Toll-Like Receptor Modulation of Murine Cerebral Malaria Is Dependent on the Genetic Background of the Host

Infection with Plasmodium berghei ANKA is a well-established model of human cerebral malaria (CM). We show herein that Toll-like receptor (TLR) signaling influences the development of lethal CM in P. berghei ANKA-infected mice. Modulation of outcome was dependent on genetic background, such that deletion of myeloid differentiation factor (MyD) 88 on the susceptible C57BL/6 background resulted in resistance to CM, whereas deletion of MyD88 on the resistant BALB/c background led to increased mortality. Our data show that MyD88 influenced the production of T helper—polarizing cytokines, including interferon (IFN)-γ, interleukin (IL)-4, and IL-17, as well as the total number of Foxp3+ regulatory T (Treg) cells in a manner dependent on host genetic background. In addition, mRNA levels of IFN-γ, CXCL10, and CXCL9 were strongly up-regulated in the brains of susceptible wild-type but not MyD88-/- infected mice. These results suggest that TLR signaling and host genetic background influences the pathogenesis of CM via modulation of cytokine production and Treg cell numbers.