{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T02:28:04Z","timestamp":1774492084127,"version":"3.50.1"},"reference-count":75,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,10,5]],"date-time":"2022-10-05T00:00:00Z","timestamp":1664928000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p><jats:italic>Mycobacterium tuberculosis<\/jats:italic> (<jats:italic>Mtb<\/jats:italic>) has developed specialized mechanisms to parasitize its host cell, the macrophage. These mechanisms allow it to overcome killing by oxidative burst and persist in the wake of an inflammatory response. <jats:italic>Mtb<\/jats:italic> infection in the majority of those exposed is controlled in an asymptomatic form referred to as latent tuberculosis infection (LTBI). HIV is a well-known catalyst of reactivation of LTBI to active TB infection (ATB). Through the use of nonhuman primates (NHPs) co-infected with <jats:italic>Mtb<\/jats:italic> and Simian Immunodeficiency Virus (<jats:italic>Mtb<\/jats:italic>\/SIV), we are able to simulate human progression of TB\/AIDS comorbidity. The advantage of NHP models is that they recapitulate the breadth of human TB outcomes, including immune control of infection, and loss of this control due to SIV co-infection. Identifying correlates of immune control of infection is important for both vaccine and therapeutics development. Using macaques infected with <jats:italic>Mtb<\/jats:italic> or <jats:italic>Mtb<\/jats:italic>\/SIV and with different clinical outcomes we attempted to identify signatures between those that progress to active infection after SIV challenge (reactivators) and those that control the infection (non-reactivators). We particularly focused on pathways relevant to myeloid origin cells such as macrophages, as these innate immunocytes have an important contribution to the initial control or the lack thereof, following <jats:italic>Mtb<\/jats:italic> infection. Using bacterial burden, C-reactive protein (CRP), and other clinical indicators of disease severity as a guide, we were able to establish gene signatures of host disease state and progression. In addition to gene signatures, clustering algorithms were used to differentiate between host disease states and identify relationships between genes. This allowed us to identify clusters of genes which exhibited differential expression profiles between the three groups of macaques: ATB, LTBI and <jats:italic>Mtb<\/jats:italic>\/SIV. The gene signatures were associated with pathways relevant to apoptosis, ATP production, phagocytosis, cell migration, and Type I interferon (IFN), which are related to macrophage function. Our results suggest novel macrophage functions that may play roles in the control of <jats:italic>Mtb<\/jats:italic> infection with and without co-infection with SIV. These results particularly point towards an interplay between Type I IFN signaling and IFN-\u03b3 signaling, and the resulting impact on lung macrophages as an important determinant of progression to TB.<\/jats:p>","DOI":"10.3389\/fimmu.2022.777733","type":"journal-article","created":{"date-parts":[[2022,10,5]],"date-time":"2022-10-05T08:51:49Z","timestamp":1664959909000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["System-wide identification of myeloid markers of TB disease and HIV-induced reactivation in the macaque model of Mtb infection and Mtb\/SIV co-infection"],"prefix":"10.3389","volume":"13","author":[{"given":"Maya","family":"Gough","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dhiraj K.","family":"Singh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bindu","family":"Singh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deepak","family":"Kaushal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Smriti","family":"Mehra","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,10,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI153090","article-title":"Antiretroviral therapy timing impacts latent tuberculosis infection reactivation in a tuberculosis\/simian immunodeficiency virus coinfection model","volume":"132","author":"Sharan","year":"2021","journal-title":"J Clin Invest"},{"key":"B2","first-page":"57","volume-title":"Global tuberculosis report 2021","year":"2021"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1086\/426827","article-title":"How soon after infection with HIV does the risk of tuberculosis start to increase? a retrospective cohort study in south African gold miners","volume":"191","author":"Sonnenberg","year":"2005","journal-title":"J Infect Dis"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1097\/QAI.0b013e31819367e7","article-title":"Effect of simultaneous use of highly active antiretroviral therapy on survival of HIV patients with tuberculosis","volume":"50","author":"Velasco","year":"2009","journal-title":"J Acquir Immune Defic Syndr"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1128\/JB.00064-09","article-title":"Functional genomics reveals extended roles of the mycobacterium tuberculosis stress response factor sigmaH","volume":"191","author":"Mehra","year":"2009","journal-title":"J bacteriol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.102055799","article-title":"Reduced immunopathology and mortality despite tissue persistence in a mycobacterium tuberculosis mutant lacking alternative sigma factor, SigH","volume":"99","author":"Kaushal","year":"2002","journal-title":"Proc Natl Acad Sci United States America"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/nm.1795","article-title":"A membrane protein preserves intrabacterial pH in intraphagosomal mycobacterium tuberculosis","volume":"14","author":"Vandal","year":"2008","journal-title":"Nat Med"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1126\/science.1088063","article-title":"Immune control of tuberculosis by IFN-gamma-inducible LRG-47","volume":"302","author":"MacMicking","year":"2003","journal-title":"Science"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.176.7.4323","article-title":"Mycobacterium tuberculosis 19-kDa lipoprotein inhibits IFN-gamma-induced chromatin remodeling of MHC2TA by TLR2 and MAPK signaling","volume":"176","author":"Pennini","year":"2006","journal-title":"J Immunol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jix625","article-title":"High turnover of tissue macrophages contributes to tuberculosis reactivation in simian immunodeficiency virus-infected rhesus macaques","volume":"217","author":"Kuroda","year":"2018","journal-title":"J Infect Dis"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2020.11.013","article-title":"The immune landscape in tuberculosis reveals populations linked to disease and latency","volume":"29","author":"Esaulova","year":"2020","journal-title":"Cell Host Microbe"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20210615","article-title":"Single cell analysis of m","volume":"218","author":"Pisu","year":"2021","journal-title":"tuberculosis phenotype macrophage lineages infected lung. 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