Epidemiology of Coxiella burnetii infection in Africa: a OneHealth systematic review

Background: Q fever is a common cause of febrile illness and community-acquired pneumonia in resource-limited settings. Coxiella burnetii, the causative pathogen, is transmitted among varied host species, but the epidemiology of the organism in Africa is poorly understood. We conducted a systematic review of C. burnetii epidemiology in Africa from a “One Health” perspective to synthesize the published data and identify knowledge gaps.<p></p> Methods/Principal Findings: We searched nine databases to identify articles relevant to four key aspects of C. burnetii epidemiology in human and animal populations in Africa: infection prevalence; disease incidence; transmission risk factors; and infection control efforts. We identified 929 unique articles, 100 of which remained after full-text review. Of these, 41 articles describing 51 studies qualified for data extraction. Animal seroprevalence studies revealed infection by C. burnetii (≤13%) among cattle except for studies in Western and Middle Africa (18–55%). Small ruminant seroprevalence ranged from 11–33%. Human seroprevalence was <8% with the exception of studies among children and in Egypt (10–32%). Close contact with camels and rural residence were associated with increased seropositivity among humans. C. burnetii infection has been associated with livestock abortion. In human cohort studies, Q fever accounted for 2–9% of febrile illness hospitalizations and 1–3% of infective endocarditis cases. We found no studies of disease incidence estimates or disease control efforts.<p></p> Conclusions/Significance: C. burnetii infection is detected in humans and in a wide range of animal species across Africa, but seroprevalence varies widely by species and location. Risk factors underlying this variability are poorly understood as is the role of C. burnetii in livestock abortion. Q fever consistently accounts for a notable proportion of undifferentiated human febrile illness and infective endocarditis in cohort studies, but incidence estimates are lacking. C. burnetii presents a real yet underappreciated threat to human and animal health throughout Africa.<p></p&gt

Proceedings of a Sickle Cell Disease Ontology workshop - Towards the first comprehensive ontology for Sickle Cell Disease

Sickle cell disease (SCD) is a debilitating single gene disorder caused by a single point mutation that results in physical deformation (i.e. sickling) of erythrocytes at reduced oxygen tensions. Up to 75% of SCD in newborns world-wide occurs in sub-Saharan Africa, where neonatal and childhood mortality from sickle cell related complications is high. While SCD research across the globe is tackling the disease on multiple fronts, advances have yet to significantly impact on the health and quality of life of SCD patients, due to lack of coordination of these disparate efforts. Ensuring data across studies is directly comparable through standardization is a necessary step towards realizing this goal. Such a standardization requires the development and implementation of a disease-specific ontology for SCD that is applicable globally. Ontology development is best achieved by bringing together experts in the domain to contribute their knowledge. The SCD community and H3ABioNet members joined forces at a recent SCD Ontology workshop to develop an ontology covering aspects of SCD under the classes: phenotype, diagnostics, therapeutics, quality of life, disease modifiers and disease stage. The aim of the workshop was for participants to contribute their expertise to development of the structure and contents of the SCD ontology. Here we describe the proceedings of the Sickle Cell Disease Ontology Workshop held in Cape Town South Africa in February 2016 and its outcomes. The objective of the workshop was to bring together experts in SCD from around the world to contribute their expertise to the development of various aspects of the SCD ontology

Towards Machine Wald

The past century has seen a steady increase in the need of estimating and predicting complex systems and making (possibly critical) decisions with limited information. Although computers have made possible the numerical evaluation of sophisticated statistical models, these models are still designed \emph{by humans} because there is currently no known recipe or algorithm for dividing the design of a statistical model into a sequence of arithmetic operations. Indeed enabling computers to \emph{think} as \emph{humans} have the ability to do when faced with uncertainty is challenging in several major ways: (1) Finding optimal statistical models remains to be formulated as a well posed problem when information on the system of interest is incomplete and comes in the form of a complex combination of sample data, partial knowledge of constitutive relations and a limited description of the distribution of input random variables. (2) The space of admissible scenarios along with the space of relevant information, assumptions, and/or beliefs, tend to be infinite dimensional, whereas calculus on a computer is necessarily discrete and finite. With this purpose, this paper explores the foundations of a rigorous framework for the scientific computation of optimal statistical estimators/models and reviews their connections with Decision Theory, Machine Learning, Bayesian Inference, Stochastic Optimization, Robust Optimization, Optimal Uncertainty Quantification and Information Based Complexity.Comment: 37 page

Genome-wide analysis of ivermectin response by Onchocerca volvulus reveals that genetic drift and soft selective sweeps contribute to loss of drug sensitivity

