Helminth alleviates COVID-19-related cytokine storm in an IL-9-dependent way

Zengguo Cao; Jiaqi Wang; Xiaolei Liu; Yang Liu; Fangxu Li; Mingyuan Liu; Sandra Chiu; Xuemin Jin

doi:10.1128/mbio.00905-24

Helminth alleviates COVID-19-related cytokine storm in an IL-9-dependent way

mBio. 2024 May 10:e0090524. doi: 10.1128/mbio.00905-24. Online ahead of print.

Authors

Zengguo Cao^#^{1

2}, Jiaqi Wang^#¹, Xiaolei Liu¹, Yang Liu², Fangxu Li², Mingyuan Liu¹, Sandra Chiu³, Xuemin Jin¹

Affiliations

¹ State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory of Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, China.
² State Key Laboratory of Virology, Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
³ Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.

^# Contributed equally.

PMID: 38727220
DOI: 10.1128/mbio.00905-24

Abstract

Hyperactivation of pro-inflammatory type 1 cytokines (e.g., tumor necrosis factor alpha [TNF-α] and interferon gamma [IFN-γ]) mirrors the inflammation of coronavirus disease 2019. Helminths could alleviate excessive immune responses. Here, helminth Trichinella spiralis (Ts) infection was shown to protect against TNF-α- and IFN-γ-induced shock. Mechanistically, Ts-induced protection was interleukin-9 (IL-9) dependent but not IL-4Rα. Recombinant IL-9 treatment not only improved the survival of wild-type mice with TNF-α- and IFN-γ-induced shock but also that of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected K18-human angiotensin-converting enzyme 2 (hACE2) mice, emphasizing the significance of IL-9 in alleviating cytokine storm syndromes during SARS-CoV-2 infection. Interestingly, Ts excretory/secretory (TsES)-induced protection was also observed in SARS-CoV-2 infection, indicating that identifying anti-inflammatory molecules from TsES could be a novel way to mitigate adverse pathological inflammation during pathogen infection.IMPORTANCESevere coronavirus disease 2019 (COVID-19) is linked to cytokine storm triggered by type 1 pro-inflammatory immune responses. TNF-α and IFN-γ shock mirrors cytokine storm syndromes, including COVID-19. Helminths (e.g., Trichinella spiralis, Ts) can potently activate anti-inflammatory type 2 immune response. Here, we found that helminth Ts-induced protection against TNF-α and IFN-γ shock was IL-9 dependent. Treatment with recombinant IL-9 could protect against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in K18-hACE2 mice. Helminth Ts excretory/secretory (TsES) products also ameliorated SARS-CoV-2 infection-related cytokine storm. In conclusion, our study emphasizes the significance of IL-9 in protecting from cytokine storm syndromes associated with SARS-CoV-2 infection. Anti-inflammatory molecules from TsES could be a new source to mitigate adverse pathological inflammation associated with infections, including COVID-19.

Keywords: SARS-CoV-2; Trichinella spiralis; cytokine shock; recombinant IL-9.