Antimicrobial stewardship in the era of the COVID-19 pandemic : A systematic review protocol on the opportunities and challenges for Sub-Saharan Africa

Background: Antimicrobial resistance (AMR) remains one of the leading threats to global public health and this may increase following COVID-19 pandemic. This is particularly the case in Africa where regulations on antimicrobial usage are weak. This protocol outlines the steps to undertake a systematic review to synthesize evidence on drivers of AMR and evaluate existing approaches to strengthening antimicrobial stewardship (AMS) programs in Sub-Saharan Africa (SSA). On the basis of the evidence generated from the evidence synthesis, the overarching goal of this work is to provide recommendations to support best practices in AMS implementation in SSA. Methods: A systematic search will be conducted using the following databases: Global Health Library, PubMed, Cumulative Index to Nursing and Allied Health Literature, Scopus, Google Scholar, Global Health, Embase, African Journals Online Library, Web of Science, antimicrobial databases (WHO COVID-19, TrACSS, NDARO, and JPIAMR), and the Cochrane databases for systematic reviews. Studies will be included if they assess AMR and AMS in SSA from January 2000 to January 31, 2023. Results: The primary outcomes will include the drivers of AMR and approaches to AMS implementation in SSA. The Preferred Reporting Items for Systematic Reviews and Meta-analyses will guide the reporting of this systematic review. Conclusions: The findings are expected to provide evidence on best practices and resource sharing for policy consideration to healthcare providers and other stakeholders both at the local and international levels. Additionally, the study seeks to establish drivers specific to AMR during the COVID-19 era in the SSA, for example, with the observed increasing trend of antimicrobial misuse during the first or second year of the pandemic may provide valuable insights for policy recommendation in preparedness and response measures to future pandemics. PROSPERO registration number: CRD42022368853.publishedVersionPeer reviewe

Clinical Signs and Blood Test Results Among Humans Infected With Zoonotic Simian Foamy Virus: A Case-Control Study

International audienceBackground. A spillover of simian foamy virus (SFV) to humans, following bites from infected nonhuman primates (NHPs), is ongoing in exposed populations. These retroviruses establish persistent infections of unknown physiological consequences to the human host. Methods. We performed a case-control study to compare 24 Cameroonian hunters infected with gorilla SFV and 24 controls matched for age and ethnicity. A complete physical examination and blood test were performed for all participants. Logistic regression and Wilcoxon signed rank tests were used to compare cases and controls. Results. The cases had significantly lower levels of hemoglobin than the controls (median, 12.7 vs 14.4 g/dL; P = .01). Basophil levels were also significantly lower in cases than controls, with no differences for other leukocyte subsets. Cases had significantly higher urea, creatinine, protein, creatinine phosphokinase, and lactate dehydrogenase levels and lower bilirubin levels than controls. Cases and controls had similar frequencies of general, cutaneous, gastrointestinal, neurological, and cardiorespiratory signs. Conclusions. The first case-control study of apparently healthy SFV-infected Cameroonian hunters showed the presence of hematological abnormalities. A thorough clinical and laboratory workup is now needed to establish the medical relevance of these observations because more than half of cases had mild or moderate anemia. Clinical Trials Registration. NCT03225794

Case-control study of the immune status of humans infected with zoonotic gorilla simian foamy viruses

This work was presented at the 26th conference on retroviruses and opportunistic infections (CROI) held in Seattle in 2019.International audienceBackground. Zoonotic simian foamy viruses (SFVs) establish persistent infections in humans, for whom the long-term consequences for health are poorly described. Here, we aimed to characterize blood-cell phenotypes and plasma biomarkers associated with gorilla SFV infection in humans. Methods. We used a case-control design to compare 15 Cameroonian hunters infected with gorilla SFV to 15 controls matched for age and ethnicity. A flow cytometry-based phenotypic study and quantification of soluble immune biomarkers were carried out on blood samples from all participants. Wilcoxon signed rank tests were used to compare cases and controls. Results. Cases had a significantly higher percentage of CD8 T lymphocytes than controls (median: 17.6% vs. 13.7%, P = 0.03), but similar levels of B, NK, and CD4 T lymphocytes. Cases also had a lower proportion of recent CD4 thymic emigrants (10.9% vs. 18.6%, P = 0.05), a higher proportion of programmed death receptor 1 (PD-1) expressing memory CD4 T lymphocytes (31.7% vs. 24.7%, P = 0.001), and higher plasma levels of the soluble CD163 scavenger receptor (0.84 vs 0.59 µg/mL, P = 0.003) than controls. Conclusions. We show, for the first time, that chronic infection with SFV is associated with T lymphocyte differentiation and monocyte activation

Plasma antibodies from humans infected with zoonotic simian foamy virus do not inhibit cell-to-cell transmission of the virus despite binding to the surface of infected cells

