Mice lacking TLR4 function exhibit enhanced susceptibility to Rickettsia conorii, correlated with decreased NK cell activity (44.14)

Abstract

Abstract Toll-like receptors (TLR) are critical in the initiation and polarization of protective immune responses to a wide variety of pathogens. However, the importance of TLRs in immunity to rickettsial diseases has been poorly defined. We demonstrated in a model of human rickettsiosis that mice lacking TLR4 function exhibited enhanced susceptibility to R. conorii infection compared to mice having functional TLR4 responses. Lack of TLR4 signaling resulted in overwhelming rickettsial growth in the brain and lung—the major pathologic organs. Infected mice lacking TLR4 function had decreased splenic NK cells and an increase in regulatory T-cells in peripheral lymph nodes. Further, splenocytes obtained from infected mice lacking TLR4 activity had decreased NK cell cytotoxicity activity. The lack of TLR4 signaling resulted in significantly reduced serum IL-12, IL-23, and IL-17. Thus, TLR4 is important in initiating early rickettsial immunity, possibly because of enhanced Th1 proinflammatory cytokines and increased NK cell activity.