Dampened TLR2–mediated Inflammatory Signaling in Bats

Bats are considered natural hosts for numerous viruses. Their ability to carry viruses that cause severe diseases or even death in other mammals without falling ill themselves has attracted widespread research attention. Toll-like receptor 2 forms heterodimers with Toll-like receptor 1 or Toll-like receptor 6 on cell membranes, recognizing specific pathogen-associated molecular patterns and playing a key role in innate immune responses. Previous studies have shown that moderate Toll-like receptor 2-mediated immune signals aid in pathogen clearance, while excessive or inappropriate Toll-like receptor 2-mediated immune signals can cause self-damage. In this study, we observed that TLR2, unlike TLR1 or TLR6, has undergone relaxed selection in bats compared with other mammals, indicating a reduced functional constraint on TLR2 specifically in bats. Indeed, our cell-based functional assays demonstrated that the ability of Toll-like receptor 2 to bind with Toll-like receptor 1 or Toll-like receptor 6 was significantly reduced in bats, leading to dampened inflammatory signaling. We identified mutations unique to bats that were responsible for this observation. Additionally, we found that mutations at residues 375 and 376 of Toll-like receptor 2 in the common ancestor of bats also resulted in reduced inflammatory response, suggesting that this reduction occurred early in bat evolution. Together, our study reveals that the Toll-like receptor 2-mediated inflammatory response has been specifically dampened in bats, which may be one of the reasons why they could harbor many viruses without falling ill.