The hepatitis C virus (HCV; genus Hepacivirus) is a highly relevant human pathogen. Unique hepaciviruses (HV) were discovered recently in animal hosts. The direct ancestor of HCV has not been found, but the genetically most closely related animal HVs exist in horses. To investigate whether other peridomestic animals also carry HVs, we analyzed sera from Ghanaian cattle for HVs by reverse transcription-PCR (RT-PCR). Nine of 106 specimens from different sampling sites contained HV RNA (8.5%) at median viral loads of 1.6 ؋ 10 5 copies/ml. Infection seemed unrelated to cattle age and gender. Near-full-genome sequencing of five representative viruses confirmed taxonomic classifications. Cattle HVs formed two distinct phylogenetic lineages that differed by up to 17.7% on the nucleotide level in the polyprotein-encoding region, suggesting cocirculation of different virus subtypes. A conserved microRNA122-binding site in the 5= internal ribosomal entry site suggested liver tropism of cattle HVs. Phylogenetic analyses suggested the circulation of HVs in cattle for several centuries. Cattle HVs were genetically highly divergent from all other HVs, including HCV. HVs from genetically related equine and bovine hosts were not monophyletic, corroborating host shifts during the evolution of the genus Hepacivirus. Similar to equine HVs, the genetic diversity of cattle HVs was low compared to that of HCV genotypes. This suggests an influence of the human-modified ecology of peridomestic animals on virus diversity. Further studies should investigate the occurrence of cattle HVs in other geographic areas and breeds, virus pathogenicity in cattle, and the potential exposure of human risk groups, such as farmers, butchers, and abattoir workers. IMPORTANCEHCV (genus Hepacivirus) is a major human pathogen, causing liver failure and cancer. Unique hepaciviruses (HVs) were discovered over the last few years in animals, but the direct ancestor of HCV has not been found. The animal HV most closely related to HCV so far originated from horses, suggesting that other livestock animals also harbor HVs. Therefore, we investigated African cattle and discovered previously unknown HVs at high prevalence and viral loads. Because of the agricultural importance of cattle, it may be relevant to investigate HV pathogenicity. The frequent exposure of humans to cattle also may warrant investigations of the zoonotic potential of these viruses. Evolutionary analyses suggested that cattle HVs have existed for centuries. Despite the genetic relatedness of their animal hosts, HVs from cattle and horses were not phylogenetically related, corroborating frequent host shifts during the evolution of the genus Hepacivirus.

T-cells critically contribute to protection against Mycobacterium tuberculosis infection, and impaired T-cell responses can lead to disease progression. Pro-inflammatory and immunosuppressive cytokines affect T-cells, and fine-tuned regulation of cytokine signaling via the Jak/STAT signaling pathways is crucial for appropriate T-cell function. Constitutive STAT3 phosphorylation as a consequence of aberrant cytokine signaling has been described to occur in pathognomonic T-cell responses in inflammatory and autoimmune diseases. We characterized blood samples from tuberculosis patients (n=28) and healthy contacts (n=28) from Ghana for M. tuberculosis-specific T-cell responses, constitutive cytokine production, and SOCS3 and pSTAT3 expression. Lentiviral modulation of primary CD4 T-cells was performed to determine the effects of SOCS3 on T-cell functions. T-cells from tuberculosis patients expressed higher levels of IL-10 and IL-6 and lower levels of T helper type (T)17 cytokines after M. tuberculosis-specific stimulation compared to healthy contacts. In addition, tuberculosis patients had higher IL-10 and IL-6 levels in the supernatants of non-stimulated immune cells and plasma samples compared to healthy contacts. Notably, aberrant cytokine expression was accompanied by high constitutive pSTAT3 levels and SOCS3 expression in T-cells. Multivariate analysis identified an IL-6/IL-10 co-expression-based principal component in tuberculosis patients that correlated with high pSTAT3 levels. SOCS3 contributed to a regulatory component, and tuberculosis patients with high SOCS3 expression showed decreased T1 cytokine expression and impaired IL-2-induced STAT5 phosphorylation. SOCS3 over-expression in primary CD4 T-cells confirmed the SOCS3 inhibitory function on IL-2-induced STAT5 phosphorylation. We conclude that constitutive pSTAT3 and high SOCS3 expression are influential factors that indicate impaired T-cell functions in tuberculosis patients.Cellular and Molecular Immunology advance online publication, 19 March 2018; doi:10.1038/cmi.2018.5.

