Low-Dose Lipopolysaccharide Protects from Lethal Paramyxovirus Infection in a Macrophage- and TLR4-Dependent Process.

ABSTRACT

Respiratory diseases are a major public health burden and a leading cause of death and disability in the world. Understanding antiviral immune responses is crucial to alleviate morbidity and mortality associated with these respiratory viral infections. Previous data from human and animal studies suggested that pre-existing atopy may provide some protection against severe disease from a respiratory viral infection. However, the mechanism(s) of protection is not understood. Low-dose LPS has been shown to drive an atopic phenotype in mice. In addition, LPS has been shown in vitro to have an antiviral effect. We examined the effect of LPS treatment on mortality to the murine parainfluenza virus Sendai virus. Low-dose LPS treatment 24 h before inoculation with a normally lethal dose of Sendai virus greatly reduced death. This protection was associated with a reduced viral titer and reduced inflammatory cytokine production in the airways. The administration of LPS was associated with a marked increase in lung neutrophils and macrophages. Depletion of neutrophils failed to reverse the protective effect of LPS; however, depletion of macrophages reversed the protective effect of LPS. Further, we demonstrate that the protective effect of LPS depends on type I IFN and TLR4-MyD88 signaling. Together, these studies demonstrate pretreatment with low-dose LPS provides a survival advantage against a severe respiratory viral infection through a macrophage-, TLR4-, and MyD88-dependent pathway.