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Lane, Charlotte E.; Widen, Elizabeth M.; Collins, Shalean M.; Young, Sera L.
HIV-uninfected infants of HIV-positive women may experience worse growth and health outcomes than infants of HIV-negative women, but this has not been thoroughly investigated under the WHO’s most recent recommendations to reduce vertical transmission.
To determine if HIV-exposed and -uninfected (HEU) infants whose mothers received Option B+ have higher odds of experiencing suboptimal growth trajectories than HIV-unexposed, -uninfected infants and if this relationship is affected by food insecurity.
Repeated anthropometric measures were taken on 238 infants (HEU=86) at 1 week and 1,3,6,9, and 12 months after delivery in Gulu, Uganda. Latent class growth mixture modeling was used to develop trajectories for length-for-age z-scores (LAZ), weight-for-length z-scores, mid-upper arm circumference (MUAC), sum of skinfolds, and arm fat area. Multinomial logistic models were built to predict odds of trajectory class membership, controlling for socioeconomic factors.
HEU infants had greater odds of being in the shortest two LAZ trajectory classes (OR=3.80[1.22,11.82], OR=8.72 [1.80,42.09]) and higher odds of being in smallest sum of skinfolds trajectory class (OR=3.85[1.39,10.59]) vs. unexposed infants. Among HEU infants, increasing food insecurity was associated with lower odds of being in the lowest sum of skinfolds class (OR=0.86[0.76,0.98]).
There continues to be differences in growth patterns by HIV-exposure under the new set of WHO guidelines for the prevention of mother-to-child transmission of HIV and the feeding of HEU infants in low-resource settings that are not readily identified through traditional mixed effects modeling. Food insecurity was not associated with class membership, but differentially affected adiposity by HIV-exposure status.
Corresponding Author: Sera L. Young, 1819 Hinman Avenue, 1(847)467-2174, Evanston, Illinois 60208
Conflict of interest statement: The authors report no conflicts of interest
Sources of support: CL was supported by the Royster Society of Fellows. Data collection was supported by the Feed the Future Innovation Laboratory for Nutrition, which is funded by the United States Agency for International Development (USAID) and based at Tufts University (USAID OAA-L-10- 00006), and by a seed grant for collaborations between Cornell University and Weill Cornell Medical College faculty. EMW was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (K99/R00 HD086304), the National Institute of Diabetes and Digestive and Kidney Diseases (T32 DK091227 and T32 DK007559), and PepsiCo Global R+D (unrestricted grant to support research in maternal and child health). SLY was supported by the National Institute of Mental Health (K01 MH098902). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Mental Health or the National Institutes of Health.
Clinical trial registry: clinicaltrials.gov NCT02922829 and NCT02925429
Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.
Jenson, R. E., Baines, S. L., Howden, B. P., Mishra, N. N., Farah, S., Lew, C., Berti, A. D., Shukla, S. K., Bayer, A. S., Rose, W. E.
Daptomycin-nonsusceptible (DAP-NS) S. aureus often exhibit gain-in-function mutations in the mprF gene (involved in positive surface charge maintenance). Standard β-lactams, although relatively inactive against MRSA, may prevent emergence of mprF mutations and DAP-NS. We determined if β-lactams might also impact DAP-NS isolates already possessing an mprF mutation to revert them to DAP-susceptible (DAP-S) phenotypes, and if so, whether this is associated with specific penicillin-binding protein (PBP) targeting.This study included 25 DAP-S/DAP-NS isogenic, clinically-derived MRSA bloodstream isolates. MICs were performed to DAP; nafcillin (NAF; PBP-promiscuous), cloxacillin (LOX; PBP-1), ceftriaxone (CRO; PBP-2) and cefoxitin (FOX; PBP-4). Three DAP-NS isolates were selected for 28-day serial passage in subinhibitory β-lactams. DAP MICs and time-kill assays, host defense peptide (LL-37) susceptibilities and whole genome sequencing were performed to associate genetic changes to key phenotypic profiles.Pronounced decreases in baseline MICs were observed for NAF and LOX (but not for CRO or FOX) among DAP-NS vs DAP-S isolates ("see-saw" effect). Prolonged (28d) β-lactam passage of three DAP-NS isolates significantly reduced DAP MICs. LOX was most impactful (~16-fold decrease in DAP MIC; 2-to-0.125 mg/L). In these DAP-NS isolates with preexisting mprF polymorphisms, accumulation of additional mprF mutations occurred with prolonged LOX exposures. This was associated with enhanced LL-37 killing activity and reduced surface charge (both mprF-dependent phenotypes). β-lactams which either promiscuously or specifically target PBP-1 have significant DAP ‘re-sensitizing' effects against DAP-NS S. aureus strains. This may relate to acquisition of multiple mprF SNPs which, in turn, affect cell envelope function and metabolism.
