. Additionally, to characterize electrographic seizure and hyperexcitable pattern predictors in each group and determine seizure risk with thalamic involvement.
Retrospective cohort study.
Tertiary academic medical center.
Consecutive adult patients with nontraumatic intraparenchymal hemorrhage undergoing continuous electroencephalography at our center between January 2013 and December 2016.
Measurements and Main Results:
Based on head CT closest to the initial continuous electroencephalography session, we classified intraparenchymal hemorrhage as isolated deep (no insular, subarachnoid, subdural extension) or lobar. Hyperexcitable patterns included the following: periodic discharges, spike-wave complexes, any rhythmic delta other than generalized. We used Fisher exact test for categorical and Mann-Whitney U test for continuous variables. Multivariable regression identified predictors of electrographic seizures, hyperexcitable patterns, and poor outcomes (score of 1–2 on Glasgow Outcome Scale) in lobar intraparenchymal hemorrhage. The cohort comprised of 128 patients, 88 lobar, and 40 deep intraparenchymal hemorrhage. Electrographic seizures occurred in 17% of lobar and 5% of deep intraparenchymal hemorrhage (p = 0.09). Hyperexcitable patterns were more frequent in the lobar group (44.3% vs 17.5%; p = 0.005). In multivariable analyses in the lobar group, lateralized rhythmic delta activity predicted electrographic seizures (odds ratio, 6.24; CI, 1.49–26.08; p = 0.012); insular involvement predicted hyperexcitable patterns (odds ratio, 4.88; CI, 1.36–17.57; p = 0.015); coma, temporal lobe involvement, intraparenchymal hemorrhage volume, and electrographic seizures predicted poor outcome. Thalamic involvement did not affect electrographic seizures or hyperexcitable patterns in either group.
Electrographic seizures are frequent in lobar intraparenchymal hemorrhage, occurring in one in six monitored patients, as opposed to only 5% in isolated deep intraparenchymal hemorrhage not extending to cortex/insula, subarachnoid, or subdural spaces. Patients with lobar intraparenchymal hemorrhage and lateralized rhythmic delta activity were six times as likely to have electrographic seizures, which were associated with 5.47 higher odds of a poor outcome. Coma, temporal lobe involvement, hematoma volume, and electrographic seizures predicted poor outcome in lobar intraparenchymal hemorrhage.
This work was performed at Yale-New Haven Hospital.
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).
Dr. Sheikh has received money for conference-related travel from Medtronic. Dr. Stretz received a Travel Grant Award for the 2017 Neurocritical Care Society’s Annual Meeting. Dr. Maciel has received the Claude D. Pepper Older Americans Independence Center Junior Scholar award that supports preclinical studies of mechanisms of secondary brain injury in a rodent cardiac arrest model. Dr. Dhakar has received research money for clinical trials from Marinus Pharmaceuticals. Dr. Hirsch has received research support from Yale University for investigator-initiated studies from Eisai and Upsher-Smith and consultation fees for advising from Adamas, Aquestive, Ceribell, Eisai, Marinus, Medtronic, Monteris, Neuropace Sun Pharma, UCB and Engage Therapeutics. Furthermore, he has received royalties for authoring chapters for UpToDate-Neurology, chapters for Medlink—Neurology and from Wiley for coauthoring the book “Atlas of EEG in Critical Care,” by Hirsch and Brenner, as well as honoraria for speaking from Neuropace. Dr. Gilmore has received funding from Yale’s Center for Clinical Investigation, Clinical and Translational Science Awards Grant (ULTR000142), Yale’s Claude D. Pepper Older Americans Independence Center (P30AG021342 National Institutes of Health/National Institute on Aging), the American Brain Foundation, and the National Institutes of Health Loan Repayment Program. The remaining authors have disclosed that they do not have any potential conflicts of interest.
For information regarding this article, E-mail: Christoph_stretz@brown.edu
Copyright © by 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
Cavalcante, P. A., Knight, C. G., Tan, Y.-L., Monteiro, A. P. A., Barkema, H. W., Cobo, E. R.
Staphylococcus aureus, an important cause of mastitis in mammals, is becoming increasingly problematic due to the development of resistance to conventional antibiotics. The ability of S. aureus to invade host cells is key to its propensity to evade immune defense and antibiotics. This study focused on functions of cathelicidins, small cationic peptides secreted by epithelial cells and leukocytes, in the pathogenesis of S. aureus mastitis in mice. We determined that endogenous murine cathelicidin (CRAMP; Camp) was important in controlling S. aureus infection, as cathelicidin knock-out mice (Camp-/-) intramammarily challenged with S. aureus had a higher bacterial burden and more severe mastitis than wild-type mice. Exogenous administration of both synthetic human cathelicidin (LL-37) and synthetic murine cathelicidin (CRAMP) (8 μM), reduced invasion of S. aureus into murine mammary epithelium. Additionally, this exogenous LL-37 was internalized into cultured mammary epithelial cells and impaired S. aureus growth in vitro. We concluded that cathelicidins may be potential therapeutic agents against mastitis; both endogenous and exogenous cathelicidins conferred protection against S. aureus infection by reducing bacterial internalization and potentially by directly killing this pathogen.
Kim, D., Yoon, E.-J., Hong, J. S., Lee, H., Shin, K. S., Shin, J. H., Kim, Y. R., Kim, H. S., Kim, Y. A., Uh, Y., Shin, J. H., Park, Y. S., Jeong, S. H.
Introduction: This study was performed to evaluate the impacts of vanA-positivity of Enterococcus faecium (EFM) exhibiting diverse susceptibility phenotypes to glycopeptides on clinical outcomes in patients with a bloodstream infection (BSI) through a prospective, multicenter, observational study.Methods: A total of 509 patients with an EFM BSI from eight sentinel hospitals in South Korea during a two-year period were enrolled in this study. Risk factors of the hosts and causative EFM isolates were assessed to determine associations with the 30-day mortality of EFM BSI patients via multivariable logistic regression analyses.Results: The vanA gene was detected in 35.2% (179/509) of EFM isolates; 131 EFM isolates exhibited typical VanA phenotypes (group vanA-VanA), while the remaining 48 EFM isolates exhibited atypical phenotypes (group vanA-Atypical), including VanD (n = 43) and vancomycin-variable phenotypes (n = 5). A multivariable logistic regression indicated that vanA-positivity of causative pathogens was independently associated with the increased 30-day mortality rate in the patients with an EFM BSI; however, there was no significant difference in the survival rates between the patients of the vanA-VanA and vanA-Atypical groups (log-rank test, P = 0.904).Conclusions: A high 30-day mortality rate was observed in patients with vanA-positive EFM BSIs, and vanA-positivity of causative EFM was an independent risk factor for early mortality irrespective of the susceptibility phenotypes to glycopeptides; thus, intensified antimicrobial stewardship is needed to improve clinical outcome of patients with vanA-positive EFM BSI.
