{"doi":"10.1111/resp.13875","title":"Targeting the interleukin‐17 pathway to prevent acute respiratory distress syndrome associated with <scp>SARS‐CoV</scp>‐2 infection","abstract":"The novel coronavirus causing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for coronavirus disease 2019 (COVID-19) pandemic. This is spurring a global response and accelerating trials of a panoply of antivirals, antibiotics, cell therapies, anticoagulants, convalescent plasma infusion and immune modulation using steroids and anti-cytokine therapies. In the absence of SARS-CoV-2-specific interventions to treat the infection, there are urgent needs to identify adjunctive treatments that prevent or counteract the ‘cytokine storm’ underlying the severe acute respiratory distress syndrome (ARDS) manifestations.1, 2 Trials underway using immune modulation focus on targeting interleukin (IL)-6, IL-6 receptor (IL-6R), tumour necrosis factor-alpha (TNF-α), IL-1R, granulocyte-macrophage colony-stimulating factor (GM-CSF) and janus kinase (JAK) inhibition among others. Here, we provide the rationale for considering clinical trial testing of IL-17 blockade as a therapeutic strategy for overt pulmonary inflammation caused by SARS-CoV-2 infection. IL-17 plays a key role in the cytokine storm observed in ARDS of any cause and is associated with alveolar inflammation and a poor prognosis.3-5 In mouse models, both the direct IL-17 blockade and the upstream blockade of histone acetyltransferase p300 and transcription factor retinoic acid receptor-related orphan receptor gamma t (RORγt), which upregulate IL-17 production, resulted in an attenuation of the lung injury.6, 7 Consistently, peripheral blood mononuclear cells (PBMC) from ARDS patients have an increased expression of p300 and RORγt, especially among non-survivors.7 In severe compared to non-severe COVID-19, different studies found increased levels of IL-17-regulated cytokines, including IL-6, monocyte chemoattractant protein-1 (MCP-1), IL-8, granulocyte colony-stimulating factor (G-CSF), macrophage inflammatory protein (MIP)-1-α and TNF-α; however, IL-17 was only increased in severe cases compared to non-infected controls.2, 8, 9 Another study observed that IL-17 distinguished between mild and severe cases and correlated positively with an increased lung injury severity score.10 A pathological assessment found a high frequency of peripheral T-helper (Th) 17 in a patient with severe COVID-19 who did not survive.11 Furthermore, IL-17 plays a role in facilitating early neutrophil recruitment into the lungs, a deleterious phenomenon associated with poor prognosis in severe cases of COVID-19.12 Activation of the IL-17 pathway is also a marker of severity in various other known viral infections. Infections due to the Middle East respiratory syndrome coronavirus (MERS-CoV) outbreak in 2012 were associated with a pro-inflammatory Th1 and Th17 cytokine profile and IL-17 responses.13-15 In the 2009 influenza A (H1N1) pandemic, the IL-17 response played a detrimental role in lung injury and was higher in patients with ARDS who did not survive.16, 17 In childhood respiratory syncytial virus (RSV) infections, high IL-17 expression was associated with a poor interferon (IFN) production, abrogated type I IFN (IFN-I) responses and RSV infection severity.5, 18, 19 IFN-I is implicated in reducing viral spread, and high levels of IFN-I seem particularly relevant in the early infection phase for disease control. Indeed, in mice, early IFN-I administration was protective against MERS-CoV lung disease.20, 21 Noteworthy, our observations revealed that IL-17A decreased IFN-I responses in intestinal epithelial cells, thus favouring human immunodeficiency virus type 1 (HIV-1) cell-to-cell spread.22 Similarly, in simian immunodeficiency virus (SIV) infections, mucosal IFN-I responses only developed at late time points post-infection and coincided with a vanished IL-17 response.23 These results point to the detrimental role of IL-17 in mounting a rapid IFN-I-mediated antiviral response. However, the beneficial impact of IFN-I on human lung diseases remains under investigation. A rec","journal":"Respirology","year":2020,"id":64582,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":30,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9607,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":341640,"name":"Boyang Zheng","orcid":"0000-0003-2509-5766","position":1,"is_corresponding":false},{"id":233493,"name":"Jean‐Pierre Routy","orcid":"0000-0001-9897-7589","position":2,"is_corresponding":false},{"id":18101,"name":"Petronela Ancuța","orcid":"0000-0003-1922-5640","position":3,"is_corresponding":false},{"id":343164,"name":"Tomas Raul Wiche Salinas","orcid":null,"position":0,"is_corresponding":true}],"reference_count":34,"raw_metadata":null,"created_at":"2026-07-18T21:12:58.081635Z","pmid":"32557955","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}