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

PLoS Pathogens

Susan L. Welkos¹  Christopher K. Cote¹  Amy Jenkins¹  Joel A. Bozue¹  Calvin Pan²  Richard C. Davis²  Margarete Mehrabian²  Kenneth A. Bradley³  Steven M. LeVine³  Chi-Lee Ho⁴  Jill K. Terra⁴  Ragini Bhargava⁴  Bryan France⁴  Aldons J. Lusis⁴ 

[1] Bacteriology Division, U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Frederick, Maryland, United States of America;Department of Human Genetics, University of California at Los Angeles, Los Angeles, California, United States of America;Department of Medicine, University of California at Los Angeles, Los Angeles, California, United States of America;Department of Microbiology, Immunology, and Molecular Genetics, University of California at Los Angeles, Los Angeles, California, United States of America

关键词: Cytokines;    Bacillus anthracis;    Inflammation;    Ataxia;    Bacterial spores;    Macrophages;    Toxins;    Alleles;   

DOI  :  10.1371/journal.ppat.1002469

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY