{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T12:20:06Z","timestamp":1787833206490,"version":"build-2784847793"},"reference-count":106,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T00:00:00Z","timestamp":1787788800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Severe COVID-19 is strongly associated with a high incidence of secondary bacterial, fungal, and viral infections, which substantially contribute to prolonged hospitalization and increased mortality. Although cytokine storm characterized by elevated levels of IL-6, TNF-\u03b1, and IL-1\u03b2 has long dominated the understanding of the immunopathology of severe COVID-19, accumulating clinical and mechanistic evidence indicates that persistent immunosuppression and impaired antimicrobial immunity are equally critical determinants of disease outcomes. The coexistence of excessive inflammatory activation and profound immune paralysis within the same patient represents a major unresolved paradox in COVID-19 immunology. In this review, we systematically summarize recent advances in the mechanisms underlying SARS-CoV-2-induced immune remodeling and propose an integrated signaling network model that links inflammatory amplification with immunosuppressive reprogramming. We highlight the central roles of the GM-CSF, MAPK, TNF-\u03b1\u2013NF-\u03baB, and IL-6\u2013JAK\u2013STAT3 signaling networks in sustaining inflammatory activation, driving myeloid cell reprogramming, impairing antigen presentation, and promoting T-cell dysfunction and exhaustion. Furthermore, we propose an \u201cinflammation\u2013immunosuppression loop\u201d model, in which persistent inflammatory signaling actively induces immunosuppressive states through STAT3-dependent transcriptional programs, while impaired antimicrobial immunity facilitates secondary infections. Infection-associated activation of pattern recognition receptors subsequently reinforces inflammatory signaling, establishing a self-amplifying positive feedback loop that accelerates disease progression. This model provides a mechanistic explanation for the paradoxical coexistence of hyperinflammation and immune paralysis in severe COVID-19 and redefines secondary infections as active drivers of disease deterioration rather than merely downstream complications. Finally, we evaluate current and emerging host-directed therapeutic strategies and propose that future immunotherapeutic approaches should shift from single cytokine blockade toward precision restoration of immune homeostasis guided by dynamic monitoring of immune network states.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1934930","type":"journal-article","created":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T11:41:58Z","timestamp":1787830918000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["The inflammation\u2013immunosuppression loop as a driver of immune dysfunction and secondary infections in severe COVID-19"],"prefix":"10.3389","volume":"17","author":[{"given":"Guochao","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Clinical Laboratory, Ninth Hospital of Xi\u2019an","place":["Xi\u2019an, Shaanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanjun","family":"Lai","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Ninth Hospital of Xi\u2019an","place":["Xi\u2019an, Shaanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingying","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Pathology, Shanxi University of Medicine","place":["Fenyang, Shanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1002\/iub.2356","article-title":"Bacterial co-infections with SARS-coV-2","volume":"72","author":"Mirzaei","year":"2020","journal-title":"IUBMB Life"},{"key":"B2","doi-asserted-by":"publisher","first-page":"FSO819","DOI":"10.2144\/fsoa-2022-0011","article-title":"Co-infection associated with SARS-CoV-2 and their 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