Lessons in self-defence: inhibition of virus entry by intrinsic immunity

Abstract

Virus entry, consisting of attachment to and penetration into the host target cell, is the first step of the virus life cycle and is a critical ‘do or die’ event that governs virus emergence in host populations. Most antiviral vaccines induce neutralizing antibodies that prevent virus entry into cells. However, while the prevention of virus invasion by humoral immunity is well appreciated, considerably less is known about the immune defences present within cells (known as intrinsic immunity) that interfere with virus entry. The interferon-induced transmembrane (IFITM) proteins, known for inhibiting fusion between viral and cellular membranes, were once the only factors known to restrict virus entry. However, the progressive development of genetic and pharmacological screening platforms and the onset of the COVID-19 pandemic have galvanized interest in how viruses infiltrate cells and how cells defend against it. Several host factors with antiviral potential are now implicated in the regulation of virus entry, including cholesterol 25-hydroxylase (CH25H), lymphocyte antigen 6E (LY6E), nuclear receptor co-activator protein 7 (NCOA7), interferon-γ-inducible lysosomal thiol reductase (GILT), CD74 and ARFGAP with dual pleckstrin homology domain-containing protein 2 (ADAP2). This Review summarizes what is known and what remains to be understood about the intrinsic factors that form the first line of defence against virus infection.

Rapalogs downmodulate intrinsic immunity and promote cell entry of SARS-CoV-2

“…Rapamycin, everolimus, and especially temsirolimus boosted HA- and VSV G-mediated infections (up to 30-fold and 11-fold, respectively) (Figure 4D-E) . Since IFITM proteins have been previously shown to inhibit infection by SARS-CoV-1, MERS-CoV, VSV, and Influenza A virus [40], these data suggest that rapalogs promote infection, at least in part, by lowering the barrier to virus entry imposed by IFITM proteins.…”

Antiviral Immunity in SARS-CoV-2 Infection: From Protective to Deleterious Responses

“…An important part of the innate antiviral immunity is represented by the intrinsic immunity, which is mediated by constitutively expressed or induced factors that recognize specific viral components and restrict the viral multiplication cycle, rendering host cells non-permissive to a certain virus [40]. These proteins could be included in the PRR category, as they bind directly to viral components; however, unlike other PRRs that inhibit viral infection indirectly by inducing interferons and other antiviral molecules, intrinsic antiviral factors block the viral replication immediately and directly, often before the onset of the IFN response [41].…”

Dynamic cholesterol redistribution favors membrane fusion pore constriction

“…This work focuses on chol. A body of literature has demonstrated that chol chemistry and concentration dramatically affect virus-endosome fusion [17, 32], as well as plasma membrane fusion and fission [16, 33]. Understanding chol’s role in mechanics is complicated by disparate observations.…”