International audienceZoonotic simian foamy viruses (SFV) establish lifelong infection in their human hosts. Despite repeated transmission of SFV from nonhuman primates to humans, neither transmission between human hosts nor severe clinical manifestations have been reported. We aim to study the immune responses elicited by chronic infection with this retrovirus and previously reported that SFV-infected individuals generate potent neutralizing antibodies that block cell infection by viral particles. Here, we assessed whether human plasma antibodies block SFV cell-to-cell transmission and present the first description of cell-to-cell spreading of zoonotic gorilla SFV. We set-up a microtitration assay to quantify the ability of plasma samples from 20 Central African individuals infected with gorilla SFV and 9 uninfected controls to block cell-associated transmission of zoonotic gorilla SFV strains. We used flow-based cell cytometry and fluorescence microscopy to study envelope protein (Env) localization and the capacity of plasma antibodies to bind to infected cells. We visualized the cell-to-cell spread of SFV by real-time live imaging of a GFP-expressing prototype foamy virus (CI-PFV) strain. None of the samples neutralized cell-associated SFV infection, despite the inhibition of cell-free virus. We detected gorilla SFV Env in the perinuclear region, cytoplasmic vesicles and at the cell surface. We found that plasma antibodies bind to Env located at the surface of cells infected with primary gorilla SFV strains. Extracellular labeling of SFV proteins by human plasma samples showed patchy staining at the base of the cell and dense continuous staining at the cell apex, as well as staining in the intercellular connections that formed when previously connected cells separated from each other. In conclusion, SFV-specific antibodies from infected humans do not block cell-to-cell transmission, at least in vitro , despite their capacity to bind to the surface of infected cells

Epidemiological Evidence of Nosocomial and Zoonotic Transmission of Human T-Cell Leukemia Virus-1 in a Large Survey in a Rural Population of Central Africa

International audienceBackgroundCentral Africa is one of the largest areas of high endemicity for human T-cell leukemia virus-1 (HTLV-1). However, no preventive measures are yet implemented to reduce its transmission, which can be sexual, from mother-to-child, or through contaminated blood products. Rare zoonotic transmissions from nonhuman primates (NHPs) have also been reported in this region. Here we investigated the HTLV-1 prevalence and associated risk factors in a rural population in Cameroon.MethodsFrom 2019 to 2021, we performed a cross-sectional survey in the eastern region of Cameroon. HTLV-1 infection was first screened by ELISA, then tested by western blot and envelope gene targeted polymerase chain reaction. Risk factors associated with HTLV-1 infection were identified by logistic regression in univariable and multivariable analyses.ResultsAmong 3400 participants, HTLV-1 prevalence was 1.1% (95% confidence interval [CI], .7–1.5). Factors independently associated with HTLV-1 infection were Pygmy ethnicity (adjusted odd ratio [aOR], 2.9; 95% CI, 1.3–6.2), history of surgery (aOR, 6.3; 95% CI, 2.2–17.8), and NHP bite (aOR, 6.6; 95% CI, 2.2–19.8).ConclusionsThese results suggest both iatrogenic and zoonotic transmission of HTLV-1 in Cameroon. Further studies are needed to assess the risk of nosocomial transmission of HTLV-1, to guide public health authorities in implementing preventive measures to control HTLV-1 transmission

Neutralization of zoonotic retroviruses by human antibodies: Genotype-specific epitopes within the receptor-binding domain from simian foamy virus.

Infection with viruses of animal origin pose a significant threat to human populations. Simian foamy viruses (SFVs) are frequently transmitted to humans, in which they establish a life-long infection, with the persistence of replication-competent virus. However, zoonotic SFVs do not induce severe disease nor are they transmitted between humans. Thus, SFVs represent a model of zoonotic retroviruses that lead to a chronic infection successfully controlled by the human immune system. We previously showed that infected humans develop potent neutralizing antibodies (nAbs). Within the viral envelope (Env), the surface protein (SU) carries a variable region that defines two genotypes, overlaps with the receptor binding domain (RBD), and is the exclusive target of nAbs. However, its antigenic determinants are not understood. Here, we characterized nAbs present in plasma samples from SFV-infected individuals living in Central Africa. Neutralization assays were carried out in the presence of recombinant SU that compete with SU at the surface of viral vector particles. We defined the regions targeted by the nAbs using mutant SU proteins modified at the glycosylation sites, RBD functional subregions, and genotype-specific sequences that present properties of B-cell epitopes. We observed that nAbs target conformational epitopes. We identified three major epitopic regions: the loops at the apex of the RBD, which likely mediate interactions between Env protomers to form Env trimers, a loop located in the vicinity of the heparan binding site, and a region proximal to the highly conserved glycosylation site N8. We provide information on how nAbs specific for each of the two viral genotypes target different epitopes. Two common immune escape mechanisms, sequence variation and glycan shielding, were not observed. We propose a model according to which the neutralization mechanisms rely on the nAbs to block the Env conformational change and/or interfere with binding to susceptible cells. As the SFV RBD is structurally different from known retroviral RBDs, our data provide fundamental knowledge on the structural basis for the inhibition of viruses by nAbs. Trial registration: The study was registered at www.clinicaltrials.gov: https://clinicaltrials.gov/ct2/show/NCT03225794/