Sex-related differences in gene expression following Coxiella burnetii infection in mice: potential role of circadian rhythm

• Published in: PloS one Vol. 5; no. 8; p. e12190
• Main Authors: Textoris, Julien, Ban, Leang Heng, Capo, Christian, Raoult, Didier, Leone, Marc, Mege, Jean-Louis
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 13-08-2010; Public Library of Science (PLoS)
• Subjects: Analysis; Animals; Annotations; Anopheles; Autoantibodies; Autoimmunity; Bacteria; Bacterial infections; Bioinformatics; Castration; Cell adhesion; Cellular signal transduction; Circadian rhythm; Circadian Rhythm - genetics; Circadian rhythms; Clusters; Coxiella burnetii; Coxiella burnetii - physiology; Cystic fibrosis; Defensins; Disease susceptibility; DNA microarrays; Feedback loops; Female; Females; Fever; Gender differences; Gene expression; Gene Expression Profiling; Genes; Genetic research; Genomes; Genomics; Health aspects; Hepatitis; Hepatocytes; Hormones; Humans; Immunology/Immune Response; Infection; Infections; Infectious diseases; Infectious Diseases/Bacterial Infections; Interleukin 10; Intracellular Space - metabolism; Legionella; Liver; Male; Males; Mice; Mice, Inbred C57BL; Microbiology; Microbiology/Immunity to Infections; Multivariate analysis; Oligonucleotide Array Sequence Analysis; Physiology; Polymerase chain reaction; Principal components analysis; Protein Transport; Proteins; Pseudomonas aeruginosa; Q fever; Q Fever - genetics; Q Fever - pathology; Q Fever - physiopathology; Sex; Sex Characteristics; Sex differences; Sex hormones; Sexual dimorphism; Stat3 protein; Studies; Transcription factors; Transduction; Womens health; Zoonoses; France
• ISSN: 1932-6203; 1932-6203
• 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.
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.