Treatment of onchocerciasis using mass ivermectin administration has reduced morbidity and transmission throughout Africa and Central/South America. Mass drug administration is likely to exert selection pressure on parasites, and phenotypic and genetic changes in several Onchocerca volvulus populations from Cameroon and Ghana-exposed to more than a decade of regular ivermectin treatment-have raised concern that sub-optimal responses to ivermectin's anti-fecundity effect are becoming more frequent and may spread.Pooled next generation sequencing (Pool-seq) was used to characterise genetic diversity within and between 108 adult female worms differing in ivermectin treatment history and response. Genome-wide analyses revealed genetic variation that significantly differentiated good responder (GR) and sub-optimal responder (SOR) parasites. These variants were not randomly distributed but clustered in ~31 quantitative trait loci (QTLs), with little overlap in putative QTL position and gene content between the two countries. Published candidate ivermectin SOR genes were largely absent in these regions; QTLs differentiating GR and SOR worms were enriched for genes in molecular pathways associated with neurotransmission, development, and stress responses. Finally, single worm genotyping demonstrated that geographic isolation and genetic change over time (in the presence of drug exposure) had a significantly greater role in shaping genetic diversity than the evolution of SOR.This study is one of the first genome-wide association analyses in a parasitic nematode, and provides insight into the genomics of ivermectin response and population structure of O. volvulus. We argue that ivermectin response is a polygenically-determined quantitative trait (QT) whereby identical or related molecular pathways but not necessarily individual genes are likely to determine the extent of ivermectin response in different parasite populations. Furthermore, we propose that genetic drift rather than genetic selection of SOR is the underlying driver of population differentiation, which has significant implications for the emergence and potential spread of SOR within and between these parasite populations

Antimicrobial and toxicological activities of five medicinal plant species from Cameroon Traditional Medicine

<p>Abstract</p> <p>Background</p> <p>Infectious diseases caused by multiresistant microbial strains are on the increase. Fighting these diseases with natural products may be more efficacious. The aim of this study was to investigate the <it>in vitro </it>antimicrobial activity of methanolic, ethylacetate (EtOAc) and hexanic fractions of five Cameroonian medicinal plants (<it>Piptadeniastum africana</it>, <it>Cissus aralioides, Hileria latifolia, Phyllanthus muellerianus </it>and <it>Gladiolus gregasius) </it>against 10 pathogenic microorganisms of the urogenital and gastrointestinal tracts.</p> <p>Methods</p> <p>The fractions were screened for their chemical composition and <it>in vivo </it>acute toxicity was carried out on the most active extracts in order to assess their inhibitory selectivity.</p> <p>The agar well-diffusion and the micro dilution methods were used for the determination of the inhibition diameters (ID) and Minimum inhibitory concentrations (MIC) respectively on 8 bacterial species including two Gram positive species (<it>Staphylococcus aureus, Enterococcus faecalis)</it>, and six Gram negative <it>(Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Proteus mirabilis, Shigella flexneri, Salmonella typhi) </it>and two fungal isolates (<it>Candida albicans, Candida krusei)</it>. The chemical composition was done according to Harbone (1976), the acute toxicity evaluation according to WHO protocol and the hepatic as well as serum parameters measured to assess liver and kidney functions.</p> <p>Results</p> <p>The chemical components of each plant's extract varied according to the solvent used, and they were found to contain alkaloids, flavonoids, polyphenols, triterpens, sterols, tannins, coumarins, glycosides, cardiac glycosides and reducing sugars. The methanolic and ethylacetate extracts of <it>Phyllanthus muellerianus </it>and <it>Piptadeniastum africana </it>presented the highest antimicrobial activities against all tested microorganisms with ID varying from 8 to 26 mm and MIC from 2.5 to 0.31 mg/ml. The <it>in vivo </it>acute toxicity study carried out on the methanolic extracts of <it>Phyllanthus muellerianus </it>and <it>Piptadeniastrum africana </it>indicated that these two plants were not toxic. At the dose of 4 g/kg body weight, kidney and liver function tests indicated that these two medicinal plants induced no adverse effect on these organs.</p> <p>Conclusion</p> <p>These results showed that, all these plant's extracts can be used as antimicrobial phytomedicines which can be therapeutically used against infections caused by multiresistant agents.</p> <p>Phyllanthus muellerianus, Piptadeniastum africana, antimicrobial, acute toxicity, kidney and liver function tests, Cameroon Traditional Medicine</p

Major Depletion of Plasmacytoid Dendritic Cells in HIV-2 Infection, an Attenuated Form of HIV Disease

