Expression of human hTLR4/MD2 <i>in vivo</i> in mice alters infection with <i>C. burnetii</i>
Аннотация
Abstract Human and mouse TLR4/MD2 molecules respond differently to specific types of LPS. Their response to normally acylated LPS is similar, but they respond differently to hypoacylated LPS found on specific gram-negative bacteria. The LPS of Coxiella burnetii is hypoacylated, heavily glycosylated and is known to cause a minimal response by human cells. We hypothesized that mice expressing human TLR4/MD2 (hTLR4/MD2) molecules would respond differently to C. burnetii infection compared to wild type mice. Mice expressing hTLR4/MD2 molecules had enhanced weight loss, and more bacteria in tissues than did wild-type mice. Bone marrow chimera experiments indicated that mice expressing hTLR4/MD2 on stromal/epithelia cells had more severe disease and enhanced bacterial replication compared to when mouse TLR4 was expressed on these cells. Surprisingly, hTLR4 expression on hematopoietic cells was of minimal consequence. These data suggest that species-specific TLR4/MD2 responses in stromal and epithelial compartments can alter the disease course. Studying C. burnetii infection in hTLR4/MD2-expressing mice will result in findings that are likely more readily applicable to human patients.