Amelia J. Lawler, Peter A. Lambert, Tony Worthington
The dormant resistant spores of Clostridioides difficile are transformed into metabolically active cells through the process of germination. Spore germination in C. difficile is regulated by the detection of bile salt germinants and amino acid cogerminants by pseudoproteases CspC and CspA, respectively. The germinant signal is transduced to the serine protease CspB, which processes the cortex lytic enzyme SleC, leading to degradation of the spore cortex peptidoglycan and subsequent reactivation of the spore.
Hensen, Bernadette; Schaap, Albertus J; Mulubwa, Chama; Floyd, Sian; Shanaube, Kwame; Phiri, Mwelwa; Bond, Virginia; Bwalya, Chiti; Simwinga, Musonda; Fidler, Sarah; Hayes, Richard; Mwinga, Alwyn; Ayles, Helen
HPTN071(PopART) was a community-randomised trial of a universal testing-and-treatment intervention on HIV incidence at population-level in Zambia and South Africa. In Zambia, a trial of community-based distribution of HIV self-testing (HIVST) kits, including secondary distribution, as an option for HIV-testing was nested within four PopART intervention communities. We used data from the intervention arm of the nested trial to measure levels of and factors associated with acceptance and use of secondary distribution HIVST kits.
Community HIV Care Providers (CHiPs) offered the PopART combination HIV-prevention intervention door-to-door, systematically visiting all households and enumerating all household members. From 1 February-30 April 2017, individuals ≥16-years consenting to PopART were offered the option to HIV self-test, if eligible for HIV-testing services. Individuals ≥18-years who reported a partner absent during household visits were offered an HIVST kit for secondary distribution to this partner. We used two data sources to measure acceptance and use of secondary distribution HIVST kits.
Among 9,105 individuals ≥18-years consenting to PopART, 9.1% (n=825) accepted an HIVST kit for secondary distribution. 55.8% reported that the kit had been used. Women were more likely to accept, and men more likely to use, secondary distribution HIVST kits. Kits were more likely to be used by individuals aged 30+ and who had not participated in a previous round of PopART. 6.8% had a reactive result.
Community-based secondary distribution of HIVST kits reached men absent during CHiPs household visits and is a complement to facility- and community-based HIV-testing services, which often miss men.
Corresponding Author: Bernadette Hensen, PhD, London School of Hygiene and Tropical Medicine, London, UNITED KINGDOM
The authors report no conflicts of interest related to this work.
Funding: The HIVST study was funded by the International Initiative for Impact Evaluation, (3ie, grant no. TW2.2.18), with support from the Bill & Melinda Gates Foundation. The HIVST kits used in this study were provided through the UNITAID funded STAR consortium. Zambart was the sponsor of the HIVST sub-study. HPTN 071 was sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), under Cooperative Agreements UM1-AI068619, UM1-AI068617, and UM1-AI068613, with funding from the US President’s Emergency Plan for AIDS Relief (PEPFAR). Additional funding for HPTN 071 was provided by 3ie with support from the Bill & Melinda Gates Foundation, NIAID, the National Institute on Drug Abuse (NIDA), and the National Institute of Mental Health (NIMH), all part of the National Institutes of Health (NIH).
Author contributions: BH conceived and conducted the analysis and led the writing of the article, AJS, SF and RH provided critical input to the analyses, and AJS, SF, RH and HA to the presentation and interpretation of the results. AS, CM, MP and KS led delivery of the study, including overseeing data collection; VB, CB, and MS provided critical input to the writing of the manuscript. SFi, RH, and HA designed and led the HPTN 071 (PopART) trial and AM and HA designed and led the nested CRT from which this analysis arose, all provided expert knowledge and oversaw the study. All authors contributed to the writing of the article and have agreed the final draft for submission.
This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.
Molina, K. C., Morrisette, T., Miller, M. A., Huang, V., Fish, D. N.
Methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections (BSI) are associated with substantial morbidity and mortality. Monotherapy with first-line antimicrobials such as vancomycin (VAN; glycopeptide) and daptomycin (DAP; lipopeptide) are inadequate in some cases due to reduced antibiotic susceptibilities or therapeutic failure. In recent years, β-lactam antibiotics have emerged as a potential option for combination therapy with VAN/DAP that may meet an unmet therapeutic need for MRSA BSI. Ceftaroline (CPT), the only commercially available β-lactam in the United States with intrinsic in vitro activity against MRSA, has been increasingly studied in the setting of VAN and DAP failures. Novel combinations of first-line agents (VAN and DAP) with β-lactams have been the subject of many recent investigations due to in vitro findings such as the "see-saw effect", where β-lactam susceptibility may be improved in the presence of decreased glycopeptide and lipopeptide susceptibility. The combination of CPT and DAP, in particular, has become the focus of many scientific evaluations, due to intrinsic anti-MRSA activities and potent in vitro synergistic activity against various MRSA strains. This article reviews the available literature describing these innovative therapeutic approaches for MRSA BSI, focusing on preclinical and clinical studies, and evaluates the potential benefits and limitations of each strategy.
Jin, H., Siwak, E. B., Smith, R., LiWang, P. J.
This article, published ahead of print on 28 July 2008, has been withdrawn by the authors. Although moderate synergy between P2-RANTES and C peptides can be observed with high statistical significance in cell fusion assays, this synergy was not able to be verified in HIV viral assays. The authors regret the overstatement of synergy and will revise the paper for publication at a later date.
Avdoshina, Valeria; Mahoney, Matthew; Gilmore, Sean F.; Wenzel, Erin D.; Anderson, Albert; Letendre, Scott L.; Imamichi, Tomozumi; Fischer, Nicholas O.; Mocchetti, Italo
Postmortem brains of subjects diagnosed with human immunodeficiency virus-1 (HIV) associated neurocognitive disorders (HAND) exhibit loss of dendrites. However, the mechanisms by which synapses are damaged are not fully understood.
Dendrite length and remodeling occurs via microtubules (MTs) the dynamics of which are regulated by microtubule binding proteins, including MT associated protein 2 (MAP2). The HIV protein gp120 is neurotoxic and interferes with neuronal MTs. We measured MAP2 concentrations in human cerebrospinal fluid (CSF) and MAP2 immunoreactivity in rat cortical neurons exposed to HIV and gp120.
First, we examined whether HIV affects MAP2 levels by analyzing the CSF of 27 persons living with HIV (PLH) whose neurocognitive performance had been characterized. We then used rat cortical neurons to study the mechanisms of HIV-mediated dendritic loss.
PLH who had HAND had greater MAP2 concentrations within the CSF than cognitive normal PLH. In cortical neurons, the deleterious effect of HIV on MAP2 positive dendrites occurred through a gp120-mediated mechanism. The neurotoxic effect of HIV was blocked by a CCR5 antagonist and prevented by Helix-A, a peptide that displaces gp120 from binding to MTs, conjugated to a nanolipoprotein particle delivery platform.
Our findings support that HIV at least partially effects its neurotoxicity via neuronal cytoskeleton modifications and provide evidence of a new therapeutic compound that could be used to prevent the HIV-associated neuropathology.
