| Melioidosis is an infection caused by Burkholderia pseudomallei. In northeastern Thailand melioidosis accounts for 20% of all community acquired septicemias, with a high mortality rate of almost 40%. A high proportion of cases presents as pneumonia. The innate immune system can recognize conserved motifs on pathogens termed pathogen-associated molecular patterns or PAMPs. Toll-like receptors (TLRs) play an essential role in the innate recognition of PAMPs by the host, and as such are crucial for the activation of signaling pathways involved in antibacterial defense. We hypothesize that (I) an as yet unknown repertoire of different (combinations of) TLRs is involved in the recognition of B. pseudomallei, and that (II) B. pseudomallei can influence the expression of different TLRs by which this bacterium can escape from the host innate immune response. Our key objectives are to determine (1) which TLRs are involved in the innate recognition of B. pseudomallei, (2) which cell type (hematopoietic or non-hematopoietic cells) are most important for TLR mediated host defense against this bacterium, and (3) whether B. pseudomallei downregulates the expression of TLRs in cells involved in the innate immune response, enabling this pathogen to escape from immune surveillance by TLRs. Our approach includes systematic evaluation of the responsiveness of a cell line transfected with (combinations of) TLRs toward B. pseudomallei, monitoring the host response of TLR deficient mice in models of systemic and pulmonary melioidosis, and investigations addressing alterations in TLR expression on cells involved in innate immunity in mice with melioidosis and in Thai patients with various manifestations of this disease. Increased knowledge of the innate immune response to B. pseudomallei can contribute to the development of new preventive and therapeutic strategies in patients with melioidosis. |
