A crowdsourced analysis to identify ab initio molecular signatures predictive of susceptibility to viral infection

The response to respiratory viruses varies substantially between individuals, and there are currently no known molecular predictors from the early stages of infection. Here we conduct a community-based analysis to determine whether pre- or early post-exposure molecular factors could predict physiologic responses to viral exposure. Using peripheral blood gene expression profiles collected from healthy subjects prior to exposure to one of four respiratory viruses (H1N1, H3N2, Rhinovirus, and RSV), as well as up to 24 h following exposure, we find that it is possible to construct models predictive of symptomatic response using profiles even prior to viral exposure. Analysis of predictive gene features reveal little overlap among models; however, in aggregate, these genes are enriched for common pathways. Heme metabolism, the most significantly enriched pathway, is associated with a higher risk of developing symptoms following viral exposure. This study demonstrates that pre-exposure molecular predictors can be identified and improves our understanding of the mechanisms of response to respiratory viruses

Microbiota epitope similarity either dampens or enhances the immunogenicity of disease-associated antigenic epitopes

<div><p>The microbiome influences adaptive immunity and molecular mimicry influences T cell reactivity. Here, we evaluated whether the sequence similarity of various antigens to the microbiota dampens or increases immunogenicity of T cell epitopes. Sets of epitopes and control sequences derived from 38 antigenic categories (infectious pathogens, allergens, autoantigens) were retrieved from the Immune Epitope Database (IEDB). Their similarity to microbiome sequences was calculated using the BLOSUM62 matrix. We found that sequence similarity was associated with either dampened (tolerogenic; e.g. most allergens) or increased (inflammatory; e.g. Dengue and West Nile viruses) likelihood of a peptide being immunogenic as a function of epitope source category. Ten-fold cross-validation and validation using sets of manually curated epitopes and non-epitopes derived from allergens were used to confirm these initial observations. Furthermore, the genus from which the microbiome homologous sequences were derived influenced whether a tolerogenic versus inflammatory modulatory effect was observed, with <i>Fusobacterium</i> most associated with inflammatory influences and <i>Bacteroides</i> most associated with tolerogenic influences. We validated these effects using PBMCs stimulated with various sets of microbiome peptides. “Tolerogenic” microbiome peptides elicited IL-10 production, “inflammatory” peptides elicited mixed IL-10/IFNγ production, while microbiome epitopes homologous to self were completely unreactive for both cytokines. We also tested the sequence similarity of cockroach epitopes to specific microbiome sequences derived from households of cockroach allergic individuals and non-allergic controls. Microbiomes from cockroach allergic households were less likely to contain sequences homologous to previously defined cockroach allergens. These results are compatible with the hypothesis that microbiome sequences may contribute to the tolerization of T cells for allergen epitopes, and lack of these sequences might conversely be associated with increased likelihood of T cell reactivity against the cockroach epitopes. Taken together this study suggests that microbiome sequence similarity influences immune reactivity to homologous epitopes encoded by pathogens, allergens and auto-antigens.</p></div

HLA class II restricted T cell epitopes vary in similarity to human microbiome sequences.

<p>Epitope (black) and non-epitope (red) maximum BLOSUM score per individual peptide are shown for the <i>Aspergillus</i> (A) and Gluten (B) epitope categories. Median ± interquartile range are shown for each distribution.</p

Microbiome peptides homologous to dominant epitopes are associated with constitutive IL-10 production.

<p>(A) Combined responses to microbiome derived epitopes for the inflammatory (blue) and tolerogenic (red). (B, C) Combined response to self, pathogen and microbiome derived epitopes for (B) IL-10 and (C) IFNγ. Response is expressed as fold above background. Each dot represents one donor/category combination. IFNγ (dots) and IL-10 (squares). Median ± interquartile range is shown. Two-tailed Mann-Whitney, *, p≤0.05, **, p≤0.01.</p

Tolerogenic versus inflammatory categories.

<p>Tolerogenic versus inflammatory categories.</p

List of epitopes and non-epitopes per category.

<p>List of epitopes and non-epitopes per category.</p

Genera found to be enriched in the inflammatory and tolerogenic categories and overall.

<p>Genera found to be enriched in the inflammatory and tolerogenic categories and overall.</p