Differences in the M1 and M2 macrophage subtypes between the sexes determine susceptibility to Francisella tularensis infection

Abstract

Abstract Francisella tularensis is the causative agent of the human disease tularemia. F. tularensis infects a variety of cells, including macrophages, in order to cause pathogenicity. As few as 10 inhaled microorganisms cause a lethal infection by over-activating the host’s own inflammatory response. Differences in the intensity of the inflammatory response exist between the sexes which leads to differences in sensitivity to autoimmune and infectious disease. Males tend to be more susceptible to infectious diseases whereas females tend to be more susceptible to autoimmune diseases. However, our preliminary data unexpectedly demonstrated that female mice were more susceptible to F. tularensis--mediated disease than male mice. We hypothesized that female macrophages respond to F. tularensis infection by generating a more intense inflammatory response which makes females more susceptible to F. tularensis. Indeed, female mice infected with F. tularensis generate significantly more inflammatory M1 macrophages compared to male mice. Furthermore, naïve M1 and M2 macrophages were infected in vitro to directly compare cellular responses between male and female mice. On a per cell basis, M1 macrophages from female mice generated a more robust inflammatory response compared with M1 macrophages from male mice. This suggests that M1 macrophages from females respond more strongly to infection resulting in the heightened inflammatory response.