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We then performed a stratified analysis based on mortality amongst the COVID-19 cohort with known outcomes of deceased (<jats:italic>n<\/jats:italic>\u2009=\u200910) versus survived (<jats:italic>n<\/jats:italic>\u2009=\u200915). Our overarching hypothesis was that there are detectable and functionally significant relationships between BALF microbial metatranscriptomes and the severity of COVID-19 disease onset and progression. We observed 34 functionally discriminant gene ontology (GO) terms in COVID-19 disease compared to the CAP and uninfected cohorts, and 21 GO terms functionally discriminant to COVID-19 mortality (q\u2009&lt;\u20090.05). GO terms enriched in the COVID-19 disease cohort included hydrolase activity, and significant GO terms under the parental terms of biological regulation, viral process, and interspecies interaction between organisms. Notable GO terms associated with COVID-19 mortality included nucleobase-containing compound biosynthetic process, organonitrogen compound catabolic process, pyrimidine-containing compound biosynthetic process, and DNA recombination, RNA binding, magnesium and zinc ion binding, oxidoreductase activity, and endopeptidase activity. A Dirichlet multinomial mixtures clustering analysis resulted in a best model fit using three distinct clusters that were significantly associated with COVID-19 disease and mortality. We additionally observed discriminant taxonomic differences associated with COVID-19 disease and mortality in the genus<jats:italic>Sphingomonas,<\/jats:italic>belonging to the Sphingomonadacae family,<jats:italic>Variovorax,<\/jats:italic>belonging to the Comamonadaceae family, and in the class Bacteroidia<jats:italic>,<\/jats:italic>belonging to the order Bacteroidales. To our knowledge, this is the first study to evaluate significant differences in taxonomic and functional signatures between BALF metatranscriptomes from COVID-19, CAP, and uninfected cohorts, as well as associating these taxa and microbial gene functions with COVID-19 mortality. Collectively, while this data does not speak to causality nor directionality of the association, it does demonstrate a significant relationship between the human microbiome and COVID-19. The results from this study have rendered testable hypotheses that warrant further investigation to better understand the causality and directionality of host\u2013microbiome\u2013pathogen interactions.<\/jats:p>","DOI":"10.1038\/s41598-022-25463-0","type":"journal-article","created":{"date-parts":[[2022,12,7]],"date-time":"2022-12-07T11:09:59Z","timestamp":1670411399000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Analysis of bronchoalveolar lavage fluid metatranscriptomes among patients with COVID-19 disease"],"prefix":"10.1038","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2398-356X","authenticated-orcid":false,"given":"Michael","family":"Jochum","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7750-9145","authenticated-orcid":false,"given":"Michael D.","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8375-397X","authenticated-orcid":false,"given":"Kristen","family":"Curry","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7916-4902","authenticated-orcid":false,"given":"Victoria","family":"Zaksas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6036-1543","authenticated-orcid":false,"given":"Elizabeth","family":"Vitalis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3760-564X","authenticated-orcid":false,"given":"Todd","family":"Treangen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2960-0371","authenticated-orcid":false,"given":"Kjersti","family":"Aagaard","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1138-5308","authenticated-orcid":false,"given":"Krista L.","family":"Ternus","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2022,12,7]]},"reference":[{"issue":"4","key":"25463_CR1","doi-asserted-by":"publisher","first-page":"e0177721","DOI":"10.1128\/mBio.01777-21","volume":"12","author":"C Merenstein","year":"2021","unstructured":"Merenstein, C. et al. 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