{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T17:06:55Z","timestamp":1779815215294,"version":"3.53.1"},"posted":{"date-parts":[[2026,5,21]]},"group-title":"Immunology","reference-count":29,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T00:00:00Z","timestamp":1779321600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"crossref","award":["R01 AI142784"],"award-info":[{"award-number":["R01 AI142784"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"crossref","award":["T32A I007520"],"award-info":[{"award-number":["T32A I007520"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"crossref","award":["R35 GM142654"],"award-info":[{"award-number":["R35 GM142654"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Host cell metabolic pathways influence innate immune responses to intracellular pathogens, but the contribution of nucleotide metabolism to antimicrobial defense remains incompletely defined. Here, we identify the mitochondrial nucleoside monophosphate kinase CMPK2 as a regulator of macrophage responses to\n                  <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                  (Mtb). Using a targeted genetic screen of candidate host factors, we found that depletion of CMPK2 enhances intracellular Mtb replication in human macrophages. This phenotype was confirmed using both shRNA-mediated knockdown and CRISPR-Cas9-mediated knockout approaches. CMPK2 expression increased following macrophage activation and Mtb infection. Transcriptomic profiling revealed that loss of CMPK2 is associated with broad alterations in gene expression, including reduced expression of genes linked to innate immune and inflammatory responses early after infection. In contrast, myeloid-specific deletion of\n                  <jats:italic>Cmpk2<\/jats:italic>\n                  in mice did not significantly alter bacterial burden or survival following aerosol Mtb infection, indicating that the contribution of CMPK2 to host defense is context dependent. Together, these findings identify CMPK2 as a host factor that limits Mtb replication in human macrophages and shapes innate immune gene expression programs.\n                <\/jats:p>","DOI":"10.64898\/2026.05.19.726211","type":"posted-content","created":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T23:05:19Z","timestamp":1779404719000},"source":"Crossref","is-referenced-by-count":0,"title":["CMPK2 restricts\n                  <i>Mycobacterium tuberculosis<\/i>\n                  replication and regulates macrophage gene expression"],"prefix":"10.64898","author":[{"given":"John","family":"Neff","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1276-6563","authenticated-orcid":false,"given":"Victoria A.","family":"Ektnitphong","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1789-3290","authenticated-orcid":false,"given":"Priscila C.","family":"Campos","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4703-9466","authenticated-orcid":false,"given":"Kubra F.","family":"Naqvi","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7433-3869","authenticated-orcid":false,"given":"Beatriz R. S.","family":"Dias","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8101-5604","authenticated-orcid":false,"given":"Kathryn C.","family":"Rahlwes","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenyu","family":"Zhong","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of Texas Southwestern Medical Center, Dallas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4329-2253","authenticated-orcid":false,"given":"Michael U.","family":"Shiloh","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, USA"},{"name":"Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026052609500808000_2026.05.19.726211v2.1","unstructured":"Anonymous. 2025. 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Geneva: World Health Organization."},{"key":"2026052609500808000_2026.05.19.726211v2.2","doi-asserted-by":"crossref","first-page":"2150449","DOI":"10.1080\/21505594.2022.2150449","article-title":"Pathogenicity and virulence of Mycobacterium tuberculosis","volume":"14","year":"2023","journal-title":"Virulence"},{"key":"2026052609500808000_2026.05.19.726211v2.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2012.03.007"},{"key":"2026052609500808000_2026.05.19.726211v2.4","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3813"},{"key":"2026052609500808000_2026.05.19.726211v2.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2015.05.005"},{"key":"2026052609500808000_2026.05.19.726211v2.6","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1005809"},{"key":"2026052609500808000_2026.05.19.726211v2.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2015.05.004"},{"key":"2026052609500808000_2026.05.19.726211v2.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2015.05.003"},{"key":"2026052609500808000_2026.05.19.726211v2.9","doi-asserted-by":"publisher","DOI":"10.1021\/acsinfecdis.5c00984"},{"key":"2026052609500808000_2026.05.19.726211v2.10","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M707997200"},{"key":"2026052609500808000_2026.05.19.726211v2.11","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1011286"},{"key":"2026052609500808000_2026.05.19.726211v2.12","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0010777"},{"key":"2026052609500808000_2026.05.19.726211v2.13","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-021-02470-6"},{"key":"2026052609500808000_2026.05.19.726211v2.14","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0372-z"},{"key":"2026052609500808000_2026.05.19.726211v2.15","doi-asserted-by":"publisher","DOI":"10.1023\/A:1008942828960"},{"key":"2026052609500808000_2026.05.19.726211v2.16","doi-asserted-by":"crossref","first-page":"eadq9006","DOI":"10.1126\/science.adq9006","article-title":"Nucleotide metabolic rewiring enables NLRP3 inflammasome hyperactivation in obesity","volume":"391","year":"2026","journal-title":"Science"},{"key":"2026052609500808000_2026.05.19.726211v2.17","doi-asserted-by":"crossref","unstructured":"Yu X , Song Y , Dong T , Ouyang W , Shao L , Quan C , Lee KE , Tan T , Tsung A , Kurabayashi K , Alam HB , Zhang M , Ma J , Li Y. 2024. Loss of PADI2 and PADI4 ameliorates sepsis-induced acute lung injury by suppressing NLRP3+ macrophages. 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