Deficiencies in myeloid cell populations lead to increased sensitivity of females compared with males to Francisella tularensis infection

Abstract

Preliminary data demonstrated that a greater percentage of female mice infected with F. tularensis succumbed to disease and developed symptoms faster than male mice. Increases in the serum inflammatory cytokine levels corresponded to this enhanced sensitivity in females consistent with a stronger inflammatory. Herein, we sought to understand the cellular basis for this sex difference in the inflammatory response between males and females. We used a combination of in vivo and ex vivo cellular analysis to determine differences in the cellular response to F. tularensis. Multiparametric cytokine analysis was used to quantify changes in serum and supernatant cytokines, real-time RT-PCR was used to measure cytokine mRNA expression in tissues, and multiparametric flow cytometry was used to discriminate cell populations responsive to infection. Despite a tendency for fewer T regulatory (Treg) cells, males had fewer inflammatory macrophage and an increase in regulatory macrophages. This corresponded with an overall decrease in the transcripts of IL-10, IL-5, and IL-4 in the tissues of mice succumbing to disease and an increase in IL-6 transcripts, a marker for the level of inflammation. The functional deficiency of regulatory macrophages and increase of M1 macrophages may enhance the inflammatory response to F. tularensis ultimately leading to decreased survival. Further investigations will focus on understanding the interactions between these myeloid populations with F. tularensis and other cells of the immune system. Development of therapeutics that activate or induce expansion of regulatory macrophages or that suppress the activity/activation of M1 macrophages may prevent death from this disease.