Correspondence to Italo Mocchetti, Georgetown University Medical Center, Department of Neuroscience, EP09, New Research Building, 3970 Reservoir Rd, NW, Washington DC, 20057. Tel: +202 687 1197; fax: +202 687 0617; e-mail: firstname.lastname@example.org
Received 27 August, 2019
Revised 30 December, 2019
Accepted 23 January, 2020
Copyright © 2020 Wolters Kluwer Health, Inc.
Li, Guan-Han; Maric, Dragan; Major, Eugene O.; Nath, Avindra
Astrocytes are proposed to be a critical reservoir of HIV in the brain. However, HIV infection of astrocytes is inefficient in vitro except for cell-to-cell transmission from HIV-infected cells. Here, we explore mechanisms by which cell-free HIV bypasses entry and post-entry barriers leading to a productive infection.
HIV infection of astrocytes was investigated by a variety of techniques including transfection of CD4-expressing plasmid, treatment with lysosomotropic agents or using a transwell culture system loaded with HIV-infected lymphocytes. Infection was monitored by HIV-1 p24 in culture supernatants and integrated proviral DNA was quantified by Alu-PCR.
Persistent HIV infection could be established in astrocytes by transfection of proviral DNA, transduction with VSV-G-pseudotyped viruses, transient expression of CD4 followed by HIV infection, or the infection treated with lysosomotropic chloroquine or Tat-HA2 peptide. In absence of these treatments, HIV entered via endocytosis as seen by electronmicroscopy and underwent lysosomal degradation without proviral integration, indicating endocytosis is a dead end for HIV in astrocytes. Nevertheless, productive infection was observed when astrocytes were in close proximity but physically separated from HIV-infected lymphocytes in the transwell cultures. This occurred with X4 or dual tropic R5X4 viruses and was blocked by an antibody or antagonist to CXCR4.
A CD4-independent, CXCR4-dependent mechanism of viral entry is proposed, by which immature HIV particles from infected lymphocytes might directly bind to CXCR4 on astrocytes and trigger virus-cell fusion during or after the process of viral maturation. This mechanism may contribute to the formation of brain HIV reservoirs.
Correspondence to Avindra Nath, MD or Guanhan Li, PhD, Bldg 10, Room 7C-103, National Institutes of Health, Bethesda, MD 20892. Tel.: + 301 496 1561; e-mails:email@example.com,firstname.lastname@example.org
Received 27 October, 2019
Revised 21 January, 2020
Accepted 3 February, 2020
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 © 2020 Wolters Kluwer Health, Inc.
Mahale, Parag; Ugoji, Chinenye; Engels, Eric A.; Shiels, Meredith S.; Peprah, Sally; Morton, Lindsay M.
HIV–infected people have increased cancer risk. Lymphoma survivors have an increased risk of certain second primary cancers in the general population, but second cancer risk among HIV–infected people is poorly understood. Herein, we characterized the risk of cancers following lymphoid malignancies among HIV–infected people.
Population-based linkage of HIV and cancer registries.
We used data from the US HIV/AIDS Cancer Match Study (1996–2015) and evaluated the risk of first non–lymphoid malignancy in Cox regression models, with first lymphoid malignancy diagnosis as a time–dependent variable.
Among 531,460 HIV–infected people included in our study, 6,513 first lymphoid and 18,944 first non–lymphoid malignancies were diagnosed. Risk of non–lymphoid cancer following a lymphoid malignancy was increased overall (adjusted hazard ratio [aHR] = 2.7; 95% confidence interval [CI] = 2.3-3.2), and specifically for cancers of the oral cavity (aHR = 2.6; 95%CI = 1.2–5.5), colon (2.4; 1.1–5.0), rectum (3.6; 1.9–6.7), anus (3.6; 2.5–5.1), liver (2.0; 1.2–3.5), lung (1.6; 1.1–2.4), vagina/vulva (6.1; 2.3–16.3), and central nervous system (5.0; 1.6–15.6), Kaposi sarcoma (4.6; 3.4–6.2), and myeloid malignancies (9.7; 6.1–15.4). After additional adjustment for prior AIDS diagnosis and time since HIV diagnosis, aHRs were attenuated overall (aHR = 1.7; 95%CI = 1.5–2.0) and remained significant for cancers of the rectum, anus, and vagina/vulva, Kaposi sarcoma, and myeloid malignancies.
HIV–infected people with lymphoid malignancies have an increased risk of subsequent non–lymphoid cancers. As risks remained significant after adjustment for time since HIV diagnosis and prior AIDS diagnosis, it suggests that immunosuppression may explain some, but not all, of these risks.
Correspondence to Parag Mahale, PhD, Address: 9609 Medical Center Dr, Room 6E214, Rockville, MD 20850. Tel: +240 276 5855; e-mail: email@example.com
Received 14 November, 2019
Revised 18 March, 2020
Accepted 18 March, 2020
Conflicts of interest: The authors have no conflicts of interest to disclose.
Sources of funding: This research was supported in part by the Intramural Research Program of the National Cancer Institute.
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 © 2020 Wolters Kluwer Health, Inc.
Park, Y.-D., Chen, S. H., Camacho, E., Casadevall, A., Williamson, P. R.
The endosomal sorting complex required for transport (ESCRT) plays a crucial role in the transportation and degradation of proteins. We determined that Vps27, a key protein of the ESCRT-0 complex, is required for the transport of the virulence factor laccase to the cell wall in Cryptococcus neoformans. Laccase activity was perturbed as well as melanin production in vps27 strains. In the absence of VPS27 there was an accumulation of multi-vesicular bodies with vacuolar fragmentation and mistargeting of the vacuolar carboxypeptidase CPY/Prc1 resulting to an extracellular localization. In addition, deletion of VPS27 resulted a defect in laccase targeting of a Lac1-green fluorescent protein fusion protein to the cell wall with trapping within intracellular puncta and was accompanied by reduced virulence in a mouse model. However, the actin cytoskeleton remained intact suggesting that the trafficking defect is not due to defects in the actin-related localization. Extracellular vesicle maturation was also defective in the vps27 mutant with a larger vesicle size measured by dynamic light scattering. Our data identify cryptococcal VPS27 as a required gene for laccase trafficking and attenuates virulence of Cn in the mouse i.v. meningitis model.
Nakamura, N., Hoshino, Y., Shiga, T., Haneda, T., Okada, N., Miki, T.
