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However, growing evidence suggests that the host environment is crucial for antibacterial efficacy. Pyrazinamide (PZA), a key component of modern tuberculosis therapy, exemplifies this complexity, exhibiting potent\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      activity despite its inability to reduce\n                      <jats:italic toggle=\"yes\">Mycobacterium tuberculosis<\/jats:italic>\n                      viability in standard\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      culture. Here, using macrophage and murine infection models, we identify a critical role for CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cell-dependent cell-mediated immunity in PZA\u2019s antitubercular action. Using MHC class II knockout mice, we demonstrate that CD4 T-cell help is essential for PZA efficacy. While interferon gamma (IFN-\u03b3) is required for PZA-mediated clearance of\n                      <jats:italic toggle=\"yes\">M. tuberculosis<\/jats:italic>\n                      at extrapulmonary sites, bacterial reduction in the lungs occurs, independent of IFN-\u03b3 signaling. We show that PZA leverages cell-mediated immunity in part through activation of the oxidative burst. Our findings underscore the need to incorporate host factors into antibacterial drug evaluation and highlight potential avenues for host-directed therapies and adjunctive antibiotics in first- and second-line tuberculosis treatment.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/aac.01264-25","type":"journal-article","created":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T14:05:36Z","timestamp":1766153136000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Essential role of MHC II in the antitubercular efficacy of pyrazinamide"],"prefix":"10.1128","volume":"70","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7085-9740","authenticated-orcid":true,"given":"Elise A.","family":"Lamont","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/017zqws13","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Immunology, University of Minnesota","place":["Minneapolis, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1106-4264","authenticated-orcid":true,"given":"Shannon L.","family":"Kordus","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/017zqws13","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Immunology, University of Minnesota","place":["Minneapolis, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael D.","family":"Howe","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/017zqws13","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Immunology, University of Minnesota","place":["Minneapolis, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8279-5561","authenticated-orcid":true,"given":"Ziyi","family":"Jia","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/017zqws13","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Immunology, University of Minnesota","place":["Minneapolis, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7081-7648","authenticated-orcid":true,"given":"Nathan","family":"Schacht","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/017zqws13","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Immunology, University of Minnesota","place":["Minneapolis, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9485-6453","authenticated-orcid":false,"given":"Muzafar Ahmad","family":"Rather","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/017zqws13","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Immunology, University of Minnesota","place":["Minneapolis, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8928-852X","authenticated-orcid":true,"given":"Gebremichal","family":"Gebretsadik","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/017zqws13","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Immunology, University of Minnesota","place":["Minneapolis, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1188-4238","authenticated-orcid":true,"given":"Anthony D.","family":"Baughn","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/017zqws13","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Immunology, University of Minnesota","place":["Minneapolis, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1164\/artpd.1956.74.2-2.100"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.2.4891.767"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.3181\/00379727-79-19447"},{"key":"e_1_3_4_5_2","first-page":"511","article-title":"The effect of pyrazinamide (aldinamide) on experimental tuberculosis in mice","volume":"65","author":"Malone L","year":"1952","unstructured":"Malone L, Schurr A, Lindh H, McKenzie D, Kiser JS, Williams JH. 1952. 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