Identification of a spike-specific CD8+ T cell epitope following vaccination against the Middle East respiratory syndrome coronavirus in humans.

Licensed vaccines against the Middle East respiratory syndrome coronavirus (MERS-CoV), an emerging pathogen of concern, are lacking. The Modified Vaccinia virus Ankara vector-based vaccine MVA-MERS-S, expressing the MERS-CoV-spike glycoprotein (MERS-S), is one of three candidate vaccines in clinical development and elicits robust humoral and cellular immunity. Here, we identified for the first time a MERS-S-specific CD8+ T-cell epitope in an HLA-A*03:01/HLA-B*35:01-positive vaccinee using a screening assay, intracellular cytokine staining, and in silico epitope prediction. As evidence from MERS-CoV infection suggests a protective role of long-lasting CD8+ T-cell responses, the identification of epitopes will facilitate longitudinal analyses of vaccine-induced T-cell immunity.

Suppression of epithelial proliferation and tumorigenesis by immunoglobulin A.

Immunoglobulin A (IgA) is the most abundant antibody isotype produced across mammals and plays a specialized role in mucosal homeostasis 1 . Constantly secreted into the lumen of the intestine, IgA binds commensal microbiota to regulate their colonization and function 2,3 , with unclear implications for health. IgA deficiency is common in humans but is difficult to study due to its complex etiology and comorbidities 4-8 . Using genetically and environmentally controlled mice, here we show that IgA-deficient animals have a baseline alteration in the colon epithelium that increases susceptibility to multiple models of colorectal cancer. Transcriptome, imaging, and flow cytometry-based analyses revealed that, in the absence of IgA, colonic epithelial cells induce antibacterial factors and accelerate cell cycling in response to the microbiota. Oral treatment with IgA was sufficient to suppress aberrant epithelial proliferation independently of bacterial binding, suggesting that IgA provides a feedback signal to epithelial cells in parallel with its known roles in microbiome shaping. In a primary colonic organoid culture system, IgA directly suppresses epithelial growth. Conversely, the susceptibility of IgA-deficient mice to colorectal cancer was reversed by Notch inhibition to suppress the absorptive colonocyte developmental program, or by inhibition of the cytokine MIF, the receptor for which was upregulated in stem cells of IgA-deficient animals. These studies demonstrate a homeostatic function for IgA in tempering physiological epithelial responses to microbiota to maintain mucosal health.

Defining the key intrahepatic gene networks in HCV infection driven by sex.

OBJECTIVE: The transcriptional response in the liver during HCV infection is critical for determining clinical outcomes. This issue remains relatively unexplored as tissue access to address this at scale is usually limited. We aimed to profile the transcriptomics of HCV-infected livers to describe the expression networks involved and assess the effect on them of major predictors of clinical outcome such as IFNL4 (interferon lambda 4) host genotype and sex. DESIGN: We took advantage of a large clinical study of HCV therapy accompanied by baseline liver biopsy to examine the drivers of transcription in tissue samples in 195 patients also genotyped genome-wide for host and viral single nucleotide polymorphisms. We addressed the role of host factors (disease status, sex, genotype, age) and viral factors (load, mutation) on transcriptional responses. RESULTS: We observe key modules of transcription which can be impacted differentially by host and viral factors. Underlying cirrhotic state had the most substantial impact, even in a stable, compensated population. Notably, sex had a major impact on antiviral responses in concert with IL28B (interleukin 28B)/IFNL4 genotype, with stronger interferon and humoral responses in females. Males tended towards a dominant cellular immune response. In both sexes, there was a strong influence of the underlying host disease status and of specific viral mutations, and sex-specific expression quantitative trait loci were also observed. CONCLUSION: These features help define the major influences on tissue responses in HCV infection, impacting on the response to treatment and with broader implications for responses in other sex-biased infections.