Salmonella Typhimurium is an important food-borne pathogen that causes diarrhea. S. Typhimurium elicits inflammatory responses and colonizes the gut lumen by outcompeting the microbiota. Although evidence is accumulating in regard to the underlying mechanism, the infectious stage has not been adequately defined. Peptidoglycan amidases are widely distributed among bacteria, and play a prominent role in peptidoglycan maintenance by hydrolyzing peptidoglycans. The amidase activation is required for regulation of at least one of two cognate activators: NlpD or EnvC (YibP). Recent studies established that the peptidoglycan amidase AmiC-mediated cell division specifically confers a fitness advantage on S. Typhimurium in the inflamed gut. However, it remains unknown which cognate activators are involved in the amidase activation and how the activators influence Salmonella pathogenesis. Here, we characterize the role of two activators, NlpD and EnvC, in S. Typhimurium cell division and gut infection. EnvC was found to contribute to cell division of S. Typhimurium cells through the activation of AmiA and AmiC. The envC mutant exhibited impairments in gut infection, including a gut colonization defect and reduced ability to elicit inflammatory responses. Importantly, the colonization defect of the envC mutant was unrelated to the microbiota, but was conferred by attenuated motility and chemotaxis of S. Typhimurium cells, which were not observed in the amiA amiC mutant. Furthermore, the envC mutant was impaired in its induction of mucosal inflammation and sustained gut colonization. Collectively, our findings provide a novel insight into the peptidoglycan amidase/cognate activator circuits and their dependent pathogenesis.
Michie, K. L., Dees, J. L., Fleming, D., Moustafa, D. A., Goldberg, J. B., Rumbaugh, K. P., Whiteley, M.
The opportunistic pathogen Pseudomonas aeruginosa is a leading cause of morbidity and mortality worldwide. To survive in both the environment and in the host, P. aeruginosa must cope with redox stress. In P. aeruginosa, a primary mechanism for protection from redox stress is the antioxidant glutathione (GSH). GSH is a low molecular weight thiol-containing tripeptide (L--glutamyl-L-cysteinyl-glycine) that can function as a reversible reducing agent. GSH plays an important role in P. aeruginosa physiology and is known to modulate several cellular and social processes that are likely important during infection. However, the role of GSH biosynthesis during mammalian infection is not well understood. In this study, we created a P. aeruginosa mutant defective in GSH biosynthesis to examine how loss of GSH biosynthesis affects P. aeruginosa virulence. We found that GSH is critical for normal growth in vitro and provides protection against hydrogen peroxide, bleach, antimicrobial peptides (AMPs) and ciprofloxacin. We also studied the role of P. aeruginosa GSH biosynthesis in four mouse infection models, including the surgical wound, abscess, burn wound, and acute pneumonia models. We discovered that the GSH biosynthesis mutant was slightly less virulent in the acute pneumonia infection model but was equally virulent in the three other models. This work provides new and complementary data regarding the role of GSH in P. aeruginosa during mammalian infection.
Biosca, A., Bouzon-Arnaiz, I., Spanos, L., Siden-Kiamos, I., Iglesias, V., Ventura, S., Fernandez-Busquets, X.
The rapid evolution of resistance in the malaria parasite to every single drug developed against it calls for the urgent identification of new molecular targets. Using a stain specific for the detection of intracellular amyloid deposits in live cells we have detected the presence of abundant protein aggregates in Plasmodium falciparum blood stages and female gametes cultured in vitro, in the blood stages of mice infected by Plasmodium yoelii, and in the mosquito stages of the murine malaria species Plasmodium berghei. Aggregated proteins could not be detected in early rings, the parasite form that starts the intraerythrocytic cycle. A proteomics approach was followed to pinpoint actual aggregating polypeptides in functional P. falciparum blood stages, which resulted in the identification of 369 proteins, with roles particularly enriched in nuclear import-related processes. Five aggregation-prone short peptides selected from this protein pool exhibited different aggregation propensity according to Thioflavin-T fluorescence measurements, and were observed to form amorphous aggregates and amyloid fibrils in transmission electron microscope images. The results presented suggest that generalized protein aggregation might have a functional role in malaria parasites. Future antimalarial strategies based on the upsetting of the pathogen's proteostasis and therefore affecting multiple gene products could represent the entry to new therapeutic approaches.
Ge Y, Sun A, Ojcius D, et al.
AbstractBackgroudLeptospirosis is a global zoonotic infectious disease caused by Leptospira interrogans. The pathogen rapidly invades into hosts and diffuses from bloodstream into internal organs and excretes from urine to cause transmission of leptospirosis. However, the mechanism of leptospiral invasiveness remains poorly understood.MethodsProteolytic activity of M16-type metallopeptidases (Lep-MP1/2/3) of L. interrogans was determined by spectrophotometry. Expression and secretion of Lep-MP1/2/3 during infection of cells were detected by qRT-PCR, Western Blot assay and confocal microscopy. Deletion and complementation mutants of the genes encoding Lep-MP1/2/3 were generated to determine the roles of Lep-MP1/2/3 in invasiveness using transwell assay and virulence in hamsters.ResultsL. interrogans but not saprophytic L. biflexa strains were detectable for Lep-MP-1/2/3-encoding genes. rLep-MP1/2/3 hydrolyzed ECM proteins, but rLep-MP1/3 displayed stronger proteolysis than rLep-MP2, with 123.179/340.136 µmol•L-1 Km and 0.154/0.159 s-1 Kcat values. Expression, secretion and translocation of Lep-MP1/2/3 during infection of cells were increased. ΔMP1/3 but not ΔMP2 mutant presented attenuated transmigration through cell monolayers, decreased leptospiral loading in the blood, lungs, liver, kidneys and urine, and 10/13-fold-decreased LD50 and milder histopathologic injury in hamsters.ConclusionsLep-MP1/3 are involved in virulence of L. interrogans in invasion into hosts and diffusion in vivo, and transmission of leptospirosis.
In a plague year, the numbers are the narrative. “The Bill of Mortality, to all our griefs, is encreased 399 this week, and the encrease general through the whole city and suburbs, which makes us all sad”, noted Londoner Samuel Pepys on Nov 9, 1665. Those who have been following the toll of coronavirus disease 2019 (COVID-19) infections and deaths in the news and on social media will know how Pepys felt. But what was the Bill of Mortality?
Abdelahhad Barbour, Philip Wescombe, Leif Smith
Lantibiotic salivaricins are polycyclic peptides containing lanthionine and/or β-methyllanthionine residues produced by certain strains of Streptococcus salivarius, which almost exclusively reside in the human oral cavity. The importance of these molecules stems from their antimicrobial activity towards relevant oral pathogens which has so far been applied through the development of salivaricin-producing probiotic strains. However, salivaricins may also prove to be of great value in the development of new and novel antibacterial therapies in this era of emerging antibiotic resistance.
Brown, M. M., Kwiecinski, J. M., Mejia Cruz, L., Shahbandi, A., Todd, D. A., Cech, N. B., Horswill, A. R.
