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

Textoris J, Ban LH, Capo C, Raoult D, Leone M, Mege JL - PLoS ONE (2010)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: 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.

ABSTRACT

Background: 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.

Conclusion: 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.

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Related in: MedlinePlus

Impact of sex on C. burnetii infection.Male and female mice were infected with C. burnetii for 24 hours. Transcriptional responses were assessed by microarray. A, The impacts of sex and infection on gene expression were analyzed by principal component analysis using R. Each axis distance represents the amount of variance in gene expression explained by the corresponding factor (sex or infection). B, Hierarchical clustering analysis was used to classify selected up-regulated and down-regulated genes in four clusters: sex-independent genes, male-dependent genes, female-dependent genes and genes inversely modulated in males and females (red vertical bar).
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pone-0012190-g001: Impact of sex on C. burnetii infection.Male and female mice were infected with C. burnetii for 24 hours. Transcriptional responses were assessed by microarray. A, The impacts of sex and infection on gene expression were analyzed by principal component analysis using R. Each axis distance represents the amount of variance in gene expression explained by the corresponding factor (sex or infection). B, Hierarchical clustering analysis was used to classify selected up-regulated and down-regulated genes in four clusters: sex-independent genes, male-dependent genes, female-dependent genes and genes inversely modulated in males and females (red vertical bar).

Mentions: Mice were infected with C. burnetii for 24 hours, and changes in gene expression were investigated in liver cells. C. burnetii infection generated more transcriptional changes in males than in females. When samples were plotted according to the weight of variances due to sex and infection, principal component analysis (PCA) clearly discriminated males and females and revealed that the distance between uninfected and infected males was higher than that found between uninfected and infected females (Fig. 1A). A multiclass analysis identified 2,777 probes that were modulated in response to C. burnetii. These probes were classified into four distinct clusters (Fig. 1B). The first cluster is sex-independent and includes 398 probes (14% of the total) that were similarly regulated in both males and females. The other three clusters, representing the majority of probes modulated by C. burnetii infection (86% of the total), are sex-dependent: 1,459 probes (53%) were specifically modulated in males whereas 892 (32%) were specifically modulated in females. The fourth cluster of 28 probes is divergent between males and females, with 14 probes up-regulated in males and 14 up-regulated in females (for the list, see Table S1). Using in silico analysis, we related the modulated genes to the subcellular distribution of their encoded proteins (Fig. 2). In infected males, the modulated genes encode proteins that have a high degree of interconnection. These interactions spread across the membrane, underlying that a profound reorganization occurred at the membrane after infection. In infected females, there were less interactions between proteins encoded by modulated genes at the membrane level than in males, but the interconnection between the cytosol and the nucleus was apparently more developed. These results highlight important changes in transcription in male and female mice infected with C. burnetii.


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

Textoris J, Ban LH, Capo C, Raoult D, Leone M, Mege JL - PLoS ONE (2010)

Impact of sex on C. burnetii infection.Male and female mice were infected with C. burnetii for 24 hours. Transcriptional responses were assessed by microarray. A, The impacts of sex and infection on gene expression were analyzed by principal component analysis using R. Each axis distance represents the amount of variance in gene expression explained by the corresponding factor (sex or infection). B, Hierarchical clustering analysis was used to classify selected up-regulated and down-regulated genes in four clusters: sex-independent genes, male-dependent genes, female-dependent genes and genes inversely modulated in males and females (red vertical bar).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2921390&req=5

pone-0012190-g001: Impact of sex on C. burnetii infection.Male and female mice were infected with C. burnetii for 24 hours. Transcriptional responses were assessed by microarray. A, The impacts of sex and infection on gene expression were analyzed by principal component analysis using R. Each axis distance represents the amount of variance in gene expression explained by the corresponding factor (sex or infection). B, Hierarchical clustering analysis was used to classify selected up-regulated and down-regulated genes in four clusters: sex-independent genes, male-dependent genes, female-dependent genes and genes inversely modulated in males and females (red vertical bar).
Mentions: Mice were infected with C. burnetii for 24 hours, and changes in gene expression were investigated in liver cells. C. burnetii infection generated more transcriptional changes in males than in females. When samples were plotted according to the weight of variances due to sex and infection, principal component analysis (PCA) clearly discriminated males and females and revealed that the distance between uninfected and infected males was higher than that found between uninfected and infected females (Fig. 1A). A multiclass analysis identified 2,777 probes that were modulated in response to C. burnetii. These probes were classified into four distinct clusters (Fig. 1B). The first cluster is sex-independent and includes 398 probes (14% of the total) that were similarly regulated in both males and females. The other three clusters, representing the majority of probes modulated by C. burnetii infection (86% of the total), are sex-dependent: 1,459 probes (53%) were specifically modulated in males whereas 892 (32%) were specifically modulated in females. The fourth cluster of 28 probes is divergent between males and females, with 14 probes up-regulated in males and 14 up-regulated in females (for the list, see Table S1). Using in silico analysis, we related the modulated genes to the subcellular distribution of their encoded proteins (Fig. 2). In infected males, the modulated genes encode proteins that have a high degree of interconnection. These interactions spread across the membrane, underlying that a profound reorganization occurred at the membrane after infection. In infected females, there were less interactions between proteins encoded by modulated genes at the membrane level than in males, but the interconnection between the cytosol and the nucleus was apparently more developed. These results highlight important changes in transcription in male and female mice infected with C. burnetii.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: 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.

ABSTRACT

Background: 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.

Conclusion: 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.

Show MeSH
Related in: MedlinePlus