Jessica E Manning, Fabiano Oliveira, Iliano V Coutinho-Abreu, Samantha Herbert, Claudio Meneses, Shaden Kamhawi, Holly Ann Baus, Alison Han, Lindsay Czajkowski, Luz Angela Rosas, Adriana Cervantes-Medina, Rani Athota, Susan Reed, Allyson Mateja, Sally Hunsberger, Emma James, Olga Pleguezuelos, Gregory Stoloff, Jesus G Valenzuela, Matthew J Memoli
AGS-v was well tolerated, and, when adjuvanted, immunogenic. These findings suggest that vector-targeted vaccine administration in humans is safe and could be a viable option for the increasing burden of vector-borne disease.
Peppa M, Thomas S, Minassian C, et al.
AbstractBackgroundAvailable evidence indicates that seasonal inactivated influenza vaccination during pregnancy protects both the mother and her newborn, and is safe. Nevertheless, ongoing safety assessments are important in sustaining vaccine uptake. Few studies have explored safety in relation to major congenital malformations, particularly in the first trimester when most organogenesis occurs.MethodsAnonymised UK primary care data (the Clinical Practice Research Datalink), including a recently developed Pregnancy Register, were used to identify live-born singletons delivered between 2010 and 2016. Maternal influenza vaccination was determined using primary care records and stratified by trimester. Ascertainment of major malformations from infant primary care records was maximized by linkage to hospitalization data and death certificates. The relationship between vaccination and major malformations recorded in the year after delivery and in early childhood was then assessed using multivariable Cox regression.ResultsA total of 78,150 live-birth pregnancies were identified: 6,872 (8.8%) were vaccinated in the first trimester, 11,678 (14.9%) in the second and 12,931 (16.5%) in the third. Overall, 5,707 live-births resulted in an infant with a major malformation recorded in the year after delivery and the adjusted hazard ratio when comparing first-trimester vaccination to no vaccination was 1.06 (99%CI, 0.94-1.19; p=0.2). Results were similar for second and third-trimester vaccination and for analyses considering major malformations recorded beyond the first birthday.ConclusionsIn this large, population-based historical cohort study there was no evidence to suggest that seasonal influenza vaccine was associated with major malformations when given in the first trimester or subsequently in pregnancy.
van der Weide, H., Cossio, U., Gracia, R., te Welscher, Y. M., ten Kate, M. T., van der Meijden, A., Marradi, M., Ritsema, J. A. S., Vermeulen-de Jongh, D. M. C., Storm, G., Goessens, W. H. F., Loinaz, I., van Nostrum, C. F., Llop, J., Hays, J. P., Bakker-Woudenberg, I. A. J. M.
Antimicrobial peptides (AMPs) have seen limited clinical use as antimicrobial agents, largely due to issues relating to toxicity, short biological half-life, and lack of efficacy against Gram-negative bacteria. However, the development of novel AMP-nanomedicines, i.e. AMPs entrapped in nanoparticles, has the potential to ameliorate these clinical problems. The authors investigated two novel nanomedicines based on AA139, an AMP currently in development for the treatment of multidrug-resistant Gram-negative infections. AA139 was entrapped in polymeric nanoparticles (PNP) or lipid-core micelles (MCL). The antimicrobial activity of AA139-PNP and AA139-MCL was determined in vitro. The biodistribution and limiting doses of AA139-nanomedicines were determined in uninfected rats via endotracheal aerosolization. The early bacterial killing activity of the AA139-nanomedicines in infected lungs was assessed in a rat model of pneumonia-septicemia caused by an extended-spectrum β-lactamase-producing Klebsiella pneumoniae. In this model, the therapeutic efficacy was determined by once-daily (q24h) administration over 10 days. Both AA139-nanomedicines showed equivalent in vitro antimicrobial activities (similar to free AA139) and in uninfected rats they exhibited longer residence times in the lungs compared to free AA139 (~20% longer for AA139-PNP and ~80% longer for AA139-MCL), as well as reduced toxicity enabling a higher limiting dose. In rats with pneumonia-septicemia, both AA139-nanomedicines showed significantly improved therapeutic efficacy in terms of an extended rat survival time, although survival of all rats was not achieved. These results demonstrate potential advantages that can be achieved using AMP-nanoformulations. AA139-PNP and AA139-MCL may be promising novel therapeutic agents for the treatment of patients suffering from multidrug-resistant Gram-negative pneumonia-septicemia.
Younis, U. S., Chu, H. W., Kraft, M., Ledford, J. G.
