Sex-Related Differences in Gene Expression Following Coxiella burnetii Infection in Mice: Potential Role of Circadian Rhythm

Abstract

BackgroundQ fever, a zoonosis due to Coxiella burnetii infection, exhibits sexual dimorphism; men are affected more frequently and severely than women for a given exposure. Here we explore whether the severity of C. burnetii infection in mice is related to differences in male and female gene expression profiles.Methodology/Principal FindingsMice were infected with C. burnetii for 24 hours, and gene expression was measured in liver cells using microarrays. Multiclass analysis identified 2,777 probes for which expression was specifically modulated by C. burnetti infection. Only 14% of the modulated genes were sex-independent, and the remaining 86% were differentially expressed in males and females. Castration of males and females showed that sex hormones were responsible for more than 60% of the observed gene modulation, and this reduction was most pronounced in males. Using functional annotation of modulated genes, we identified four clusters enriched in males that were related to cell-cell adhesion, signal transduction, defensins and cytokine/Jak-Stat pathways. Up-regulation of the IL-10 and Stat-3 genes may account for the high susceptibility of men with Q fever to C. burnetii infection and autoantibody production. Two clusters were identified in females, including the circadian rhythm pathway, which consists of positive (Clock, Arntl) and negative (Per) limbs of a feedback loop. We found that Clock and Arntl were down-modulated whereas Per was up-regulated; these changes may be associated with efficient bacterial elimination in females but not in males, in which an exacerbated host response would be prominent.ConclusionThis large-scale study revealed for the first time that circadian rhythm plays a major role in the anti-infectious response of mice, and it provides a new basis for elucidating the role of sexual dimorphism in human infections.

Coxiella burnetii in Rodents on Heixiazi Island at the Sino-Russian Border

“…In a human-based study, 3 it was found that sex was related with C. burnetii infection, where men were 2.5 times more likely to be infected with the pathogen than women; the same result was also reported in mice in a laboratory-based study. 16 However, the results of our study were different; no significant association was found between C. burnetii infection and sex in wild rodents.…”

“…However, it is difficult to compare these findings with those reported in other works, which present information on the presence of antibodies to C. burnetii in rodents. [13][14][15][16] The statistical results showed that weight was associated with C. burnetii infection, possibly because larger rodents become matured and move widely and have more chances to be infected with C. burnetii. The reason for the association between month of capture and C. burnetii infection may be the temperature differences between months.…”

Effect of Sex Steroids on Babesia microti Infection in Mice

“…[31][32][33][34][35][36] Males generally exhibit lower immune responses than females. 22,31,37 The phagocytic activity of macrophages and production of inflammatory cytokines are higher in females than in males.…”

Early sex-specific modulation of the molecular clock in trauma

“…10Y12 We recently found that Coxiella burnetii infection is associated with sex-specific modulation of the CLOCK, ARNTL, and PER2 genes. 12,13 It is unclear whether these changes are related to the presence of bacteria or to the development of an inflammatory response. We hypothesized that the sex-related modulation of these genes is not restricted to Q fever but may be induced by the inflammatory response, independent of infection.…”