Strains of bacterial species induce a greatly varied acute adaptive immune response: The contribution of the accessory genome

Abstract

A fundamental question in human susceptibility to bacterial infections is to what extent variability is a function of differences in the pathogen species or in individual humans. To focus on the pathogen species, we compared in the same individual the human adaptive T and B cell immune response to multiple strains of two major human pathogens, Staphylococcus aureus and Streptococcus pyogenes. We found wide variability in the acute adaptive immune response induced by various strains of a species, with a unique combination of activation within the two arms of the adaptive response. Further, this was also accompanied by a dramatic difference in the intensity of the specific protective T helper (Th) response. Importantly, the same immune response differences induced by the individual strains were maintained across multiple healthy human donors. A comparison of isogenic phage KO strains, demonstrated that of the pangenome, prophages were the major contributor to inter-strain immune heterogeneity, as the T cell response to the remaining “core genome” was noticeably blunted. Therefore, these findings extend and modify the notion of an adaptive response to a pathogenic bacterium, by implying that the adaptive immune response signature of a bacterial species should be defined either per strain or alternatively to the species’ ‘core genome’, common to all of its strains. Further, our results demonstrate that the acquired immune response variation is as wide among different strains within a single pathogenic species as it is among different humans, and therefore may explain in part the clinical heterogeneity observed in patients infected with the same species.

Strategies for understanding dynamic, personalized profiles of host-derived proteins and microbes from human stool

“…Data from both stool proteins and the microbiota will be more informative than either alone. Some microbial strains have shown to be inflammatory in one subject and benign in another subject (28). Perhaps by analyzing the microbes and proteins in complement, the health insights obtained from both the stool proteome and microbiome can provide a fuller picture for health status.…”

The role of the microbiome in nonhealing diabetic wounds

“…Strains of a single species are divergent across their pangenome, resulting in distinct phenotypes corresponding to severity of pathogenesis. This has been demonstrated in vitro , different strains of S. aureus and Streptococcus pyogenes elicited widely different adapted immune responses in healthy human donor cells . For patients with a DFU, strain variability could affect the structure of microbial communities via genes specific to modulating interactions with other members of the microbiome, and/or formation of stable biofilms in the wound tissue niche.…”

“…This has been demonstrated in vitro, different strains of S. aureus and Streptococcus pyogenes elicited widely different adapted immune responses in healthy human donor cells. 64 For patients with a DFU, strain variability could affect the structure of microbial communities via genes specific to modulating interactions with other members of the microbiome, and/or formation of stable biofilms in the wound tissue niche. Understanding the processes contributing to this variation could lead to novel biomarkers and antimicrobial targets, as well as the ability to decipher between colonization and infection, as heralded by the formation of a biofilm.…”

Complete genome screening of clinical MRSA isolates identifies lineage diversity and provides full resolution of transmission and outbreak events

“…In addition to lineage and outbreak analysis, WGS has furthered our understanding of S. aureus pathogenicity by delineating virulence and drug resistance determinants (Mwangi et al 2007; Benson et al 2014) , including those related to adaptation to the hospital environment (Senn et al 2016;Mwangi et al 2007) . Many of these elements are found in non-conserved 'accessory' genome elements that include endogenous prophages, mobile genetic element (MGE), and plasmids (Lindsay and Holden 2004;Sela et al 2018) . The repetitive nature of many of these elements means that they are often fragmented and/or incompletely represented in most WGS studies to date due to limitations of commonly used short-read sequencing technologies, curbing insights into their evolution (Sela et al 2018) .…”

“…Many of these elements are found in non-conserved 'accessory' genome elements that include endogenous prophages, mobile genetic element (MGE), and plasmids (Lindsay and Holden 2004;Sela et al 2018) . The repetitive nature of many of these elements means that they are often fragmented and/or incompletely represented in most WGS studies to date due to limitations of commonly used short-read sequencing technologies, curbing insights into their evolution (Sela et al 2018) . Recent advances in throughput of long-read sequencing technologies now enable routine assembly of complete genomes (Chin et al 2013;Madoui et al 2015) and analysis of core and accessory genome elements (Benson et al 2014;Altman et al 2014) , including DNA methylation patterns (Fang et al 2012) , but these technologies have not yet been widely used for prospective MRSA surveillance.…”