T-cell proliferation and generation of protective memory during chronic infections depend on Interleukin-7 (IL-7) availability and receptivity. Regulation of IL-7 receptor (IL-7R) expression and signalling are key for IL-7-modulated T-cell functions. Aberrant expression of soluble (s) and membrane-associated (m) IL-7R molecules is associated with development of autoimmunity and immune failure in acquired immune deficiency syndrome (AIDS) patients. Here we investigated the role of IL-7/IL-7R on T-cell immunity in human tuberculosis. We performed two independent case-control studies comparing tuberculosis patients and healthy contacts. This was combined with follow-up examinations for a subgroup of tuberculosis patients under therapy and recovery. Blood plasma and T cells were characterised for IL-7/sIL-7R and mIL-7R expression, respectively. IL-7-dependent T-cell functions were determined by analysing STAT5 phosphorylation, antigen-specific cytokine release and by analysing markers of T-cell exhaustion and inflammation. Tuberculosis patients had lower soluble IL-7R (p < 0.001) and higher IL-7 (p < 0.001) plasma concentrations as compared to healthy contacts. Both markers were largely independent and aberrant expression normalised during therapy and recovery. Furthermore, tuberculosis patients had lower levels of mIL-7R in T cells caused by post-transcriptional mechanisms. Functional in vitro tests indicated diminished IL-7-induced STAT5 phosphorylation and impaired IL-7-promoted cytokine release of Mycobacterium tuberculosis-specific CD4+ T cells from tuberculosis patients. Finally, we determined T-cell exhaustion markers PD-1 and SOCS3 and detected increased SOCS3 expression during therapy. Only moderate correlation of PD-1 and SOCS3 with IL-7 expression was observed. We conclude that diminished soluble IL-7R and increased IL-7 plasma concentrations, as well as decreased membrane-associated IL-7R expression in T cells, reflect impaired T-cell sensitivity to IL-7 in tuberculosis patients. These findings show similarities to pathognomonic features of impaired T-cell functions and immune failure described in AIDS patients.

Bats have been implicated as reservoirs of emerging viruses. Bat species forming large social groups and roosting in proximity to human communities are of particular interest. In this study, we sampled a colony of ca. 350,000 individuals of the straw-colored fruit bat Eidolon helvum in Kumasi, the second largest city of Ghana. A novel rhabdovirus (Kumasi rhabdovirus [KRV]) was isolated in E. helvum cell cultures and passaged to Vero cells as well as interferon-competent human and primate cells (A549 and MA104). Genome composition was typical for a rhabdovirus. KRV was detected in 5.1% of 487 animals, showing association with the spleen but not the brain. Antibody prevalence was 11.5% by immunofluorescence and 6.4% by plaque reduction virus neutralization test (PRNT). Detection throughout 3 sampling years was pronounced in both annual wet seasons, of which only one overlaps the postparturition season. Juvenile bats showed increased viral prevalence. No evidence of infection was obtained in 1,240 female mosquitos (6 different genera) trapped in proximity to the colony to investigate potential vector association. Antibodies were found in 28.9% (5.4% by PRNT) of 107 swine sera but not in similarly large collections of sheep, goat, or cattle sera. The antibody detection rate in human subjects with occupational exposure to the bat colony was 11% (5/45 persons), which was significantly higher than in unexposed adults (0.8% [1/118]; chi square, P < 0.001). KRV is a novel bat-associated rhabdovirus potentially transmitted to humans and swine. Disease associations should be investigated. IMPORTANCEBats are thought to carry a huge number of as-yet-undiscovered viruses that may pose epidemic threats to humans and livestock. Here we describe a novel dimarhabdovirus which we isolated from a large colony of the straw-colored fruit bat Eidolon helvum in Ghana. As these animals are exposed to humans and several livestock species, we looked for antibodies indicating infection in humans, cattle, swine, sheep, and goats. Signs of infection were found in swine and humans, with increased antibody findings in humans who are occupationally exposed to the bat colony. Our data suggest that it is worthwhile to look for diseases caused by the novel virus in humans and livestock.T he recognition of novel and emerging viral diseases requires knowledge of potential viral reservoirs. Small mammals may constitute important sources of novel viruses for humans and mammalian livestock. We and others have identified considerable diversities of reservoir-borne viruses, including paramyxoviruses, coronaviruses, filoviruses, lyssaviruses, hepaciviruses, and hepadnaviruses, in small mammals such as rodents and bats. Reservoirborne viruses typically show a larger genetic diversity than their counterparts in other hosts, including humans and livestock (1-4). Small mammals have certain properties that promote viral maintenance, diversification, and spread, such as high population turnover in the case of rodents or large sizes and densities of soci...