Unité de Recherche sur les Maladies Infectieuses Tropicales et Emergentes, Centre National de la Recherche Scientifique Unité Mixte de Recherche 6236, Faculté de Médecine, Marseille, France.
PLoS One. 2010 Aug 13;5(8):e12190. doi: 10.1371/journal.pone.0012190.
Q 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 FINDINGS: Mice 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.
This 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.
Q 热是一种由贝氏柯克斯体感染引起的动物源性疾病，表现出性别二态性；在相同暴露条件下，男性比女性更容易且更严重地受到感染。在这里，我们探讨了小鼠中贝氏柯克斯体感染的严重程度是否与雄性和雌性基因表达谱的差异有关。
方法/主要发现：用贝氏柯克斯体感染小鼠 24 小时，用微阵列测量肝细胞中的基因表达。多类分析确定了 2777 个探针，其表达受 C. burnetii 感染特异性调节。只有 14%的调节基因不受性别影响，其余 86%的基因在雄性和雌性中表达不同。对雄性和雌性进行去势实验表明，性激素负责超过 60%的观察到的基因调节，而这种减少在雄性中最为明显。使用调节基因的功能注释，我们确定了在雄性中富集的四个与细胞-细胞粘附、信号转导、防御素和细胞因子/Jak-Stat 途径相关的基因簇。IL-10 和 Stat-3 基因的上调可能解释了 Q 热男性对 C. burnetii 感染和自身抗体产生的高易感性。在雌性中确定了两个基因簇，包括昼夜节律途径，它由一个反馈环的正（Clock、Arntl）和负（Per）臂组成。我们发现 Clock 和 Arntl 下调，而 Per 上调；这些变化可能与雌性中有效的细菌消除有关，但与雄性不同，雄性中突出的是过度的宿主反应。
这项大规模研究首次揭示了昼夜节律在小鼠抗感染反应中起着重要作用，并为阐明人类感染中的性别二态性提供了新的依据。
