Dual RNA-Seq of Human Leprosy Lesions Identifies Bacterial Determinants Linked to Host Immune Response

Summary To understand how the interaction between an intracellular bacterium and the host immune system contributes to outcome at the site of infection, we studied leprosy, a disease that forms a clinical spectrum, in which progressive infection by the intracellular bacterium Mycobacterium leprae is characterized by the production of type I IFNs and antibody production. Dual RNA-seq on patient lesions identifies two independent molecular measures of M. leprae, each of which correlates with distinct aspects of the host immune response. The fraction of bacterial transcripts, reflecting bacterial burden, correlates with a host type I IFN gene signature, known to inhibit antimicrobial responses. Second, the bacterial mRNA:rRNA ratio, reflecting bacterial viability, links bacterial heat shock proteins with the BAFF-BCMA host antibody response pathway. Our findings provide a platform for the interrogation of host and pathogen transcriptomes at the site of infection, allowing insight into mechanisms of inflammation in human disease

Hepatitis E virus infection in patients with acute non-A, non-B, non-C hepatitis in Central Brazil

Hepatitis E virus (HEV) infection has a worldwide distribution and represents an important cause of acute hepatitis. This study aims to investigate the occurrence of HEV infection and factors associated with this infection in patients with acute non-A, non-B, non-C hepatitis in Central Brazil. From April 2012 to October 2014, a cross-sectional study was conducted among 379 patients with acute non-A, non-B, non-C hepatitis in the City of Goiania, Central Brazil. Serum samples of all patients were tested for serological markers of HEV infection (anti-HEV IgM and IgG) by ELISA. Positive samples were confirmed using immunoblot test. Anti-HEV IgM and IgG positive samples were tested for HEV RNA. Of the 379 serum samples, one (0.3%) and 20 (5.3%) were positive for anti-HEV IgM and IgG, respectively. HEV RNA was not found in any sample positive for IgM and/or IgG anti-HEV. After multivariate analysis, low education level was independently associated with HEV seropositivity (p = 0.005), as well as living in rural area, with a borderline p-value (p = 0.056). In conclusion, HEV may be responsible for sporadic self-limited cases of acute hepatitis in Central Brazil

IL-27 Suppresses Antimicrobial Activity in Human Leprosy

The mechanisms by which intracellular pathogens trigger immunosuppressive pathways are critical for understanding the pathogenesis of microbial infection. One pathway that inhibits host defense responses involves the induction of type I interferons and subsequently IL-10, yet the mechanism by which type I IFN induces IL-10 remains unclear. Our studies of gene expression profiles derived from leprosy skin lesions suggested a link between IL-27 and the IFN-β induced IL-10 pathway. Here, we demonstrate that the IL-27p28 subunit is upregulated following treatment of monocytes with IFN-β and Mycobacterium leprae, the intracellular bacterium that causes leprosy. The ability of IFN-β and M. leprae to induce IL-10 was diminished by IL-27 knockdown. Additionally, treatment of monocytes with recombinant IL-27 was sufficient to induce the production of IL-10. Functionally, IL-27 inhibited the ability of IFN-γ to trigger antimicrobial activity against M. leprae in infected monocytes. At the site of disease, IL-27 was more strongly expressed in skin lesions of patients with progressive lepromatous leprosy, correlating and colocalizing with IFN-β and IL-10 in macrophages. Together, these data provide evidence that in the human cutaneous immune responses to microbial infection, IL-27 contributes to the suppression of host antimicrobial responses

Comparison of molecular signatures from multiple skin diseases identifies mechanisms of immunopathogenesis

The ability to obtain gene expression profiles from human disease specimens provides an opportunity to identify relevant gene pathways, but is limited by the absence of data sets spanning a broad range of conditions. Here, we analyzed publicly available microarray data from 16 diverse skin conditions in order to gain insight into disease pathogenesis. Unsupervised hierarchical clustering separated samples by disease as well as common cellular and molecular pathways. Disease-specific signatures were leveraged to build a multi-disease classifier, which predicted the diagnosis of publicly and prospectively collected expression profiles with 93% accuracy. In one sample, the molecular classifier differed from the initial clinical diagnosis and correctly predicted the eventual diagnosis as the clinical presentation evolved. Finally, integration of IFN-regulated gene programs with the skin database revealed a significant inverse correlation between IFN-β and IFN-γ programs across all conditions. Our study provides an integrative approach to the study of gene signatures from multiple skin conditions, elucidating mechanisms of disease pathogenesis. In addition, these studies provide a framework for developing tools for personalized medicine toward the precise prediction, prevention, and treatment of disease on an individual level

Prevalence of hepatitis C Virus infection among hemophiliacs in Central Brazil

In order to investigate the hepatitis C virus (HCV) infection prevalence and risk factors in hemophiliacs in Central Brazil, 90 patients were interviewed and serum samples tested for HCV RNA and anti-HCV antibodies. An overall prevalence of 63.3% (CI 95%: 53.0-72.7) was found. Multivariate analysis of risk factors showed that number of blood transfusions was significantly associated with this infection. Most hemophiliacs received locally produced cryoprecipitate. All infected patients were transfused before the screening of blood units for anti-HCV. However, hemophiliacs who received exclusively screened cryoprecipitate were HCV negative. It confirms the expected decline in transfusion-acquired hepatitis C