Disserta on Defense - Deemah Dabbagh, PhD Biosciences July 19, 2021 2:00 PM - 4:00 PM VIEW EVENT All are invited to attend the defense. For more information please contact Graduate Coordinator at [email protected] Candidate: Deemah Dabbagh Program: PhD, Biosciences Date: Monday, July 19, 2021 Time: 2:00 PM Place: Zoom Mee ng Link: https://gmu.zoom.us/ j/96449498224? pwd=S3JYYjNVMGN6RFJlQlhMbnhlSEhKQT09 Title: Identification of PSGL-1 and the SHREK Family of Proteins as Broad-Spectrum Antiviral Host Factors
Commi ee Chair: Dr. Yuntao Wu Commi ee Members: Dr. Kylene Kehn-Hall, Dr. Mikell Paige, Dr. Ramin Hakami
ABSTRACT: PSGL-1 (P-selectin glycoprotein ligand-1) is a 120 KDa- dimeric mucin-like glycoprotein expressed on the surface of myeloid and lymphoid cells, and is up-regulated during inflammation to mediate leukocyte tethering and rolling on the endothelium for migration into inflamed tissues. Previous work has reported that PSGL-1 expression restricts HIV-1 infectivity. However, the mechanism by which PSGL-1 disrupts HIV-1 infectivity remains elusive. In this study, we demonstrate that PSGL-1 inhibits HIV-1 infectivity by incorporating into virions which subsequently prevents virus particle attachment to target cells via steric hindrance. This PSGL-1- mediated inhibition of viral binding occurred irrespectively of the molecules mediating virion-cell interaction. Mutational mapping revealed that the extracellular domain of PSGL-1 is required for its anti–HIV-1 activity, while the cytoplasmic domain contributed to a lesser extent. Additionally, we found that PSGL-1 inhibits the infectivity of other enveloped viruses including murine leukemia virus and influenza A virus. We also tested a panel of mucin and mucin-like molecules that share structural features with PSGL-1(CD43, TIM-1, CD34, PODXL1, PODXL2, CD164, MUC1, MUC4, and TMEM123). We found that, like PSGL-1, these proteins also blocked HIV-1 infectivity by virion incorporation and inhibition of virus particle attachment to target cells. Based on their shared structural characteristics and antiviral activity, we have named these proteins the Surface-Hinged, Rigidly-Extended Killer (SHREK) family of virion inactivators. In addition to inhibiting HIV-1, the proteins tested blocked infection by the influenza A virus, and a subset of them inhibited infection with hybrid alphavirus-SARS-CoV-2 (HaCoV2) virus-like particles. Collectively, our findings demonstrate that PSGL-1 and SHREK proteins are broad-spectrum host antiviral factors that may be a part of host innate immunity against enveloped viruses.