Acinetobacter baumannii virulence requires LPS activation of TLR4 (55.12)

Abstract Background: New treatments are needed for lethal infections caused by extreme-drug resistant (XDR)/pan-drug resistant (PDR) Acinetobacter baumannii. Toll-like receptor 4 (TLR4) was previously reported to enhance bacterial clearance during non-lethal A. baumannii pulmonary infection in mice. We sought to better to understand the role of LPS-TLR4 interactions in A. baumannii pathogenesis. Methods: LPS was harvested from nine clinical isolates of A. baumannii and then assayed for TLR4 activity using the HEK-Blue cells. Wild type and TLR4 mutant mice were infected via the tail-vein with A. baumannii. Results: After A. baumannii systemic infection, 100% of wild type vs. 0% of TLR4-mutant mice died. Wild type mice developed septic shock, typified by hypothermia, acidemia, and elevated inflammatory cytokine production, wherease TLR4 mutant mice did not, despite having similar bacterial burden in organs. Density of LPS in bacteria (ng/bacillus) and TLR4 activation by LPS extracted from the bacteria did not correlate with in vivo virulence. Amount of LPS shed during growth was the key correlate with in vivo virulence. Summary: LPS activation of TLR4 is a key pathogenetic factor of A. baumannii during systemic infection. Abrogation of TLR4 function protects mice from invasive A. baumannii infection by preventing induction of septic shock. These results suggest new areas of focus for developing novel therapeutics targeting these XDR/PDR infections.