Lung Epithelial TLR7 is a Factor in Viral Replication and Pathogenesis

Respiratory virus infections are the leading causes of morbidity and mortality of infants and the elderly worldwide. Currently it is not known how Respiratory Syncytial Virus (RSV) vaccination of infants can cause enhancement of RSV disease, highlighting gaps in our understanding about how viruses like RSV interact with the immune system. Here we address this and show that ERK MAP kinase signaling from Toll-like Receptor-7 (TLR7) detection of RSV and influenza, but not human parainfluenza virus type 3 (HPIV3), infections in bronchial epithelial cells (BECs) drives replication of the viruses. Virus infection is detected by pattern recognition receptors like TLR7 that bind to single stranded RNA (ssRNA) viral replication intermediates in late endosomes. Here we report that TLR7 is expressed in BECs and detects RSV ssRNA, causing ERK MAP kinase signaling. RSV and influenza use this detection and signaling in BECs to drive its replication and infection, a mechanism that counters TLR7s role in antiviral defence. Experimental blockade of TLR7 binding or downstream signalling through ERK MAP kinase decreased RSV and influenza replication, but had no effect on HPIV3. RSV viral loads in mouse and human females were higher compared to males, consistent with higher sex-dependent expression of the TLR7 gene from two copies of the X chromosome in females. In a TLR7 gain of function mouse model there was a significant enhancement of RSV replication and RSV eosinophilic and Th2 disease markers like interleukin-5 (IL-5). In summary, TLR7 is expressed in human lung BECs in the lungs where it acts as a factor in RSV and influenza replication and disease pathogenesis. We propose that this is a major factor in determining the sex-disparity of viral disease.