REVIEW article
Front. Immunol.
Sec. Viral Immunology
Hidden players of COVID-19: the evolving roles of SARS-CoV-2 accessory proteins
Provisionally accepted
Miguel Padilla-Blanco1
Tránsito García-García2Juozas Grigas3Blanca D López-Ayllón1
Juan J Garrido2
Maria A. Oliva1
Maria Montoya4*- 1Fundacion General CSIC, Madrid, Spain
- 2Universidad de Cordoba, Córdoba, Spain
- 3Lietuvos sveikatos mokslu universitetas, Kaunas, Lithuania
- 4Spanish National Research Council (CSIC), Madrid, Spain
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
SARS-CoV-2 accessory proteins (APs), particularly ORF3a and ORF9b, have emerged as key modulators of host-pathogen interaction and potential contributors to long COVID. Of the 13 predicted APs, only nine are expressed during infection – termed Infection-related APs – while the remaining are classified as Putative APs. Despite this distinction, extensive gene overlap among APs underscores the remarkable adaptability of SARS-CoV-2 viral genome. This review delves into the diverse roles of the original Wuhan APs and their Omicron counterparts in shaping host immunity, with an emphasis on their ability to suppress type I interferon (IFN-I) signalling, modulate cellular metabolism, and trigger inflammatory/apoptotic pathways. By integrating immunopathological insights with evolutionary dynamics and structural perspectives, this review provides a comprehensive understanding of the mechanism underlying Omicron's reduced pathogenicity and highlights promising, yet unexplored, therapeutic targets within the SARS-CoV-2 accessory proteome.
Keywords: SARS-CoV-2, COVID-19, accessory proteins, viral pathobiology, Omicron lineages
Received: 16 Oct 2025; Accepted: 12 Nov 2025.
Copyright: © 2025 Padilla-Blanco, García-García, Grigas, López-Ayllón, Garrido, Oliva and Montoya. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Maria Montoya, maria.montoya@cib.csic.es
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.