Multigenic Control and Sex Bias in Host Susceptibility to Spore-Induced Pulmonary Anthrax in Mice

Microbial Pathogenesis Laboratory, Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0056, USA.
Infection and immunity (Impact Factor: 3.73). 05/2011; 79(8):3204-15. DOI: 10.1128/IAI.01389-10
Source: PubMed


Mechanisms underlying susceptibility to anthrax infection are unknown. Using a phylogenetically diverse panel of inbred mice and spores of Bacillus anthracis Ames, we investigated host susceptibility to pulmonary anthrax. Susceptibility profiles for survival time and organ pathogen load differed across strains, indicating distinct genetic controls. Tissue infection kinetics analysis showed greater systemic dissemination in susceptible DBA/2J (D) mice but a higher terminal bacterial load in resistant BALB/cJ (C) mice. Interestingly, the most resistant strains, C and C57BL/6J (B), demonstrated a sex bias for susceptibility. For example, BALB/cJ females had a significantly higher survival time and required 4-fold more spores for 100% mortality compared to BALB/cJ males. To identify genetic regions associated with differential susceptibility, survival time and extent of organ infection were assessed using mice derived from two susceptibility models: (i) BXD advanced recombinant inbred strains and (ii) F2 offspring generated from polar responding C and D strains. Genome-wide analysis of BXD strain survival identified linkage on chromosomes 5, 6, 9, 11, and 14. Quantitative trait locus (QTL) analysis of the C×DF2 population revealed a significant QTL (designated Rpai1 for resistance to pulmonary anthrax infection, locus 1) for survival time on chromosome 17 and also identified a chromosome 11 locus for lung pathogen burden. The striking difference between genome-wide linkage profiles for these two mouse models of anthrax susceptibility supports our hypothesis that these are multigenic traits. Our data provide the first evidence for a differential sex response to anthrax resistance and further highlight the unlikelihood of a single common genetic contribution for this response across strains.

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Available from: Jagjit S Yadav
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    • "Thus interval mapping for the identification of quantitative trait loci (QTL) is greatly expedited. The BXD lines have been used by researchers throughout the world in many diverse studies including those centered on the eye and nervous system (for example see [23]–[27]), as well as several infectious agents (for example [28]–[31]). The BXD family is one of the largest GRP, presently containing ∼160 lines of mice, each line of which is isogenic except for sex chromosomes. "
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