ADAMTS4 modulates lung tissue repair following lethal influenza A infection in mice

Abstract

Abstract Lung tissue damage is a major contributor to morbidity and mortality following infection with influenza A virus. Tissue repair, including remodeling of the extracellular matrix (ECM), is a critical process in recovery from infection. A Disintegrin and Metalloproteinase with Thrombospondin motifs (ADAMTS) family proteins are secreted zinc metalloendopeptidases and important mediators of ECM remodeling. The role of ADAMTS proteins in lung tissue repair following influenza A infection remains unclear. To investigate the regulation of ADAMTS genes in the context of influenza A infection, we performed a microarray analysis of whole lung homogenates harvested at 24 hours post-infection from B6 mice that were uninfected or infected with mouse-adapted influenza A PR8. In the context of infection, several ADAMTS genes, including ADAMTS4, −6, and −9 exhibited a ≥ 3-fold increase in gene expression compared to uninfected lungs. ADAMTS-4 exhibited the most dramatic increase in gene expression (>100-fold) at this early timepoint. We further investigated the role of ADAMTS4 in survival and recovery from influenza A infection by infecting wild-type (WT) and ADAMTS4 −/− knockout B6 mice with a lethal dose of influenza A PR8. Interestingly, ADAMTS4 −/− mice exhibited significantly improved survival compared to WT littermates (log-rank test, p= 0.04) with 75% vs. 41% survival at 15 days post-infection, despite no observable difference in weight loss. Consistent with a role in tissue repair and recovery, differences in survival were observed after 9 days post-infection. These results raise the possibility that increased expression of ADAMTS4 following influenza A infection modulates the tissue repair process and contributes to lung pathology.