The immune receptors TLR4 and SLAMF1 regulate TNF release by human metapneumovirus in human macrophages.

Background: Human metapneumovirus (HMPV) is a major cause of acute respiratory disease in children, the elderly, and immunocompromised individuals. While pro-inflammatory cytokines and type I interferons (IFNs) are important for antiviral defense, excessive tumor necrosis factor (TNF) is associated with severe disease in HMPV and other respiratory infections. Hence, defining regulatory mechanisms by which HMPV induces TNF and IFN-β is important for therapeutic strategies in airway disease. The immunoregulatory receptors Toll-like receptor (TLR)4 and signaling lymphocytic activation molecule family 1 (SLAMF1) mediate TNF and IFN-β expression in response to LPS and Gram-negative bacteria, but their involvement in HMPV-stimulated cytokine expression is unclear. Methods: We investigated the kinetics of Results: TLR4 knockout reduced Conclusions: Together, our findings identify TLR4 and SLAMF1 as key regulators of early HMPV-induced inflammation via p38 MAPK. SLAMF1 additionally influences IFN-β responses and appears to affect viral replication dynamics. These insights suggest that targeting SLAMF1-TLR4 signaling may offer a therapeutic strategy to limit TNF-driven pathology in HMPV infection.