{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T12:02:33Z","timestamp":1779796953129,"version":"3.53.1"},"reference-count":152,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T00:00:00Z","timestamp":1779753600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Education and Science of Russia","award":["FGWS-2025-0008"],"award-info":[{"award-number":["FGWS-2025-0008"]}]},{"name":"Ministry of Education and Science of Russia","award":["125091010190-9"],"award-info":[{"award-number":["125091010190-9"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Background: Dysregulated myeloid responses are central to severe COVID-19, but the contribution of host genetics to this \u201cemergency myelopoiesis\u201d is poorly understood. Methods: We performed whole-exome sequencing in 77 hospitalized COVID-19 patients to analyze the impact of the cumulative burden of rare, high-impact variants (qualifying variants, QVs) in hemopoietic and inflammatory gene sets on longitudinal leukocyte counts. Predictive models were validated using repeated internal cross-validation (1000 resamples) and external population-scale exome data (Genebass, n &gt; 380,000). Results: The QV burden was a significant predictor of peak neutrophil and monocyte counts, independent of age, sex, and clinical severity. This association remained robust in a microbiologically confirmed \u201cpure viral\u201d subcohort (n = 54) and was stable across internal cross-validation resamples. External validation revealed an 11.2-fold enrichment of myeloid-associated genes within our candidate gene sets (p \u2248 2.2 \u00d7 10\u221263). Patients with a high QV burden exhibited significantly worse outcomes, including a four-fold increase in mortality (p = 0.00065), and a genetic profile linked to hyper-inflammation and thrombosis. Conclusion: These findings suggest that host genetic architecture may contribute to the magnitude of myeloid dysregulation in acute viral infection. Genetic stratification could identify patients predisposed to a hyperactive myeloid response, potentially guiding early, targeted immunomodulation to mitigate severe complications.<\/jats:p>","DOI":"10.3390\/v18060604","type":"journal-article","created":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T11:02:51Z","timestamp":1779793371000},"page":"604","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genetic Architectures of Myeloid Dysregulation in Severe COVID-19"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3051-6756","authenticated-orcid":false,"given":"Darya A.","family":"Kashatnikova","sequence":"first","affiliation":[{"name":"Vavilov Institute of General Genetics, Russian Academy of Sciences, 119991 Moscow, Russia"},{"name":"Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, 119435 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1361-6085","authenticated-orcid":false,"given":"Alesya S.","family":"Gracheva","sequence":"additional","affiliation":[{"name":"Vavilov Institute of General Genetics, Russian Academy of Sciences, 119991 Moscow, Russia"},{"name":"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, 107031 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5930-0118","authenticated-orcid":false,"given":"Artem N.","family":"Kuzovlev","sequence":"additional","affiliation":[{"name":"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, 107031 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9671-335X","authenticated-orcid":false,"given":"Lyubov E.","family":"Salnikova","sequence":"additional","affiliation":[{"name":"Vavilov Institute of General Genetics, Russian Academy of Sciences, 119991 Moscow, Russia"},{"name":"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, 107031 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1016\/S2213-2600(21)00218-6","article-title":"The COVID-19 puzzle: Deciphering pathophysiology and phenotypes of a new disease entity","volume":"9","author":"Osuchowski","year":"2021","journal-title":"Lancet Respir. 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