Lymphotoxin β receptor signaling promotes influenza-induced lung damage (VIR5P.1151)

Abstract

Abstract Lymphotoxin β receptor (LTβR) has been shown to play a critical role in protection against mucosal bacterial pathogens in the gut. Surprisingly, we found that genetic or biochemical inhibition of LTβR signaling confers protection against highly pathogenic H1N1 influenza virus infection. Consistent with amelioration of disease severity, LTβR-deficient mice displayed reduced expression of pro-inflammatory cytokines, reduced inflammatory dendritic cells, and drastically reduced numbers of antigen specific CD8+ T cells in the lung. Further, LTβR-deficient mice showed attenuated viral loads during the peak of viral replication. Previous studies by our group have highlighted a potential role of LT signaling in the regulation of mucin expression in the gut. Further, increased mucin secretion in the lung is known to correlate with attenuation of influenza virus replication. Immunohistochemical and gene expression analysis revealed a marked increase in goblet cell hyperplasia and MUC5AC secretion in the lungs of influenza infected LTβR-deficient mice relative to wild type mice. Additionally, treatment of infected wild type mice with an agonistic anti-LTβR antibody resulted in almost complete inhibition of MUC5AC mRNA expression in the lung. Taken together, our data suggest that LT signaling negatively regulates mucin production in response to respiratory viral infection leading to increased viral burden, lung pathology, and death.