Pasteurella multocida Pm0442 Affects Virulence Gene Expression and Targets TLR2 to Induce Inflammatory Responses

Pasteurella multocida is an important pathogenic bacterium of domestic animals.Here, we found that Pm0442 was dramatically up-regulated in infected mice among 67 predicted lipoproteins of P. multocida serotype A CQ2 strain (PmCQ2), and Pm0442 deletion of PmCQ2 significantly decreased bacterial colonization and inflammatory responses in infectious mice, resulting in improved survival. Meanwhile, PmCQ2Δ0442 could provide 70%-80% protection to mice challenged with 3.08×107 CFU of PmCQ2. Pm0442 participated in the influences of PmCQ2 capsular and lipopolysaccharide (LPS) synthesis and iron uptake-related genes expression affecting the ability of adhesion and anti-phagocytosis. PM0442 bound directly to Toll-like receptor 2 (TLR2) to mediate pro-inflammatory cytokine secretion of IL-1β, TNF-α, IL-6, and IL-12p40 in macrophages via activation of the NF-κB, ERK1/2 and p38 signaling pathways. Our findings demonstrate that PM0442 is a PmCQ2 virulence factor, and provide a new insight into the pathogenesis of P. multocida and the development of new vaccines.