Plasmacytoid dendritic cells (pDC) provide an important link between innate and acquired immunity, mediating their action mainly through IFN-α production. pDC suppress HIV-1 replication, but there is increasing evidence suggesting they may also contribute to the increased levels of cell apoptosis and pan-immune activation associated with disease progression. Although having the same clinical spectrum, HIV-2 infection is characterized by a strikingly lower viremia and a much slower rate of CD4 decline and AIDS progression than HIV-1, irrespective of disease stage. We report here a similar marked reduction in circulating pDC levels in untreated HIV-1 and HIV-2 infections in association with CD4 depletion and T cell activation, in spite of the undetectable viremia found in the majority of HIV-2 patients. Moreover, the same overexpression of CD86 and PD-L1 on circulating pDC was found in both infections irrespective of disease stage or viremia status. Our observation that pDC depletion occurs in HIV-2 infected patients with undetectable viremia indicates that mechanisms other than direct viral infection determine the pDC depletion during persistent infections. However, viremia was associated with an impairment of IFN-α production on a per pDC basis upon TLR9 stimulation. These data support the possibility that diminished function in vitro may relate to prior activation by HIV virions in vivo, in agreement with our finding of higher expression levels of the IFN-α inducible gene, MxA, in HIV-1 than in HIV-2 individuals. Importantly, serum IFN-α levels were not elevated in HIV-2 infected individuals. In conclusion, our data in this unique natural model of “attenuated” HIV immunodeficiency contribute to the understanding of pDC biology in HIV/AIDS pathogenesis, showing that in the absence of detectable viremia a major depletion of circulating pDC in association with a relatively preserved IFN-α production does occur

HIV/SIV Infection Primes Monocytes and Dendritic Cells for Apoptosis

Subversion or exacerbation of antigen-presenting cells (APC) death modulates host/pathogen equilibrium. We demonstrated during in vitro differentiation of monocyte-derived macrophages and monocyte-derived dendritic cells (DCs) that HIV sensitizes the cells to undergo apoptosis in response to TRAIL and FasL, respectively. In addition, we found that HIV-1 increased the levels of pro-apoptotic Bax and Bak molecules and decreased the levels of anti-apoptotic Mcl-1 and FLIP proteins. To assess the relevance of these observations in the context of an experimental model of HIV infection, we investigated the death of APC during pathogenic SIV-infection in rhesus macaques (RMs). We demonstrated increased apoptosis, during the acute phase, of both peripheral blood DCs and monocytes (CD14+) from SIV+RMs, associated with a dysregulation in the balance of pro- and anti-apoptotic molecules. Caspase-inhibitor and death receptors antagonists prevented apoptosis of APCs from SIV+RMs. Furthermore, increased levels of FasL in the sera of pathogenic SIV+RMs were detected, compared to non-pathogenic SIV infection of African green monkey. We suggest that inappropriate apoptosis of antigen-presenting cells may contribute to dysregulation of cellular immunity early in the process of HIV/SIV infection

The macrophage in HIV-1 infection: From activation to deactivation?

Macrophages play a crucial role in innate and adaptative immunity in response to microorganisms and are an important cellular target during HIV-1 infection. Recently, the heterogeneity of the macrophage population has been highlighted. Classically activated or type 1 macrophages (M1) induced in particular by IFN-γ display a pro-inflammatory profile. The alternatively activated or type 2 macrophages (M2) induced by Th-2 cytokines, such as IL-4 and IL-13 express anti-inflammatory and tissue repair properties. Finally IL-10 has been described as the prototypic cytokine involved in the deactivation of macrophages (dM). Since the capacity of macrophages to support productive HIV-1 infection is known to be modulated by cytokines, this review shows how modulation of macrophage activation by cytokines impacts the capacity to support productive HIV-1 infection. Based on the activation status of macrophages we propose a model starting with M1 classically activated macrophages with accelerated formation of viral reservoirs in a context of Th1 and proinflammatory cytokines. Then IL-4/IL-13 alternatively activated M2 macrophages will enter into the game that will stop the expansion of the HIV-1 reservoir. Finally IL-10 deactivation of macrophages will lead to immune failure observed at the very late stages of the HIV-1 disease

Regulating STING in health and disease.

The presence of cytosolic double-stranded DNA molecules can trigger multiple innate immune signalling pathways which converge on the activation of an ER-resident innate immune adaptor named "STimulator of INterferon Genes (STING)". STING has been found to mediate type I interferon response downstream of cyclic dinucleotides and a number of DNA and RNA inducing signalling pathway. In addition to its physiological function, a rapidly increasing body of literature highlights the role for STING in human disease where variants of the STING proteins, as well as dysregulated STING signalling, have been implicated in a number of inflammatory diseases. This review will summarise the recent structural and functional findings of STING, and discuss how STING research has promoted the development of novel therapeutic approaches and experimental tools to improve treatment of tumour and autoimmune diseases