Human surfactant protein-A2 (SP-A2) is a component of pulmonary surfactant that plays an important role in the lung's immune system by interacting with viruses, bacteria and fungi to facilitate pathogen clearance, as well as downregulating inflammatory responses after an allergic challenge. Genetic variation in SP-A2 at position Gln223Lys is present in up to ~30% of the population and has been associated with several lung diseases, such as asthma, pulmonary fibrosis, and lung cancer (M.M. Pettigrew, et al., BMC Med Genet 8:15, 2007, DOI: 10.1186/1471-2350-8-15; Y. Wang, et al., Am J Hum Genet 84:52-59, 2009, DOI: 10.1016/j.ajhg.2008.11.010). Previous work performed by our group showed differences in SP-A binding to non-live mycoplasma membrane fraction, dependent on the presence of a lysine (K) or a glutamine (Q) at amino acid position 223 in the carbohydrate region of SP-A2. Based on these differences, we have derived 20-amino acid peptides flanking this region of interest in order to test the ability of each to regulate various immune responses to live M. pneumoniae (Mp) in SP-A knockout mice and RAW 264.7 cells. In both models, the 20-mer containing 223Q significantly decreased both TNF-α mRNA and protein levels in comparison to the 20-mer containing 223K during Mp infection. While neither 20-mer peptides (223Q and 223K) had an effect on p38 phosphorylation during Mp infection, the 223Q-20mer peptide significantly reduced NF-B p65 phosphorylation in both models. Taken together, our data suggests that small peptides derived from the lectin domain of SP-A2 that contain the major allelic variant (223Q) maintain activity in reducing TNF-α induction during Mp infection.
Mucormycosis is a serious and often fatal mycotic infection caused by members of class Mucormycetes in populations with immunologic or metabolic disorders. Though several clinical manifestations are associated with mucormycetes, gastrointestinal involvement is quite rare.
We described a rare case of invasive fungal infection due to Syncephalastrum racemosum associated with gastric adenocarcinoma in a 48-year-old male patient with type II Diabetes mellitus. He presented with complaints of abdominal pain, nausea, vomiting, dyspepsia, dysphagia, loss of appetite, and weight. Histopathological examination showed broad and aseptate hyphae and culture of endoscopic biopsy tissue from pylorus and antrum yielded the fungal pathogen S. racemosum. The species was confirmed by molecular sequencing of D1/D2 region of the ribosomal DNA. The in vitro susceptibility of S. racemosum was tested by broth microdilution assay as per CLSI guidelines. The MICs suggest that the isolate was susceptible to Amphotericin B (0.25 µg/ml), Itraconazole (0.25 µg/ml) and Posaconazole (0.06 µg/ml) and showed resistance to Micafungin (>16 µg/ml). The patient was successfully treated with radical subtotal gastrectomy with lymphadenectomy and Amphotericin B antifungal therapy. There was a dilemma in concluding the pathogenicity of the isolate since; the symptoms noted were common for both gastric adenocarcinoma and mucormycosis. A review of previously reported cases on Syncephalastrum was presented in the paper with their clinical manifestations, treatment, and outcome.
To the best of our knowledge, this is the first report from India on the gastrointestinal involvement of S. racemosum. Patients with immunocompromised status are more prone to mucormycotic infections, and any typical presentations should be carefully examined for their etiological agent, and appropriate species directed therapy would help in a better outcome.
Ziegler, Maja C.; Nelde, Annika; Weber, Jeffrey K.; Schreitmüller, Christian Marius; Martrus, Glòria; Huynh, Tien; Bunders, Madeleine J.; Lunemann, Sebastian; Stevanovic, Stefan; Zhou, Ruhong; Altfeld, Marcus
Viral infections influence intracellular peptide repertoires available for presentation by HLA-I. Alterations in HLA-I/peptide complexes can modulate binding of KIRs and thereby the function of NK cells. While multiple studies have provided evidence that HLA-I/KIR interactions play a role in HIV-1 disease progression, the consequence of HIV-1 infection for HLA-I/KIR interactions remain largely unknown.
We determined changes in HLA-I-presented peptides resulting from HIV-1 infection of primary human CD4+ T-cells and assessed the impact of changes in peptide repertoires on HLA-I/KIR interactions.
Liquid chromatography-coupled tandem mass spectrometry to identify HLA-I presented peptides, cell-based in vitro assays to evaluate functional consequences of alterations in immunopeptidome and atomistic molecular dynamics simulations to confirm experimental data.
A total of 583 peptides exclusively presented on HIV-1-infected cells were identified, of which only 1.4% represented HIV-1-derived peptides. Focusing on HLA-C*03:04/KIR2DL3 interactions, we observed that HLA-C*03:04-presented peptides derived from non-infected CD4+ T-cells mediated stronger binding of inhibitory KIR2DL3 than peptides derived from HIV-1-infected cells. Furthermore, the most abundant peptide presented by HLA-C*03:04 on non-infected CD4+ T-cells (VIYPARISL) mediated the strongest KIR2DL3-binding, while the most abundant peptide presented on HIV-1-infected cells (YAIQATETL) did not mediate KIR2DL3-binding. Molecular dynamics simulations of HLA-C*03:04/KIR2DL3 interactions in the context of these two peptides revealed that VIYPARISL significantly enhanced the HLA-C*03:04/peptide contact area to KIR2DL3 compared to YAIQATETL.
