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

Abstract

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. Genomewide 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.Anthrax is one of the most ancient and lethal human diseases caused by the virulent (toxigenic and encapsulated) strains of Bacillus anthracis. In humans, anthrax may take three forms depending upon the route of infection, namely, pulmonary (inhalational), cutaneous, and gastrointestinal, with pulmonary being the most lethal and difficult to treat. While the naturally acquired pulmonary anthrax is relatively rare (occurring only ϳ5% as often as cutaneous anthrax), this form has a high potential for misuse as a weapon of bioterrorism, considering that environmental dissemination is the most expected mode of release of the agent in mass attacks (26). Pulmonary anthrax often proves fatal, with mortality approaching 100% if not treated early. Anthrax spores have long been considered a potential agent of biological warfare (25, 50, 58). Prior to the 11 cases of pulmonary anthrax that occurred via the U.S. mail delivery system in 2001 (29), fatal cases of pulmonary anthrax in the United States and other countries have been associated with occupational and accidental exposures (37,60). But the bioterrorism attack in 2001 exposed a new cause for serious concern for future and more widespread attacks on military and civilian populations.The ...

Genetic susceptibility to toxicologic lung responses among inbred mouse strains following exposure to carbon nanotubes and profiling of underlying gene networks

“…DBA/2 mice have been found to be susceptible to lung infections which include influenza (Trammell et al, 2012), Mycobacterium tuberculosis (Cardona et al, 2003), Pseudomonas aeruginosa (Gosselin et al, 1995), and Bacillus anthracis (Yadav et al, 2011). In models of hypersensitivity pneumonitis, C57Bl/ 6 mice are sensitive to lung disease while DBA/2 are resistant, and differential cytokine expression (chiefly IL-12) is shown to be the determining factor (Gudmundsson et al, 1998).…”

A Parent-of-Origin Effect Determines the Susceptibility of a Non-Informative F1 Population to Trypanosoma cruzi Infection In Vivo

“…Host genetic traits that are determined or influenced by gender have been previously identified in diverse murine models of infective diseases [33], [34], [35], [36]. For protozoan parasites such as Plasmodium chabaudi, sex-biased hormonal differences are an important factor influencing host susceptibility [37], [38], [39].…”

Genetic Control of Survival and Weight Loss during Pneumonic Burkholderia pseudomallei (Bp) Infection

“…Another study revealed that differential susceptibility to group A Steptococci is also controlled by a single host genetic locus [122]. In contrast, a study by Yadav and colleagues [121] and the present study revealed that susceptibility to the bacterial pathogens Yersina pestis and Bp, respectively, involve multiple host loci. In fact, the only clear similarity between these two studies was that two of the weaker QTLs involved in susceptibility to Yersinia overlap with the QTL on chromosome 5 that was identified in the current studies on Bp.…”

“…These findings are not surprising in light of findings that genetic factors play a key role in susceptibility to a wide range of other infectious diseases. Published findings have identified host genetic factors that are critical for variable susceptibility to intracellular parasites [115], viruses [116][117][118][119][120], and both intracellular [74,100,121] and extracellular [122] bacterial pathogens. Moreover, recent genome-wide studies have established novel associations between common polymorphisms and susceptibility to several infectious diseases that are responsible for significant morbidity and/or mortality in humans [73,100,123,124].…”