# SARS-CoV-2 and Innate Immunity: Mechanisms of Resistance to Human Interferons

> **NIH VA I01** · VA EASTERN COLORADO HEALTH CARE SYSTEM · 2024 · —

## Abstract

SARS-CoV-2 emerged in late 2019, with much evidence tracing the initial human spillover to a market with
extensive human-animal contact. As the coronavirus spread in its new host species, multiple variants of
concern representing distinct genetic lineages appeared and propagated globally. Ongoing viral evolution has
increased transmission, and also evasion of neutralizing antibodies (adaptive arm of the immune system).
Hence, many important studies have deservedly focused on dissecting consequences of Spike protein
mutations in different emerged variants. However, mutations have also been detected in viral genes other than
Spike, and several of these genes are linked to antagonism of innate immune responses. We provide detailed
evidence that compared to ancestral or early SARS-CoV-2 isolates, the five major variants of concern so far
(alpha, beta, gamma, delta and omicron) have become more resistant to multiple human interferons that
included the 12 IFNα subtypes, IFNβ, IFNω and 3 IFNλ subtypes1. The underlying mechanisms for these IFN
resistance phenotypes are unclear and, paralleling the four decades it has taken to understand innate immune
evasions mediated by the proteins encoded by the nine genes of HIV-1, a full picture for SARS-CoV-2 will
require sustained investigation over time. However, in both the short and long terms, the scientific and medical
impacts of characterizing resistance of this newly emerged coronavirus mechanistically can be highly
significant, for not only the current pandemic but potentially also for future sarbecovirus spillover events. We
thus propose to build on our ample published1 and unpublished preliminary data and accumulated experience
to track the evolution of SARS-CoV-2 IFN resistance during the course of the COVID-19 pandemic and to
determine virus mutations and effector mechanisms involved. As interferon responses can regulate virus
levels during the critical acute phase of infection, these studies will have implications for understanding
SARS-CoV-2 transmission and pathogenesis that may inform therapeutic strategies not only against SARS-
CoV-2 but also future emerging viruses.

## Key facts

- **NIH application ID:** 10701244
- **Project number:** 1I01BX006270-01
- **Recipient organization:** VA EASTERN COLORADO HEALTH CARE SYSTEM
- **Principal Investigator:** Eric M. Poeschla
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2023-10-01 → 2027-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10701244

## Citation

> US National Institutes of Health, RePORTER application 10701244, SARS-CoV-2 and Innate Immunity: Mechanisms of Resistance to Human Interferons (1I01BX006270-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10701244. Licensed CC0.

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