{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T08:48:48Z","timestamp":1768553328935,"version":"3.49.0"},"posted":{"date-parts":[[2023,2,11]]},"group-title":"Immunology","reference-count":49,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,2,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Immune networks that control antimicrobial and inflammatory mechanisms have overlapping regulation and functions to ensure effective host responses. Genetic interaction studies of immune pathways that compare host responses in single and combined knockout backgrounds are a useful tool to identify new mechanisms of immune control during infection. For disease caused by pulmonary\n                  <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                  infections, which currently lacks an effective vaccine, understanding genetic interactions between protective immune pathways may identify new therapeutic targets or disease-associated genes. Previous studies suggested a direct link between the activation of NLRP3-Caspase1 inflammasome and the NADPH-dependent phagocyte oxidase complex during Mtb infection. Loss of the phagocyte oxidase complex alone resulted in increased activation of Caspase1 and IL1\u03b2 production during Mtb infection, resulting in failed disease tolerance during the chronic stages of disease. To better understand this interaction, we generated mice lacking both\n                  <jats:italic>Cybb<\/jats:italic>\n                  , a key subunit of the phagocyte oxidase, and\n                  <jats:italic>Caspase1\/11<\/jats:italic>\n                  . We found that\n                  <jats:italic>ex vivo<\/jats:italic>\n                  Mtb infection of\n                  <jats:italic>Cybb<\/jats:italic>\n                  <jats:sup>\n                    <jats:italic>-\/-<\/jats:italic>\n                  <\/jats:sup>\n                  <jats:italic>Caspase1\/11<\/jats:italic>\n                  <jats:sup>\n                    <jats:italic>-\/-<\/jats:italic>\n                  <\/jats:sup>\n                  macrophages resulted in the expected loss of IL1\u03b2 secretion but an unexpected change in other inflammatory cytokines and bacterial control. Mtb infected\n                  <jats:italic>Cybb<\/jats:italic>\n                  <jats:sup>\n                    <jats:italic>-\/-<\/jats:italic>\n                  <\/jats:sup>\n                  <jats:italic>Caspase1\/11<\/jats:italic>\n                  <jats:sup>\n                    <jats:italic>-\/-<\/jats:italic>\n                  <\/jats:sup>\n                  mice rapidly progressed to severe TB, succumbing within four weeks to disease characterized by high bacterial burden, increased inflammatory cytokines, and the recruitment of granulocytes that associated with Mtb in the lungs. These results uncover a key genetic interaction between the phagocyte oxidase complex and Caspase1\/11 that controls protection against TB and highlight the need for a better understanding of the regulation of fundamental immune networks during Mtb infection.\n                <\/jats:p>","DOI":"10.1101\/2023.02.08.527787","type":"posted-content","created":{"date-parts":[[2023,2,11]],"date-time":"2023-02-11T23:50:11Z","timestamp":1676159411000},"source":"Crossref","is-referenced-by-count":0,"title":["Rapid lethality of mice lacking the phagocyte oxidase and Caspase1\/11 following\n                  <i>Mycobacterium tuberculosis<\/i>\n                  infection"],"prefix":"10.64898","author":[{"given":"Sean M.","family":"Thomas","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3441-3113","authenticated-orcid":false,"given":"Andrew J.","family":"Olive","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2023021401550435000_2023.02.08.527787v1.1","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00046-08"},{"key":"2023021401550435000_2023.02.08.527787v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/nri3259"},{"key":"2023021401550435000_2023.02.08.527787v1.3","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02094"},{"key":"2023021401550435000_2023.02.08.527787v1.4","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-042718-041739"},{"key":"2023021401550435000_2023.02.08.527787v1.5","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02976"},{"key":"2023021401550435000_2023.02.08.527787v1.6","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro3230"},{"key":"2023021401550435000_2023.02.08.527787v1.7","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20110919"},{"key":"2023021401550435000_2023.02.08.527787v1.8","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1800438"},{"key":"2023021401550435000_2023.02.08.527787v1.9","doi-asserted-by":"publisher","DOI":"10.1016\/1074-7613(95)90001-2"},{"key":"2023021401550435000_2023.02.08.527787v1.10","doi-asserted-by":"publisher","DOI":"10.1016\/S1359-6101(03)00054-6"},{"key":"2023021401550435000_2023.02.08.527787v1.11","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-093019-010426"},{"key":"2023021401550435000_2023.02.08.527787v1.12","first-page":"S26","article-title":"The WHO Global Tuberculosis 2021 Report - not so good news and turning the tide back to End TB","volume":"1","year":"2022","journal-title":"Int J Infect Dis 124 Suppl"},{"key":"2023021401550435000_2023.02.08.527787v1.13","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro.2016.12"},{"key":"2023021401550435000_2023.02.08.527787v1.14","doi-asserted-by":"crossref","first-page":"e1008728","DOI":"10.1371\/journal.pgen.1008728","article-title":"Interaction between host genes and Mycobacterium tuberculosis lineage can affect tuberculosis severity: Evidence for coevolution?","volume":"16","year":"2020","journal-title":"PLoS Genet"},{"key":"2023021401550435000_2023.02.08.527787v1.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.smim.2014.09.008"},{"key":"2023021401550435000_2023.02.08.527787v1.16","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.16.8841"},{"key":"2023021401550435000_2023.02.08.527787v1.17","doi-asserted-by":"publisher","DOI":"10.1038\/nature16451"},{"key":"2023021401550435000_2023.02.08.527787v1.18","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1800202"},{"key":"2023021401550435000_2023.02.08.527787v1.19","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2011.12.002"},{"key":"2023021401550435000_2023.02.08.527787v1.20","doi-asserted-by":"publisher","DOI":"10.1038\/cmi.2014.89"},{"key":"2023021401550435000_2023.02.08.527787v1.21","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1992"},{"key":"2023021401550435000_2023.02.08.527787v1.22","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20021186"},{"key":"2023021401550435000_2023.02.08.527787v1.23","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.68.3.1231-1234.2000"},{"key":"2023021401550435000_2023.02.08.527787v1.24","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2004.04078.x"},{"key":"2023021401550435000_2023.02.08.527787v1.25","doi-asserted-by":"crossref","unstructured":"Kelley N , Jeltema D , Duan Y , He Y. 2019. 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