Interferon Regulatory Factors IRF1 and IRF7 Directly Regulate Gene Expression in Bats in Response to Viral Infection

Abstract

Bat cells and tissue have elevated basal expression levels of antiviral genes commonly associated with interferon alpha (IFNa) signaling. Here, we show Interferon Regulatory Factor 1 (IRF1), 3, and 7 levels are elevated in most bat tissues and that, basally, IRFs contribute to the expression of type I IFN ligands and high expression of interferon regulated genes (IRGs). CRISPR knockout (KO) of IRF 1/3/7 in cells reveals distinct subsets of genes affected by each IRF in an IFN-ligand signaling-dependent and largely independent manner. As the master regulators of innate immunity, the IRFs control the kinetics and maintenance of the IRG response and play essential roles in response to influenza A virus (IAV), herpes simplex virus 1 (HSV-1), Melaka virus/Pteropine orthoreovirus 3 Melaka (PRV3M), and Middle East respiratory syndrome-related coronavirus (MERS-CoV) infection. With its differential expression in bats compared to that in humans, this highlights a critical role for basal IRF expression in viral responses and potentially immune cell development in bats with relevance for IRF function in human biology.

Of bats and men: Immunomodulatory treatment options for COVID-19 guided by the immunopathology of SARS-CoV-2 infection

“…The production of IFNs and IRGs in response to sensing infection is rapidly induced in bats, yet the typical mammalian-prolonged IFN production is blocked (117) and the overall abundance of IFNs produced is minimal. Through altered IRF induction, constitutive IRG expression occurs even in the absence of infection (118). Other mechanisms of altered viral sensing include deletion of PYHIN genes that recognize cytoplasmic doublestranded DNA, genetic variations decreasing cGAS/STING and TBK1 pathway activation, and mutations in IRF3 activation sites that likely facilitate more rapid responses to cytoplasmic nucleic acids (119).…”

“…Exploiting their potent antiviral functions in early COVID-19 seems promising. In bats, IFN abundance is higher at steady state, whereas induction by infection is less pronounced, suggesting tight regulation in driving antiviral IRGs while limiting IFN toxicity is desirable (Table 1) (117,118). In addition, type I and III IFNs showed promising results against other CoVs, and SARS-CoV-2 is sensitive to IFN effects (58).…”

Distinct interferon response in bat and other mammalian cell lines infected with Pteropine orthoreovirus

“…The less susceptibility of PRV in Yinpterochiropteran (or Pteropodiformes) bat cell lines (BKT1 and DEMKT1) was different from the kidney cell line derived from the black flying fox ( Pteropus alecto ) that is susceptible to the extensive syncytial formation and high viral replication when exposed to NBV [ 42 ]. Low replication of PRV has been reported recently in a bat cell line derived from Yangochiropteran (or Vespertilioniformes) bats, David’s myotis ( Myotis davidii ) [ 43 ].…”

“…Pre-treatment with IFNs can reduce viral replication and increase the expression of RIG-I and ISGs in cell lines that are susceptible to NBV [ 55 , 57 , 58 ]. In addition, several IFN-regulatory factors (IRF1, IRF3, and IRF7) control the IFN-regulated genes (IRGs) response during PRV3M infection [ 43 ]. The serine residues that were positively selected in IRF3 from multiple bats also contribute to a higher basal level of IFNs and enhance protection against MERS-CoV in bat cells [ 46 , 59 ].…”

Effects of Overexpression of the Egyptian Fruit Bat Innate Immune Genes on Filovirus Infections in the Host Cells

“…Bats of other species exhibit subclinical infections and survive infections with henipaviruses and coronaviruses that cause severe diseases in humans (12)(13)(14). Many factors have been suggested to play a role in the resistance to disease in bats, with major attention given to their immune system and relatively reduced inflammatory responses (15)(16)(17)(18). Indeed, bats are very diverse with more than 1,400 species described, and the same great diversity might be expected to be seen in their adaptation to pathogens, many of which are speciesspecific.…”