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Zika virus (ZIKV) infections have re-emerged as a global health issue due to serious clinical complications. Development of specific serological assays to detect and differentiate ZIKV from other co-circulating flaviviruses for accurate diagnosis remains a challenge.
STING is a key cytosolic receptor for small nucleotides and plays a key role in anti-cancer and antiviral immunity. Cyclic dinucleotide STING agonists may comprise a novel class of vaccine adjuvants capable of inducing cellular immune responses and protective efficacy against intracellular pathogens.
Enterotoxigenic Escherichia coli (ETEC) commonly cause diarrhea in children living in developing countries and in travelers' to those regions. ETEC are characterized by colonization factors (CFs) that mediate intestinal adherence. We assessed if bovine colostral IgG (bIgG) antibodies against one CF, CS17, or antibodies against CsbD, the minor tip subunit of CS17, would protect subjects against diarrhea following challenge with a CS17-expressing ETEC strain.
Metabolic complications relating to complex effects of viral and immune mediated mechanisms are now a focus of clinical care among persons living with HIV (PWH) and obesity is emerging as a critical problem. To address knowledge gaps, the NIH sponsored a symposium in May 2018 entitled "Obesity and Fat Metabolism in HIV-infected Individuals." Mechanisms relating to adipose dysfunction and fibrosis, immune function, inflammation, and gastrointestinal integrity were highlighted as contributors to obesity among...
Cryptosporidiosis, an enteric protozoon, causes substantial morbidity and mortality associated with diarrhea in children 75% of diarrhea reported in these children.
Conventional antibiotics have cured more diseases than all other drug classes combined. However, the pipeline of novel antibiotics is running dry while multi-drug resistance (MDR) is increasing at an alarming rate. Even though vaccines and antibodies are part of the toolkit against antimicrobial resistance, broadening the concept of 'antibiotic' is essential for innovation. Original roadmaps are needed to tackle the overwhelming MDR bacterial infections. The majority of 'in-use' antibacterial drugs derived ...
Pitting, the removal of dead parasites from their host erythrocyte, has been studied in patients with severe malaria treated parenterally with quinine or artesunate, and was recently shown to contribute to delayed hemolysis, a frequent adverse event of artesunate. We quantified pitting in 81 travelers treated with oral antimalarial therapy. Pitting rate was high (55.8%) with artemisinin-based combinations, but lower than 10% with the non-artemisinin drugs quinine, mefloquine and atovaquone-proguanil. This m...
Infection-induced thrombocytosis is a clinically important complication of tuberculosis infection. Recent studies have highlighted the utility of aspirin as a host-directed therapy modulating the inflammatory response to infection, but have not investigated the possibility that the effect of aspirin is related to an anti-platelet mode of action.
Understanding Multidrug-resistant tuberculosis cases not detected by rapid phenotypic and genotypic routine clinical tests is essential to improve diagnostics and advance towards personalized TB treatments. Here, we combine WGS with single-colony phenotyping testing to diagnose a MDR strain infecting a patient over nine years. Our investigation revealed the failure of rapid testing assays and genome-based prediction tools to identify the MDR strain. The false negative outcome was caused by uncommon RIF and ...
There is no vaccine or approved therapy against lethal Ebola virus (EBOV). We investigated a proven technology platform to produce polyclonal IgG fragments, F(ab')2, against EBOV. Horses immunized with nanoparticles harboring surface glycoprotein trimers of EBOV-Zaire/Makona produced anti-Ebola IgG polyclonal antibodies with high neutralization activity. Highly purified equine anti-Ebola F(ab')2 showed strong cross-neutralization of 2 Zaire EBOV strains (Gabon 2001 and Makona) and in vivo 3 or 5 daily F(ab'...
Plasmodium malariae is considered a 'minor' malaria parasite, although its global disease burden is underappreciated. The aim of this study was to develop an induced blood stage malaria (IBSM) model of P. malariae to study parasite biology, diagnostics, and treatment.
Little is known about the effects of life-long HIV or antiretroviral therapy on hepatic steatosis and fibrosis. Using transient elastography, we evaluated 46 young adults with life-long HIV and 20 matched HIV-negative controls. Steatosis was present in 33% of persons living with HIV and only 10% of controls (p=0.04). Hepatic fibrosis scores were not elevated and did not differ between groups. Metabolic parameters, particularly increased waist circumference, and not HIV-specific factors, were significantly a...
