Suppressor of cytokine signaling protein regulation of respiratory syncytial virus infection and evaluating avian influenza infection of human bronchial epithelial cells

Abstract

Respiratory syncytial virus (RSV) is the most common cause of hospitalization in infants due to any viral respiratory tract agent. Repeat infections are common throughout life and underscore mechanisms by which RSV can evade the immune response. Several RSV proteins have been shown to contribute to immune evasion by modification of cytokine responses, particularly the type I interferon (IFN) response. RSV nonstructural proteins are expressed early during infection and are known to contribute to type I IFN antagonism. Type I IFN signaling is negatively regulated by suppressor of cytokine signaling (SOCS) proteins, which are induced following Toll-like receptor (TLR) activation. Aspects of experimental studies described here were performed to test the hypothesis that RSV mediates TLR induction of the host SOCS pathway to inhibit the antiviral type I IFN response as a means to facilitate virus replication. The role of SOCS1 and SOCS3 regulation of the type I IFN response is examined in fully differentiated normal human bronchial epithelial (NHBE) cells infected with RSV or with a recombinant RSV mutant virus. The results show that RSV G protein modulates SOCS expression to inhibit type I IFN signaling early in infection, and increased SOCS expression is linked to TLR signaling by RSV F protein. In addition, the studies revealed that RSV surface proteins induce apical and basolateral secretion of proinflammatory chemokines early in infection. These findings suggest that RSV surface proteins signal through a TLR pathway, and indicate an important viral evasion mechanism to reduce the antiviral response to aid virus replication. Influenza virus, like RSV, is an important human respiratory pathogen. Avian influenza viruses (AIV) cause significant morbidity and mortality in poultry, and are considered an important emerging human health threat. The experiments described herein were performed to test the hypothesis that AIV can infect NHBE cells independent of sialic acid linkages present on the cell surface. The results show that AIV productively infect and replicate in NHBE cells independent of the sialic acids on the cell surface. These findings indicate that AIV may not need to acquire changes in hemagglutinin receptor binding specificity to efficiently transmit from human-to-human.