Regulation of Lysosomal Associated Membrane Protein 3 (LAMP3) in Lung Epithelial Cells by Coronaviruses (SARS-CoV-1/2) and Type I Interferon Signaling

Abstract

Abstract Severe Acute Respiratory Syndrome CoronaVirus-2 (SARS-CoV-2) infection is a major risk factor for mortality and morbidity in critical care hospitals around the world. Lung epithelial type II cells play a major role in the recognition and clearance of respiratory viruses as well as repair of lung injury in response to environmental toxicants. Gene expression profiling studies revealed that mouse lung epithelial type II cells express several cell-specific markers including surfactant proteins and Lysosomal associated membrane protein 3 (LAMP3) located in lysosomes, endosomes and lamellar bodies. These intracellular organelles are involved in vesicular transport and facilitate viral entry and release of the viral genome into the host cell cytoplasm. In this study, regulation of LAMP3 expression in human lung epithelial cells by several respiratory viruses and type I interferon signaling was investigated. Respiratory viruses including SARS-CoV-1 and SARS-CoV-2 significantly induced LAMP3 expression in lung epithelial cells within 24 hours after infection that required the presence of ACE2 viral entry receptors. Time course experiments revealed that the induced expression of LAMP3 was correlated with the induced expression of Interferon–beta (IFNB1) and STAT1 at mRNA levels. LAMP3 was also induced by direct IFN-beta treatment in multiple lung epithelial cell lines or by infection with influenza virus lacking the non-structural protein1(NS1) in NHBE bronchial epithelial cells. LAMP3 expression was also induced by several respiratory viruses in human lung epithelial cells including RSV and HPIV3. Location in lysosomes and endosomes aswell as induction by respiratory viruses and type I Interferon suggests that LAMP3 may have an important role in inter-organellar regulation of innate immunity and a potential target for therapeutic modulation in health and disease. Furthermore, bioinformatics revealed that a subset of lung type II genes were differentially regulated in the lungs of COVID-19 patients.