Elucidating the Role of Phospholipid Scramblase 1 in Antiviral Innate Immunity

Author

Gabrielle Paniccia

Date of Award

2024

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

RU Laboratory

Rice Laboratory

Abstract

Hosts possess an array of defenses against pathogens, some of which form a baseline protective barrier against infection. This baseline resistance, or intrinsic immunity, is the first layer of cellular defense that a virus must evade or antagonize in order to infect a cell. Intrinsic immunity also forms an important barrier against zoonosis—the transmission of a virus to new species outside its normal host range. Understanding these intrinsic restriction factors and their mechanisms of action can help us understand how pathogens evolve to circumvent or oppose these factors, and identify those pathogens that might be poised to infect new species.In this thesis, I detail our findings that phospholipid scramblase 1 (PLSCR1) works independently of innate immune signaling to oppose SARS-CoV-2 infection. SARS-CoV-2 is a highly contagious virus that was first discovered spreading in human populations in late 2019,having likely jumped from bats to humans. It rapidly became a pandemic, and since its emergence it has evolved to spread faster and more effectively in human populations. An arrayed CRISPR KO screen against SARS-CoV-2 identified many pro-and antiviral host factors, but the identification of PLSCR1 as an interferon (IFN) independent antiviral gene was curious, as no antiviral role for PLSCR1 outside of the IFN response had been identified before. Subsequent follow-up work revealed that, in the Huh-7.5 and A549-ACE2 cells used in this study, PLSCR1was not required for the IFN response as had previously been reported in Hey1B cells. PLSCR1KO also did not substantially alter the transcriptional landscape of the cell, indicating that its mechanism of action was unrelated to its transcriptional activation activity. In a series of mechanistic studies, we found that PLSCR1 KO cells were more susceptible to SARS-CoV-2infection, and that PLSCR1 inhibited virus entry. It did not inhibit both SARS-CoV-2 entry routes equally, primarily inhibiting endosomal entry by mechanisms that remain to be elucidated.

Comments

A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy

Recommended Citation

Paniccia, Gabrielle, "Elucidating the Role of Phospholipid Scramblase 1 in Antiviral Innate Immunity" (2024). Student Theses and Dissertations. 772.
https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/772