Innate immune pathway modulator screen identifies STING pathway activation as a strategy to inhibit multiple families of arbo and respiratory viruses

Gustavo Garcia Jr; Joseph Ignatius Irudayam; Arjit Vijey Jeyachandran; Swati Dubey; Christina Chang; Sebastian Castillo Cario; Nate Price; Sathya Arumugam; Angelica L Marquez; Aayushi Shah; Amir Fanaei; Nikhil Chakravarty; Shantanu Joshi; Sanjeev Sinha; Samuel W French; Mark S Parcells; Arunachalam Ramaiah; Vaithilingaraja Arumugaswami

doi:10.1016/j.xcrm.2023.101024

Innate immune pathway modulator screen identifies STING pathway activation as a strategy to inhibit multiple families of arbo and respiratory viruses

Cell Rep Med. 2023 May 16;4(5):101024. doi: 10.1016/j.xcrm.2023.101024. Epub 2023 Apr 28.

Authors

Gustavo Garcia Jr¹, Joseph Ignatius Irudayam¹, Arjit Vijey Jeyachandran¹, Swati Dubey¹, Christina Chang¹, Sebastian Castillo Cario¹, Nate Price¹, Sathya Arumugam², Angelica L Marquez¹, Aayushi Shah¹, Amir Fanaei¹, Nikhil Chakravarty³, Shantanu Joshi⁴, Sanjeev Sinha⁵, Samuel W French⁶, Mark S Parcells⁷, Arunachalam Ramaiah⁸, Vaithilingaraja Arumugaswami⁹

Affiliations

¹ Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA.
² Department of Mathematics, Government College Daman, Daman, Dadra and Nagar Haveli and Daman and Diu 396210, India.
³ Department of Epidemiology, University of California, Los Angeles, Los Angeles, CA, USA.
⁴ Department of Neurology, University of California, Los Angeles, Los Angeles, CA, USA; Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, USA.
⁵ All India Institute of Medical Sciences, New Delhi, India.
⁶ Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁷ Department of Animal and Food Sciences, Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA.
⁸ Tata Institute for Genetics and Society, Center at inStem, Bangalore 560065, India; City of Milwaukee Health Department, Milwaukee, WI 53202, USA. Electronic address: arama@milwaukee.gov.
⁹ Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, USA; California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA, USA. Electronic address: varumugaswami@mednet.ucla.edu.

Abstract

RNA viruses continue to remain a threat for potential pandemics due to their rapid evolution. Potentiating host antiviral pathways to prevent or limit viral infections is a promising strategy. Thus, by testing a library of innate immune agonists targeting pathogen recognition receptors, we observe that Toll-like receptor 3 (TLR3), stimulator of interferon genes (STING), TLR8, and Dectin-1 ligands inhibit arboviruses, Chikungunya virus (CHIKV), West Nile virus, and Zika virus to varying degrees. STING agonists (cAIMP, diABZI, and 2',3'-cGAMP) and Dectin-1 agonist scleroglucan demonstrate the most potent, broad-spectrum antiviral function. Furthermore, STING agonists inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and enterovirus-D68 (EV-D68) infection in cardiomyocytes. Transcriptome analysis reveals that cAIMP treatment rescue cells from CHIKV-induced dysregulation of cell repair, immune, and metabolic pathways. In addition, cAIMP provides protection against CHIKV in a chronic CHIKV-arthritis mouse model. Our study describes innate immune signaling circuits crucial for RNA virus replication and identifies broad-spectrum antivirals effective against multiple families of pandemic potential RNA viruses.

Keywords: Chikungunya virus; SARS-CoV-2; West Nile virus; Zika virus; cAIMP; cGAS-STING pathway; enterovirus-D68; pattern-recognition receptors; respiratory syncytial virus; scleroglucan.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Antiviral Agents / pharmacology
Antiviral Agents / therapeutic use
COVID-19*
Chikungunya virus* / physiology
Immunity, Innate
Mice
RNA Viruses*
SARS-CoV-2
Zika Virus Infection*
Zika Virus*

Substances

Antiviral Agents

Abstract

Publication types

MeSH terms

Substances

Grants and funding