Allelic Variation on Murine Chromosome 11 Modifies Host Inflammatory Responses and Resistance to Bacillus anthracis

Jill K Terra,Amy Jenkins,Steven M Levine,Joel A Bozue,Chi-Lee Ho,Bryan France,Kenneth A Bradley,Ragini Bhargava,Susan L Welkos,Richard C Davis,Christopher K Cote,Calvin Pan,Aldons J Lusis,Margarete Mehrabian

doi:10.1371/journal.ppat.1002469

Abstract

Anthrax is a potentially fatal disease resulting from infection with Bacillus anthracis. The outcome of infection is influenced by pathogen-encoded virulence factors such as lethal toxin (LT), as well as by genetic variation within the host. To identify host genes controlling susceptibility to anthrax, a library of congenic mice consisting of strains with homozygous chromosomal segments from the LT-responsive CAST/Ei strain introgressed on a LT-resistant C57BL/6 (B6) background was screened for response to LT. Three congenic strains containing CAST/Ei regions of chromosome 11 were identified that displayed a rapid inflammatory response to LT similar to, but more severe than that driven by a LT-responsive allele of the inflammasome constituent NRLP1B. Importantly, increased response to LT in congenic mice correlated with greater resistance to infection by the Sterne strain of B. anthracis. The genomic region controlling the inflammatory response to LT was mapped to 66.36–74.67 Mb on chromosome 11, a region that encodes the LT-responsive CAST/Ei allele of Nlrp1b. However, known downstream effects of NLRP1B activation, including macrophage pyroptosis, cytokine release, and leukocyte infiltration could not fully explain the response to LT or the resistance to B. anthracis Sterne in congenic mice. Further, the exacerbated response in congenic mice is inherited in a recessive manner while the Nlrp1b-mediated response to LT is dominant. Finally, congenic mice displayed increased responsiveness in a model of sepsis compared with B6 mice. In total, these data suggest that allelic variation of one or more chromosome 11 genes in addition to Nlrp1b controls the severity of host response to multiple inflammatory stimuli and contributes to resistance to B. anthracis Sterne. Expression quantitative trait locus analysis revealed 25 genes within this region as high priority candidates for contributing to the host response to LT.

Highlights

Microbial pathogens have evolved various mechanisms to block host immune responses and thereby increase virulence
We show that genetic variation within an 8.3 Mb region on mouse chromosome 11 controls host response to anthrax lethal toxin (LT) and resistance to infection by the Sterne strain of Bacillus anthracis
CAST/Ei chromosome 11 encodes a dominant LT-responsive allele of Nlrp1b that may partially account for the severe response to LT

Summary

Introduction

Microbial pathogens have evolved various mechanisms to block host immune responses and thereby increase virulence. The MAP kinase (MAPK) signaling pathways have a central role in innate immune responses mounted by both plants and animals, and are common targets that are inactivated by a variety of bacterial toxins and effector molecules [1,2]. B. anthracis produces anthrax lethal toxin (LT), a bipartite toxin that contributes to immunosuppression and pathology in the host [3]. The catalytic moiety of anthrax LT, lethal factor (LF), is a zinc-dependent metalloprotease that cleaves the N-termini of MAPK kinases (MKKs). By inactivating MKKs, LT blocks production of proinflammatory chemokines and cytokines such as TNF-a and inhibits survival signals activated via downstream MAPKs [4,5,6,7,8,9,10,11]. LT-mediated cleavage of MKKs leads to the silencing of a pro-inflammatory response, effectively repressing host immunity and favoring bacterial survival [9,12,13]

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