These data demonstrate that HIV-1 infection-induced changes in HLA-I-presented peptides can reduce engagement of inhibitory KIRs, providing a mechanism for enhanced activation of NK cells by virus-infected cells.
Correspondence to Marcus Altfeld, Heinrich-Pette-Institut, Leibniz-Institut für Experimentelle Virologie, Martinistraße 52, 20251 Hamburg. E-mail: email@example.com; Ruhong Zhou, Computational Biology Center IBM Thomas J. Watson Research Center, Yorktown Heights, NY 10598, USA. E-mail: firstname.lastname@example.org
Received 28 January, 2020
Revised 8 May, 2020
Accepted 19 May, 2020
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This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives 4.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0
Copyright © 2020 Wolters Kluwer Health, Inc.
M. Teresa Galán-Puchades
Christian Leborgne, Elena Barbon, Jeffrey M. Alexander, Hayley Hanby, Sandrine Delignat, Daniel M. Cohen, Fanny Collaud, Saghana Muraleetharan, Dan Lupo, Joseph Silverberg, Karen Huang, Laetitia van Wittengerghe, Béatrice Marolleau, Adeline Miranda, Anna Fabiano, Victoria Daventure, Heena Beck, Xavier M. Anguela, Giuseppe Ronzitti, Sean M. Armour, Sebastien Lacroix-Desmazes, Federico Mingozzi
Nature Medicine, Published online: 01 June 2020; doi:10.1038/s41591-020-0911-7An IgG-cleaving endopeptidase can degrade circulating anti-adeno-associated virus antibodies in mice and nonhuman primates in vivo, as well as in human plasma in vitro, offering a potential solution for a major hurdle in gene therapy.
Nicholas A. Ramirez, Asis Das, Hung Ton-That
Adhesive pili in Gram-positive bacteria represent a variety of extracellular multiprotein polymers that mediate bacterial colonization of specific host tissues and associated pathogenesis. Pili are assembled in two distinct but coupled steps, an orderly crosslinking of pilin monomers and subsequent anchoring of the polymer to peptidoglycan, catalyzed by two transpeptidase enzymes – the pilus-specific sortase and the housekeeping sortase. Here, we review this biphasic assembly mechanism based on studies of two prototypical models, the heterotrimeric pili in Corynebacterium diphtheriae and the heterodimeric pili in Actinomyces oris, highlighting some newly emerged basic paradigms.
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.
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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: email@example.com
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:firstname.lastname@example.org,email@example.com
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: firstname.lastname@example.org
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.
International AIDS Conference (AIDS) 2020
6.07.2020 - 10.07.2020
International Liver Congress (ILC) 2020
27.08.2020 - 29.08.2020
World Sepsis Day
Det 8. videnskabelige nationale møde om infektiøs endokarditis
International Congress for Tropical Medicine and Malaria (ICTMM) 2020
20.09.2020 - 24.09.2020
COVID-19 retningslinje (2020)
National handlingsplan for antibiotika til mennesker (2017)
Retningslinjer til sundhedsprofessionelle vedr. håndtering af infektion med zikavirus (2019)
Infections in Patients Colonized with Extended-Spectrum Beta-Lactamase-Producing Enterobacterales – a Retrospective Cohort Study
30.07.2020Clinical Infectious Diseases Advance Access
Zoonoses: beyond the human–animal–environment interface
Ambulatory management of primary spontaneous pneumothorax: when less is more
Surgery for benign prostatic obstruction
Investing in surgery: a value proposition for African leaders
Hvorfor anbefaler Professor Jens Lundgren artiklen"Dolutegravir plus Two Different Prodrugs of Tenofovir to Treat HIV."?
Hvorfor anbefaler Professor Troels Lillebæk artiklen"The global prevalence of latent tuberculosis: a systematic review and meta-analysis."?
Hvad tænker Professor Lars Østergaard om"Efficacy of antibiotic treatment in patients with chronic low back pain and Modic changes (the AIM study): double blind, randomised, placebo controlled, multicentre trial."?
Hvad mener Professor Thomas Benfield om artiklen"Oral versus Intravenous Antibiotics for Bone and Joint Infection."?
Hvad mener Professor Niels Obel om artiklen"Early, Goal-Directed Therapy for Septic Shock - A Patient-Level Meta-Analysis."?
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