Brucella abortus and pregnancy in mice: impact of chronic infection 1 ion on fertility and the role of regulatory T cells in tissue colonization.

Stealthy intracellular bacterial pathogens are known to establish persistent and sometimes life-long infections. Some of these pathogens also have a tropism for the reproductive system thereby increasing the risk of reproductive disease and infertility. To date, the pathogenic mechanism involved remains poorly understood. Here, we demonstrate that Brucella abortus, a notorious reproductive pathogen, has the ability to infect non-pregnant uterus, sustain infection, and induce inflammatory changes during both acute and chronic stages of infection. In addition, we demonstrated that chronically infected mice had significantly reduced number of pregnancies compared to naive controls. To investigate the immunologic mechanism responsible for uterine tropism, we explored the role of regulatory T cells (Tregs) in the pathogenesis of Brucella abortus infection. We show that highly suppressive CD4+FOXP3+TNFR2+ Tregs contribute to the persistence of Brucella abortus infection and that inactivation of Tregs with TNFR2 antagonistic antibody protected mice by significantly reducing bacterial burden both systemically and within reproductive tissues. These findings support a critical role of Tregs in the pathogenesis of persistence induced by intracellular bacterial pathogens, including B. abortus Results from this study indicate that adverse reproductive outcomes can occur as sequelae of chronic infection in non-pregnant animals, and that fine-tuning Tregs activity may provide novel immunotherapeutic and prevention strategies against intracellular bacterial infections such as brucellosis.Abstract ImportanceBacterial pathogens have developed several pathogenic mechanisms to establish persistent infections in their hosts. Several of these pathogens are also known to cause reproductive complications including stillbirth and infertility. We proposed that understanding the pathogenesis of these complications will help to devise novel therapeutic and prevention strategies to control the infection. Here, for the first time, we demonstrated that Brucella abortus has the ability to colonize and induce long-lasting inflammatory changes in the uterus of non-pregnant mice. We also showed that there is a persistent chronic infection in these tissues with the wildtype strain Brucella abortus 2308, which resulted in a significantly reduced number of pregnancies when compared to non-infected controls. These findings suggest that the tropism of Brucella spp. for the female reproductive system is independent of pregnancy, and that adverse reproductive outcomes can occur as sequelae of chronic infection in non-pregnant animals. In an effort to identify the immunologic mechanism responsible for uterine tropism, we demonstrated that highly suppressive regulatory T cells (Tregs) expressing TNFR2 contribute to the pathogenesis of Brucella abortus infection, and inactivation of Tregs with antagonistic antibody protected mice by significantly reducing bacterial burden both systemically and within reproductive tissues. Therefore, this result confirms a critical role for Tregs in Brucella persistence and also suggests that eliminating host Tregs activity may provide novel immunotherapeutic and prevention strategies against intracellular bacterial infections including brucellosis.