Recent studies highlight the abundance of commensal coagulase-negative staphylococci (CoNS) on healthy skin. Evidence suggests that CoNS actively shape the skin immunological and microbial milieu to resist colonization or infection by opportunistic pathogens, including methicillin resistant Staphylococcus aureus (MRSA), in a variety of mechanisms collectively termed colonization resistance. One potential colonization resistance mechanism is the application of quorum sensing, also called the Accessory Gene Regulator (agr) system, which is ubiquitous among staphylococci. Common and rare CoNS make autoinducing peptides (AIPs) that function as MRSA agr inhibitors, protecting the host from invasive infection. In a screen of CoNS spent media we found that Staphylococcus simulans, a rare human skin colonizer and frequent livestock colonizer, released potent inhibitors of all classes of MRSA agr signaling. We identified three S. simulans agr classes, and have shown intraspecies cross-talk between non-cognate S. simulans agr types for the first time. The S. simulans AIP-I structure was confirmed, and the novel AIP-II and AIP-III structures were solved via mass spectrometry. Synthetic S. simulans AIPs inhibited MRSA agr signaling with nanomolar potency. S. simulans in competition with MRSA reduced dermonecrotic and epicutaneous skin injury in murine models. Addition of synthetic AIP-I also effectively reduced MRSA dermonecrosis and epicutaneous skin injury in murine models. These results demonstrate potent anti-MRSA quorum sensing inhibition by a rare human skin commensal, and suggest that cross-talk between CoNS and MRSA may be important in maintaining healthy skin homeostasis and preventing MRSA skin damage during colonization or acute infection.
Burke R, Tate J, Jiang B, et al.
AbstractThough the etiology of type 1 diabetes (T1D) is not well understood, it is believed to comprise both genetic and environmental factors. Viruses are the most well studied environmental trigger, and there is a small but growing body of research on the potential influence of rotavirus on T1D. Rotavirus infections were initially identified as possible triggers of T1D given similarities between viral peptide sequences and T1D autoantigen peptide sequences. Further, rotavirus infection has been shown to modify T1D risk in T1D-prone mice. However, research into associations of rotavirus infections with T1D development in humans have yielded mixed findings and suggested interactions with age and diet. As global availability of rotavirus vaccines increases, recent studies have assessed whether rotavirus vaccination modifies T1D development, finding null or protective associations. Overall, evidence to-date suggests a possible triggering relationship between some wild-type rotavirus infections and T1D, but the potential effect of rotavirus vaccination remains unclear.
Kuss-Duerkop, S. K., Keestra-Gounder, A. M.
Prompt recognition of microbes by cells is critical to eliminate invading pathogens. Some cell-associated pattern recognition receptors (PRRs) recognize and respond to microbial ligands. However, others can respond to cellular perturbations, such as damage-associated molecular patterns (DAMPs). Nucleotide oligomerization domain 1 and 2 (NOD1, NOD2) are PRRs that recognize and respond to multiple stimuli of microbial and cellular origin, such as bacterial peptidoglycan, viral infections, parasitic infections, activated Rho GTPases and endoplasmic reticulum (ER) stress. How NOD1/2 are stimulated by such diverse stimuli is not fully understood but may partly rely on cellular changes during infection that result in ER stress. NOD1/2 are ER stress sensors that facilitate pro-inflammatory responses for pathogen clearance; thus, NOD1/2 may help mount broad anti-microbial responses through detection of ER stress, which is often induced during a variety of infections. Some pathogens may subvert this response to promote infection through manipulation of NOD1/2 responses to ER stress that lead to apoptosis. Herein, we review NOD1/2 stimuli and cellular responses. Furthermore, we discuss pathogen-induced ER stress and how it might potentiate NOD1/2 signaling.
Masi, M., Pinet, E., Pages, J.-M.
The Cpx stress response is widespread among Enterobacteriaceae. We have previously reported a mutation in cpxA in a multidrug resistant strain of Klebsiella aerogenes isolated from a patient treated with imipenem. This mutation yields to a single amino acid substitution (Y144N) located in the periplasmic sensor domain of CpxA. In this work, we sought to characterize this mutation in Escherichia coli by using genetic and biochemical approaches. Here, we show that cpxAY144N is an activated allele that confers resistance to β-lactams and aminoglycosides in a CpxR-dependent manner, by regulating the expression of the OmpF porin and the AcrD efflux pump, respectively. We also demonstrate the intimate interconnection between Cpx system and peptidoglycan integrity on the expression of an exogenous AmpC β-lactamase by using imipenem as a cell wall active antibiotic or inactivation of penicillin-binding proteins. Moreover, our data indicate that the Y144N substitution abrogates the interaction between CpxA and CpxP and increase phosphotransfer activity on CpxR. Because the addition of a strong AmpC inducer such as imipenem is known to causes abnormal accumulation of muropeptides (disaccharide-pentapeptide, N-acetylglucosamyl-1,6-anhydro-N-acetylmuramyl-l-alanyl-d-glutamy-meso-diaminopimelic-acid-d-alanyl-d-alanine) in the periplasmic space, we propose these molecules activate the Cpx system by displacing CpxP from the sensor domain of CpxA. Altogether, these data could explain why large perturbations to peptidoglycan caused by imipenem lead to mutational activation of the Cpx system and bacterial adaptation through multidrug resistance. These results also validate the Cpx system, in particular the interaction between CpxA and CpxP, as a promising therapeutic target.
There is an urgent need for an effective vaccine to control and eradicate malaria, one of the most serious global infectious diseases. Plasmodium merozoite surface protein 4 (MSP4) has been listed as a blood-stage subunit vaccine candidate for malaria. Infection with Plasmodium ovale species including P. ovale wallikeri and P. ovale curtisi, is also a source of malaria burden in tropical regions where it is sometimes mixed with other Plasmodium species. However, little is known about P. ovale MSP4.
The msp4 gene was amplified through polymerase chain reaction using genomic DNA extracted from blood samples of 46 patients infected with P. ovale spp. and amplified products were sequenced. Open reading frames predicted as immunogenic peptides consisting of 119 and 97 amino acids of P. ovale curtisi MSP4 (PocMSP4) and P. ovale wallikeri MSP4 (PowMSP4), respectively, were selected for protein expression. Recombinant proteins (rPoMSP4) were expressed in Escherichia coli, purified, analysed, and immunized in BALB/c mice. The specificity of anti-MSP4-immunoglobulin (Ig) G antibodies was evaluated by Western blot and enzyme-linked immunosorbent assays, and cellular immune responses were analysed via lymphocyte proliferation assays.
Full peptide sequences of PocMSP4 and PowMSP4 were completely conserved in all clinical isolates, except in the epidermal growth factor-like domain at the carboxyl terminus where only one mutation was observed in one P. o. wallikeri isolate. Further, truncated PoMSP4 segments were successfully expressed and purified as ~ 32 kDa proteins. Importantly, high antibody responses with end-point titres ranging from 1:10,000 to 1:2,560,000 in all immunized mouse groups were observed, with high IgG avidity to PocMSP4 (80.5%) and PowMSP4 (92.3%). Furthermore, rPocMSP4 and rPowMSP4 cross-reacted with anti-PowMSP4-specific or anti-PocMSP4-specific antibodies. Additionally, anti-PoMSP4 IgG antibodies showed broad immuno-specificity in reacting against rPoMSP1 and rPoAMA1. Lastly, PocMSP4- and PowMSP4-immunized mice induced cellular immune responses with PocMSP4 (36%) and PowMSP4 cells (15.8%) during splenocyte proliferation assays.
