Differential Involvement of Toll-Like Receptors 2 and 4 in the Host Response to Acute Respiratory Infections with Wild-Type and MutantHaemophilus influenzaeStrains

Abstract

We used a mouse model of acute respiratory infections to investigate the role of Toll-like receptor 2 (TLR2) and TLR4 in the host response toHaemophilus influenzae. Acute aerosol exposures to wild-type strains ofH. influenzaeshowed that TLR4 function was essential for TNF-α induction, neutrophil influx, and bacterial clearance. To determine how lipooligosaccharide (LOS) modifications would affect the role of TLR4 in inducing the host response, we used acute infections with anH. influenzaestrain expressing a mutation in thehtrBgene. This mutant strain expresses an LOS subunit with decreased acylation. In response toH. influenzae htrBinfection, tumor necrosis factor alpha (TNF-α) secretion remained TLR4 dependent. But the decrease in LOS acylation made the neutrophil influx and the bacterial clearance also dependent on TLR2, as shown by the decreased host response elicited in TLR2 knockout mice compared to C57BL/6 mice. A subsequent analysis of TLR2 and TLR4 gene expression by quantitative PCR indicated that TLR4 function induces TLR2 expression and vice versa. These results indicate that some changes in the LOS subunit ofH. influenzaecan favor signaling through non-TLR4 receptors, such as TLR2. The results also indicate a close interaction between TLR4 and TLR2 that tightly regulates the expression of both receptors.