Mechanisms of Brucella abortus survival during chronic infection during chronic infection: the role of IL-10 and PPARy

Abstract

Evasion of host immune responses is a prerequisite for chronic bacterial diseases; however, the underlying mechanisms are not fully understood. This study demonstrated that Brucella abortus prevents immune activation of macrophages by inducing CD4+CD25+ T cells to produce interleukin-10 (IL-10) early during infection. Moreover, either a lack of IL-10 production by T cells or a lack of macrophage responsiveness to this cytokine resulted in an increased ability of mice to control B. abortus infection, while inducing elevated production of pro-inflammatory cytokines, and severe pathology in liver and spleen of infected mice. In spite of the significant advances in understanding intracellular survival of B. abortus at the cellular level, little is known about the chronic intracellular niche of B. abortus in vivo. This study demonstrated that B. abortus is able to survive and replicate preferentially in alternatively activated macrophages (AAM), which increase in numbers during chronic infection. The underlying mechanism to this enhanced survival in AAM is a shift in metabolism induced by peroxisome proliferator activated receptor gamma (PPAR), which increases the availability of intracellular glucose. The ability to take up glucose was crucial for increased replication of B. abortus in AAM, and for persistence. Taken together our results suggest that early IL-10 production by CD25+CD4+ T cells modulates macrophage function in order to promote persistent infection. Additionally, B. abortus persistence was also determined by a shift in intracellular nutrient availability induced by PPAR in AAM.