Findings from this study suggest conservation in PoMSP4 protein sequences and high immunogenicity was observed in rPoMSP4. Furthermore, induction of immune responses in PocMSP4- and PowMSP4-immunized mice informed that both humoral and cellular immune responses play crucial roles for PoMSP4 in protection.
Watkins R, File T, Jr.
AbstractCommunity-acquired bacterial pneumonia (CABP) remains a significant cause of morbidity and mortality worldwide. Antimicrobial resistance, including in pathogens that cause CABP, continues to spread at an alarming rate. Because of these factors, the development of new antibiotic classes is urgently needed. Lefamulin, previously known as BC-3781, is a semisynthetic pleuromutilin antibiotic that was approved by the Federal Drug Administration for the treatment of CABP in adults. Available in both oral and intravenous (IV) formulations, lefamulin has potent in vitro activity against both typical and atypical CABP pathogens. The first pleuromutilin to be used systemically in humans, lefamulin has a unique mechanism of action that inhibits protein synthesis by preventing the binding of tRNA for peptide transfer. This review summarizes the available data about lefamulin, including recent evidence from two phase III clinical trials (LEAP 1 and LEAP 2), and discusses its potential role in the treatment of CABP.
Kuba, M., Neha, N., Newton, P., Lee, Y. W., Bennett-Wood, V., Hachani, A., De Souza, D. P., Nijagal, B., Dayalan, S., Tull, D., McConville, M. J., Sansom, F. M., Newton, H. J.
The zoonotic bacterial pathogen Coxiella burnetii is the causative agent of Q fever, a febrile illness which can cause a serious chronic infection. C. burnetii is a unique intracellular bacterium which replicates within host lysosome-derived vacuoles. The ability of C. burnetii to replicate within this normally hostile compartment is dependent on the activity of the Dot/Icm type 4B secretion system. In a previous study, a transposon mutagenesis screen suggested that disruption of the gene encoding the novel protein CBU2072 rendered C. burnetii incapable of intracellular replication. This protein, subsequently named EirA (Essential for intracellular replication A), is indispensable for intracellular replication and virulence, as demonstrated by infection of human cell lines, and in vivo infection of Galleria mellonella. The putative N-terminal signal peptide is essential for protein function but is not required for localization of EirA to the bacterial inner membrane compartment and axenic culture supernatant. In the absence of EirA, C. burnetii remains viable but non-replicative within the host phagolysosome, as co-infection with C. burnetii expressing native EirA rescues the replicative defect in the mutant strain. In addition, while the bacterial ultrastructure appears intact, there is an altered metabolic profile shift in the absence of EirA, suggesting that EirA may impact overall metabolism. Most strikingly, in the absence of EirA, Dot/Icm effector translocation was inhibited even when EirA deficient C. burnetii replicated in WT supported Coxiella-containing vacuoles. EirA may therefore have a novel role in control of Dot/Icm activity and may therefore represent an important new therapeutic target.
Gong, J., Bing, J., Guan, G., Nobile, C. J., Huang, G.
Antimicrobial peptides and proteins play critical roles in the host defense against invading pathogens. We recently discovered that recombinantly expressed human and mouse serum amyloid A1 (rhSAA1 and rmSAA1) proteins have potent antifungal activities against the major human fungal pathogen Candida albicans. At high concentrations, rhSAA1 disrupts C. albicans membrane integrity and induces rapid fungal cell death. In the current study, we find that rhSAA1 promotes cell aggregation and targets the C. albicans cell wall adhesin Als3. Inactivation of ALS3 in C. albicans leads to a striking decrease in cell aggregation and cell death upon rhSAA1 treatment, suggesting that Als3 plays a critical role in SAA1 sensing. We further demonstrate that deletion of the transcriptional regulators controlling the expression of ALS3, such as AHR1, BCR1, and EFG1 in C. albicans results in similar effects to that of the als3/als3 mutant upon rhSAA1 treatment. Global gene expression profiling indicates that rhSAA1 has a discernible impact on the expression of cell wall- and metabolism-related genes, suggesting that rhSAA1 treatment could lead to a nutrient starvation effect on C. albicans cells.
Ongoing efforts to fight Plasmodium falciparum malaria has reduced malaria in many areas, but new tools are needed to monitor further progress, including indicators of decreasing exposure to parasite infection. Sero-surveillance is considered promising to monitor exposure, transmission and immunity.
IgG responses to three antigen biomarkers were evaluated in a retrospective study involving: (i) surveys of 798 asymptomatic villagers from 2 Senegalese endemic settings conducted before 2002 and after the 2013 intensification of control measures, and (ii) in 105 symptomatic individuals from different settings in Côte d’Ivoire. Response to up to eight P. falciparum antigens, including recombinant MSP1p9 antigen and LSA141 peptide, were analysed using multiplex technology and responses to whole P. falciparum schizont extract (SE, local strain adapted to culture) were measured by ELISA.
MSP1p9 and LSA141 IgG responses were shown to be relevant indicators monitoring immune status in the different study sites both from Côte d’Ivoire and Senegal. Between 2002 and 2013, individuals participating in both studies showed higher decline of sero-positivity in young ( 15 years: no decline to 15%) individuals from Dielmo and Ndiop. A mathematical sero-catalytic model from the complete Dielmo/Ndiop survey was used to reconstruct declining levels of sero-positivity in more detail, demonstrating that anti-SE seroprevalence levels most accurately reflected malaria exposure in the two villages.
For standard screening of population immune status at sites envisaging elimination, the use of ELISA-based assays targeting selected antigens can contribute to provide important epidemiologic surveillance data to aid malaria control programmes.
Malaria is a major public health problem in Cameroon. The study of the genetic diversity within parasite population is essential for understanding the mechanism underlying malaria pathology and to determine parasite clones profile in an infection, for proper malaria control strategies. The objective of this study was to perform a molecular characterization of highly polymorphic genetic markers of Plasmodium falciparum, and to determine allelic distribution with their influencing factors valuable to investigate malaria transmission dynamics in Cameroon.
A total of 350 P. falciparum clinical isolates were characterized by genotyping block 2 of msp-1, block 3 of msp-2, and region II of glurp gene using nested PCR and DNA sequencing between 2012 and 2013.
