Prevalence, persistence, and genetics of antibody responses to protein toxins and virulence factors

Abstract

Microbial exposures are crucial environmental factors that impact healthspan by sculpting the immune system and microbiota. Antibody profiling via programmable Phage ImmunoPrecipitation Sequencing (PhIP-Seq) provides a high-throughput, cost-effective approach for multiplexed detection of exposure and response to thousands of microbial protein products. Here we designed and constructed a library of 95,601 56 amino acid peptide tiles spanning a subset of environmental proteins more likely to be associated with immune responses: those with "toxin" or "virulence factor" keyword annotations. PhIP-Seq was used to profile the circulating antibodies of ~1,000 individuals against this "ToxScan" library of 14,430 toxins and virulence factors from 1,312 genera of organisms. In addition to a detailed analysis of six commonly encountered human commensals and pathogens, we study the age-dependent stability of the ToxScan profile and use a genome-wide association study (GWAS) to find that the MHC-II locus modulates the selection of bacterial epitopes. We detect previously described anti-flagellin antibody responses in a Crohn's disease cohort and identify a novel association between anti-flagellin antibodies and juvenile dermatomyositis (JDM). PhIP-Seq with the ToxScan library provides a new window into exposure and immune responses to environmental protein toxins and virulence factors, which can be used to study human health and disease at cohort scale.

Phage display sequencing reveals that genetic, environmental, and intrinsic factors influence variation of human antibody epitope repertoire

“…21 Females also demonstrated increased enrichment of EBV and CMV peptides. Males showed a higher prevalence of antibody-bound peptides from Haemophilus influenzae bacteria (e.g., serotype Rd KW20 or strain 3179B), also as previously described, 55,56 and of several peptides derived from Streptococcus, Staphylococcus, Bacteroides, and alphaherpesviruses (including HSV-1 and varicella zoster virus).…”

In-depth characterization of the serum antibody epitope repertoire in inflammatory bowel disease using phage-displayed immunoprecipitation sequencing

“…Flagellins are dominant antigens and elicit strong IgG immune responses in CD (Lodes et al, 2004; Christmann et al, 2015). However, the exact nature of the antigens to which these responses are directed to is now gradually being uncovered, although not yet so comprehensively within a large cohort of patients with IBD (Angkeow et al, 2021). More specifically, we found many antibody responses against Lachnospiraceae flagellins (e.g.…”