Pneumonia constitutes a substantial disease burden among adults overall and those who are elderly. We aimed to identify all studies investigating the disease burden among older adults (age, ≥65 years) admitted to the hospital with pneumonia. We estimated the hospital admission rate and in-hospital case-fatality ratio (CFR) of pneumonia in older adults, stratified by age and economic status (industrialized vs developing), with data from a systematic review of studies published from 1996 through 2017 and fr...
Acute respiratory tract infections (ARI) constitute a substantial disease burden in adults and elderly individuals. We aimed to identify all case-control studies investigating the potential role of respiratory viruses in the etiology of ARI in older adults aged ≥65 years. We conducted a systematic literature review (across 7 databases) of case-control studies published from 1996 to 2017 that investigated the viral profile of older adults with and those without ARI. We then computed a pooled odds ratio (OR...
Therapeutic strategies for achieving sustained virologic remission are being explored in HIV-infected individuals who began antiretroviral therapy (ART) during the early phase of infection. In the evaluation of such therapies, clinical protocols should include analytical treatment interruption (ATI); however, the immunologic and virologic impact of ATI in early-treated individuals has not been fully delineated. We demonstrate that ATI causes neither expansion of HIV reservoirs nor immunologic abnormalities ...
Estimation of temporal changes in HIV transmission patterns can help to elucidate the impact of preventative strategies and public health policies.
During the 2014 West-African outbreak, Ebola vaccine development was accelerated. The Phase 1 VAC52150EBL1003 study was performed to investigate 2-dose heterologous vaccination with Ad26.ZEBOV, MVA-BN-Filo in an African population located in a high-altitude setting in Nairobi, Kenya.
Ebola vaccine development was accelerated in response to the 2014 Ebola virus outbreak. This Phase 1 study (VAC52150EBL1004) assessed safety, tolerability, and immunogenicity of heterologous prime-boost Ad26.ZEBOV, MVA-BN-Filo vaccination regimens in the Lake Victoria Basin of Tanzania and Uganda in mid-level altitude, malarial-endemic settings.
Control of visceral leishmaniasis (VL) caused by Leishmania donovani requires IFNγ production by CD4+ T cells. In VL patients, anti-parasitic CD4+ T cell responses are ineffective for unknown reasons. In this study, we measured the expression of genes associated with various immune functions in these cells from VL patients and compared them to CD4+ T cells from the same patients after drug treatment and from endemic controls. We found reduced GATA3, RORC and FOXP3 gene expression in VL patient CD4+ T cells...
We analyzed the virulence of pandemic H1N1 2009 influenza A viruses in vivo and in vitro. Selected viruses isolated in 2009, 2010, 2014, and 2015 were assessed using an aerosol-mediated high-dose infection model for pigs as well as air-liquid interface cultures of differentiated airway epithelial cells. Using a dyspnea score, rectal temperature, lung lesions, and viral load in the lung as parameters, the strains from 2014-2015 were significantly less virulent than the strains isolated in 2009-2010. In vitro...
Scale-up of direct-acting antiviral(DAA) therapy is expected to abate HCV incidence among HIV-positive men-who-have-sex-with-men(MSM). Treatment programs in neighbouring countries may influence each other's outcomes through international transmission. We aimed at classifying HCV infections in HIV-positive MSM as either domestically or internationally acquired, and at estimating how this classification changed over time.
In 2015-2016, a Zika virus (ZIKV) outbreak occurred in the Americas. In 2017, we conducted a ZIKV serosurvey in Suriname in which 770 participants were recruited from one urban area and two rural villages in the tropical rainforest. All collected samples were tested for presence of ZIKV antibodies using a ZIKV IgG ELISA and a virus neutralisation assay. We found that 35.1% of the participants had neutralizing antibodies against ZIKV. In one remote village in the rainforest, 24.5% of the participants had neu...
Metformin, the most widely administered diabetes drug, has been proposed as a candidate adjunctive host-directed therapy for tuberculosis, but little is known about its effects on human host responses to Mycobacterium tuberculosis.
The Mycobacterium tuberculosis lineage 4 strains CDC1551 and H37Rv develop tolerance to multiple antibiotics upon macrophage residence. To determine whether macrophage-induced tolerance is a general feature of clinical M. tuberculosis isolates, we assessed macrophage-induced drug tolerance in strains from lineages 1-3, representing the other predominant M. tuberculosis strains responsible for tuberculosis globally. All 3 lineages developed isoniazid tolerance. While lineage 1, 3, and 4 strains developed rif...