A total of 5 different genotypes with fragment sizes ranging from 597 to 817 bp were recorded for GLURP. Overall, 16 MSP-1 genotypes, including K1, MAD20 and RO33 were identified, ranging from 153 to 335 bp. A peculiarity about this study is the RO33 monomorphic pattern revealed among the Pfmsp-1 allelic type. Again, this study identified 27 different Pfmsp-2 genotypes, ranging from 140 to 568 bp in size, including 15 belonging to the 3D7-type and 12 to the FC27 allelic families. The analysis of the MSP-1 and MSP-2 peptides indicates that the region of the alignment corresponding K1 polymorphism had the highest similarity in the MSP1and MSP2 clade followed by MAD20 with 93% to 100% homology. Therefore, population structure of P. falciparum isolates is identical to that of other areas in Africa, suggesting that vaccine developed with K1 and MAD20 of Pfmsp1 allelic variant could be protective for Africa children but these findings requires further genetic and immunological investigations. The multiplicity of infection (MOI) was significantly higher (P
To the Editor The JAMA Insights article on bisphosphonates for postmenopausal osteoporosis commented that no clinical trials have assessed benefit of treatment with bisphosphonates in women with osteopenia. I disagree. A double-blind, randomized, placebo-controlled trial of nearly 2000 older women with osteopenia with average bone mineral density (BMD) T scores between −0.91 at the lumbar spine and −1.67 at the femoral neck showed a fracture reduction rate at 6 years of at least 33% from intravenous zoledronate given at 18-month intervals. The reduction in hip fracture rates did not achieve statistical significance; however, the fracture reduction rates outside the hip occurred without the adverse effects of jaw osteonecrosis or atypical hip fractures. The results held true even when data from a subset of 163 women with osteoporosis who were included in the study were later excluded from statistical analysis. The results are remarkable given that 62 of the 954 women (6.4%) in the treatment group received only 1 infusion of zoledronate because of acute phase reactions or iritis and that 115 women (12.2%) in the placebo group vs 33 (3.5%) in the treatment group received bisphophonates outside the study. In addition, the benefits of zoledronate were sustained in women with or without 10-year baseline fracture risks of greater than 3% for hip fractures and 20% for any fracture as determined by the Fracture Risk Assessment Tool (FRAX) calculator proposed by the National Osteoporosis Foundation and in individuals with a history of a nonvertebral fracture after 45 years of age. These data are consistent with the reduction in bone turnover markers, procollagen type 1 N-terminal propeptide and carboxy-terminal collagen crosslinks by 37% to 50% at the end of the study. Similar data have shown bone turnover markers that are suppressed nearly 50% and significant increases in bone mineral density apparent 5 years after a single infusion of zoledronate.
Zhao, X., Yin, Z., Breukink, E., Moll, G. N., Kuipers, O. P.
Lipid II is an essential precursor of the bacterial cell wall biosynthesis and thereby an important target for various antibiotics. Several lanthionine-containing peptide antibiotics target lipid II with lanthionine-stabilized lipid II-binding motifs. Here, we used the biosynthesis system of the lantibiotic nisin to synthesize a two lipid II binding motifs-containing lantibiotic, termed TL19, which contains the N-terminal lipid II binding motif of nisin and the distinct C-terminal lipid II binding motif of one peptide of the two-component haloduracin (i.e. HalA1). Further characterization demonstrated that (i) TL19 exerts 64-fold stronger antimicrobial activity against E. faecium than nisin (1-22), which has only one lipid II binding site, and (ii) both the N- and C-terminal domains are essential for the potent antimicrobial activity of TL19, as evidenced by mutagenesis of each single and double domains. These results show the feasibility of a new approach to synthesize potent lantibiotics with two different lipid II binding motifs to treat specific antibiotic-resistant pathogens.
Rodriguez, F., John, S. F., Iniguez, E., Montalvo, S., Michael, K., White, L., Liang, D., Olaleye, O. A., Maldonado, R. A.
Leishmania major is the causative agent of cutaneous leishmaniasis (CL). No human vaccine is available for CL and current drug regimens present several drawbacks such as emerging resistance, severe toxicity, medium effectiveness, and/or high cost. Thus, the need for better treatment options against CL is a priority. In the present study, we validate the enzyme methionine aminopeptidase-1 (MetAP1), a metalloprotease that catalyzes the removal of N-terminal methionine from peptides and proteins, as a chemotherapeutic target against CL infection. The in vitro antileishmanial activity of eight novel MetAP1 inhibitors (OJT001-OJT008) were investigated. Three compounds OJT006, OJT007, and OJT008 demonstrated potent anti-proliferative effect in macrophages infected with L. major amastigotes and promastigotes at submicromolar concentrations, with no cytotoxicity against host cells. Importantly, the leishmanicidal effect was diminished by almost 10-fold in transgenic L. major promastigotes overexpressing MetAP1LM in comparison to wild-type promastigotes. Furthermore, the in vivo activity of OJT006, OJT007, and OJT008 were investigated in L. major-infected BALB/c mice. In comparison to the control group, OJT008 significantly decreased footpad parasite load by 86%, and exhibited no toxicity against in treated mice. We propose MetAP1 inhibitor OJT008 as a potential chemotherapeutic candidate against CL infection caused by L. major infection.
Christopher A. Cleveland, Kayla B. Garrett, Erin K. Box, Zavier Eure, Ania A. Majewska, Jessica A. Wilson, Michael J. Yabsley
Fernandes, K. E., Weeks, K., Carter, D. A.
Lactoferrin (LF) is a multifunctional milk protein with antimicrobial activity against a range of pathogens. While numerous studies report that LF is active against fungi, there are considerable differences in the level of antifungal activity and the capacity of LF to interact with other drugs. Here we undertake a comprehensive evaluation of the antifungal spectrum of activity of three defined sources of LF across 22 yeast and 24 mould species, and assess interactions with six widely used antifungal drugs. LF was broadly and consistently active across all yeast species (MIC 8-64 μg/ml), with the extent of activity strongly affected by iron saturation. LF was synergistic with amphotericin B (AMB) in 19 out of 22 yeast species tested and synergy was unaffected by iron saturation but affected by the extent of LF digestion. LF+AMB combination therapy significantly prolonged the survival of Galleria mellonella infected with Candida albicans or Cryptococcus neoformans and decreased fungal burden 12-25 fold. Evidence that LF directly interacts with the fungal cell surface was seen via SEM, which showed pore formation, hyphal thinning and major cell collapse in response to LF+AMB synergy. Important virulence mechanisms were disrupted by LF+AMB treatment, which significantly prevented biofilms in C. albicans and C. glabrata, inhibited hyphal development in C. albicans, and reduced cell and capsule size and phenotypic diversity in Cryptococcus. Our results demonstrate the potential of LF+AMB as an antifungal treatment that is broadly synergistic against important yeast pathogens, with synergy attributed to the presence of one or more LF peptides.
Huang, P.-N., Wang, H.-C., Hung, H.-C., Tseng, S.-N., Chang, T.-Y., Chou, M.-Y., Chen, Y.-J., Wang, Y.-M., Shih, S.-R., Hsu, J. T.-A.
In the past few decades, Enterovirus A71 (EVA71) has caused devastating outbreaks in the Asia-Pacific region resulting in serious sequelae in infected young children. No preventive and therapeutic interventions are currently available for curing EVA71 infection, highlighting a great unmet medical need for this disease. Here, we showed that one novel single domain antibody (sdAb, F1) isolated from an immunized llama could alleviate EVA71 infection, both in vitro and in vivo. We also confirmed that the sdAb clone F1 recognizes EVA71 through a novel conformational epitope comprising the highly conserved region of VP3 capsid protein by using competitive-binding and overlapping-peptide ELISA assays. Because of the virion's icosahedral structure, we reasoned that adjacent epitopes must be clustered within molecular ranges that may be simultaneously bound by an engineered antibody with multiple valency. Therefore, two single domain binding modules (F1) were fused to generate an sdAb-in-tandem design so that the capture of viral antigens can be further increased by valency effects. We showed that the tetravalent construct, F1xF1-hFc, containing two sdAb-in-tandem on an Fc scaffold, exhibits more potent neutralization activity against EVA71 than the bivalent sdAb, F1-hFc, for at least 5.8-fold. We also demonstrated that, using a human scavenger receptor class B member 2 (hSCARB2) transgenic mouse model, a half-dose of the F1xF1-hFc provided better protection against EVA71 infection than did the F1-hFc. Thus, our study furnishes important insights into multivalent sdAb engineering against viral infection and provides a novel strategic deployment approach for preparedness of emerging infectious diseases such as EVA71.
Rabies is endemic in southern Bhutan, associated with 1–2 human deaths and high post exposure prophylaxis (PEP) costs annually. Evaluation of clinicians’ management of human cases potentially exposed to rabies could contribute to improving PEP prescribing practices to both reduce unnecessary costs associated with PEP and reach the target of zero human deaths due to rabies by 2023.
A cross-sectional survey of 50 clinicians’ management of human cases potentially exposed to rabies was conducted in 13 health centers in high-rabies-risk areas of Bhutan during February–March 2016.
Data were collected on clinicians’ management of 273 human cases potentially exposed to rabies. The 50 clinicians comprised health assistants or clinical officers (55%) and medical doctors (45%) with a respective median of 19, 21 and 2 years’ experience. There was poor agreement between clinicians’ rabies risk assessment compared with an independent assessment for each case based on criteria in the National Rabies Management Guidelines (NRMG). Of the 194 cases for which clinicians recorded a rabies risk category, only 53% were correctly classified when compared with the NRMG. Clinicians were more likely to underestimate the risk of exposure to rabies and appeared to prescribe PEP independently of their risk classification.. Male health assistants performed the most accurate risk assessments while female health assistants performed the least accurate. Clinicians in Basic Health Units performed less accurate risk assessments compared with those in hospitals.
This study highlights important discrepancies between clinicians’ management of human cases potentially exposed to rabies and recommendations in the NRMG. In particular, clinicians were not accurately assessing rabies risk in potentially exposed cases and were not basing their PEP treatment on the basis of their risk assessment. This has significant implications for achieving the national goal of eliminating dog-mediated human rabies by 2030 and may result in unnecessary costs associated with PEP. Recommendations to improve clinician’s management of human cases potentially exposed to rabies include: reviewing and updating the NRMG, providing clinicians with regular and appropriately targeted training about rabies risk assessment and PEP prescription, and regularly reviewing clinicians’ practices.
Yan, R., Zhang, Y., Li, Y., Xia, L., Guo, Y., Zhou, Q.
Angiotensin-converting enzyme 2 (ACE2) is the cellular receptor for SARS coronavirus (SARS-CoV) and the new coronavirus (SARS-CoV-2) that is causing the serious epidemic COVID-19. Here we present cryo-EM structures of full-length human ACE2, in the presence of a neutral amino acid transporter B0AT1, with or without the receptor binding domain (RBD) of the surface spike glycoprotein (S protein) of SARS-CoV-2, both at an overall resolution of 2.9 Å, with a local resolution of 3.5 Å at the ACE2-RBD interface. The ACE2-B0AT1 complex is assembled as a dimer of heterodimers, with the Collectrin-like domain (CLD) of ACE2 mediating homo-dimerization. The RBD is recognized by the extracellular peptidase domain (PD) of ACE2 mainly through polar residues. These findings provide important insights to the molecular basis for coronavirus recognition and infection.
Staton, G. J., Carter, S. D., Ainsworth, S., Mullin, J., Smith, R. F., Evans, N. J.
Bovine Digital Dermatitis (BDD), an infectious disease of the bovine foot with a predominant treponemal aetiology, is a leading cause of lameness in dairy and beef herds worldwide. BDD is poorly responsive to antimicrobial therapy and exhibits a relapsing clinical course; an effective vaccine is therefore urgently sought. Using a ‘reverse vaccinology' approach, the present study surveyed the genomes of the three BDD-associated Treponema phylogroups for putative β-barrel outer membrane proteins and considered their potential as vaccine candidates. Selection criteria included the presence of a signal peptidase I cleavage site, a predicted β-barrel fold and cross-phylogroup homology. Four candidate genes were overexpressed in Escherichia coli BL21 (DE3), refolded and purified. Consistent with their classification as β-barrel OMPs, circular dichroism spectroscopy revealed the adoption of a predominantly β-sheet secondary structure. These recombinant proteins, when screened for their ability to adhere to immobilised ECM components, exhibited a diverse range of ligand specificities. All four proteins specifically and dose-dependently adhered to bovine fibrinogen. One recombinant protein was identified as a candidate diagnostic antigen (disease specificity, 75%). Finally, when adjuvanted with aluminium hydroxide and administered to BDD-naïve calves using a prime-boost vaccination protocol, these proteins were immunogenic, eliciting specific IgG antibodies. In summary, we present the description of four putative treponemal β-barrel OMPs that exhibit the characteristics of multispecific adhesins. The observed interactions with fibrinogen may be critical to host colonisation and dissemination and it is hypothesised that vaccination-induced antibody blockade of these interactions will impede treponemal virulence and thus be of therapeutic value.
Northern European Conference on Travel Medicine (NECTM) 2020
Mødet udskudt på grund af COVID-19
3.06.2020 - 5.06.2020
ASM Microbe 2020
Aflyst på grund af COVID-19
18.06.2020 - 22.06.2020
Ph.d. forsvar ved Kristina Langholz Kristensen
International AIDS Conference (AIDS) 2020
6.07.2020 - 10.07.2020
International Liver Congress (ILC) 2020
27.08.2020 - 29.08.2020
COVID-19 retningslinje (2020)
National handlingsplan for antibiotika til mennesker (2017)
Retningslinjer til sundhedsprofessionelle vedr. håndtering af infektion med zikavirus (2019)
Antiviral behandling af hiv smittede personer (2019)
Unusual dermatomycoses caused by Nannizzia nana : the geophilic origin of human infections
1.06.2020Latest Results for Infection
Asymptomatic transmission during the COVID-19 pandemic and implications for public health strategies
28.05.2020Clinical Infectious Diseases Advance Access
Ratio, rate, or risk?
28.05.2020The Lancet Infectious Diseases
Ethics and governance for digital disease surveillance
27.05.2020Science Express TOC RSS Feed
Reducing transmission of SARS-CoV-2
27.05.2020Science Express TOC RSS Feed
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