{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T14:51:19Z","timestamp":1775487079380,"version":"3.50.1"},"reference-count":76,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,5,17]],"date-time":"2023-05-17T00:00:00Z","timestamp":1684281600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01HL146628"],"award-info":[{"award-number":["R01HL146628"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:p>Age-related illnesses, including hypertension and accompanying metabolic disorders, compromise immunity and exacerbate infection-associated fatalities. Renin-angiotensin system (RAS) is the key mechanism that controls blood pressure. Upregulation of RAS through angiotensin receptor type 1 (AT1R), a G-protein coupled receptor, contributes to the pathophysiological consequences leading to vascular remodeling, hypertension, and end-organ damage. Genetic variations that increase the expression of human AT1R may cause the above pathological outcomes associated with hypertension. Previously we have shown that our chronically hypertensive transgenic (TG) mice containing the haplotype-I variant (Hap-I, hypertensive genotype) of human <jats:italic>AT1R<\/jats:italic> (<jats:italic>hAT1R<\/jats:italic>) gene are more prone to develop the metabolic syndrome-related disorders as compared to the TG mice containing the haplotype-II variant (Hap-II, normotensive genotype). Since aging and an increased risk of hypertension can impact multiple organ systems in a complex manner, including susceptibility to various infections, the current study investigated the susceptibility and potential effect of acute bacterial infection using a Gram-negative intracellular bacterial pathogen, <jats:italic>Francisella tularensis<\/jats:italic> in our hAT1R TG mice. Our results show that compared to Hap-II, <jats:italic>F. tularensis-<\/jats:italic>infected aged Hap-I TG mice have significantly higher mortality post-infection, higher bacterial load and lung pathology, elevated inflammatory cytokines and altered gene expression profile favoring hypertension and inflammation. Consistent with worsened phenotype in aged Hap-I mice post-<jats:italic>Francisella<\/jats:italic> infection, gene expression profiles from their lungs revealed significantly altered expression of more than 1,400 genes. Furthermore, bioinformatics analysis identified genes associated with RAS and IFN-\u03b3 pathways regulating blood pressure and inflammation. These studies demonstrate that haplotype-dependent over-expression of the <jats:italic>hAT1R<\/jats:italic> gene leads to enhanced susceptibility and lethality due to <jats:italic>F. tularensis<\/jats:italic> LVS infection, which gets aggravated in aged animals. Clinically, these findings will help in exploring the role of AT1R-induced hypertension and enhanced susceptibility to infection-related respiratory diseases.<\/jats:p>","DOI":"10.3389\/fmicb.2023.1173577","type":"journal-article","created":{"date-parts":[[2023,5,17]],"date-time":"2023-05-17T05:33:15Z","timestamp":1684301595000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Chronically hypertensive transgenic mice expressing human AT1R haplotype-I exhibit increased susceptibility to Francisella tularensis"],"prefix":"10.3389","volume":"14","author":[{"given":"Harshada","family":"Ketkar","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maha","family":"Alqahtani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samantha","family":"Tang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sreema Puthiya","family":"Parambath","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chandra Shekhar","family":"Bakshi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sudhir","family":"Jain","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,5,17]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"2015","DOI":"10.1111\/bph.14364","article-title":"Human monocyte transcriptional profiling identifies IL-18 receptor accessory protein and lactoferrin as novel immune targets in hypertension","volume":"176","author":"Alexander","year":"2019","journal-title":"Br. J. Pharmacol."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"e0190457","DOI":"10.1371\/journal.pone.0190457","article-title":"Global mapping of transcription factor motifs in human aging","volume":"13","author":"Alfego","year":"2018","journal-title":"PLoS One"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"e00693-17","DOI":"10.1128\/JB.00693-17","article-title":"Characterization of a unique outer membrane protein required for oxidative stress resistance and virulence of Francisella tularensis","volume":"200","author":"Alqahtani","year":"2018","journal-title":"J. Bacteriol."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1177\/216507990205000810","article-title":"Tularemia","volume":"50","author":"Altman","year":"2002","journal-title":"AAOHN J."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1007\/s10875-010-9499-x","article-title":"Gain and loss of T cell subsets in old age \u2013 age-related reshaping of the T cell repertoire","volume":"31","author":"Arnold","year":"2011","journal-title":"J. Clin. Immunol."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1016\/j.mad.2011.08.005","article-title":"Natural killer cell function is altered during the primary response of aged mice to influenza infection","volume":"132","author":"Beli","year":"2011","journal-title":"Mech. Ageing Dev."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"524","DOI":"10.1172\/JCI36703","article-title":"Disruption of the Ang II type 1 receptor promotes longevity in mice","volume":"119","author":"Benigni","year":"2009","journal-title":"J. Clin. Investig."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"100116","DOI":"10.1016\/j.crpvbd.2023.100116","article-title":"Tularemia cases increase in the USA from 2011 through 2019","volume":"3","author":"Bishop","year":"2023","journal-title":"Curr. Res. Parasitol. Vector-Borne Dis."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1111\/cei.12881","article-title":"Innate immune responses in the ageing lung","volume":"187","author":"Boe","year":"2017","journal-title":"Clin. Exp. Immunol."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1038\/nbt.3519","article-title":"Near-optimal probabilistic RNA-seq quantification","volume":"34","author":"Bray","year":"2016","journal-title":"Nat. Biotechnol."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"881","DOI":"10.1189\/jlb.70.6.881","article-title":"Senescence in innate immune responses: reduced neutrophil phagocytic capacity and CD16 expression in elderly humans","volume":"70","author":"Butcher","year":"2001","journal-title":"J. Leukoc. Biol."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"eabj2138","DOI":"10.1126\/scitranslmed.abj2138","article-title":"An ACE inhibitor reduces bactericidal activity of human neutrophils in vitro and impairs mouse neutrophil activity in vivo","volume":"13","author":"Cao","year":"2021","journal-title":"Sci. Transl. Med."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"963","DOI":"10.2174\/138161212799436593","article-title":"Role of renin-angiotensin system in inflammation, immunity and aging","volume":"18","author":"Capettini","year":"2012","journal-title":"Curr. Pharm Des."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"1023","DOI":"10.1161\/HYPERTENSIONAHA.115.05779","article-title":"Obligatory role for B cells in the development of angiotensin II-dependent hypertension","volume":"66","author":"Chan","year":"2015","journal-title":"Hypertension"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"610","DOI":"10.1056\/nejmra052723","article-title":"The many roles of chemokines and chemokine receptors in inflammation","volume":"354","author":"Charo","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1111\/j.1532-5415.1994.tb06077.x","article-title":"Aging and marrow neutrophil reserves","volume":"42","author":"Chatta","year":"1994","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref17","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1000427","article-title":"Cytomegalovirus infection causes an increase of arterial blood pressure","volume":"5","author":"Cheng","year":"2009","journal-title":"PLoS Pathog."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1016\/S0002-9343(02)01484-5","article-title":"Coagulation and activation of inflammatory pathways in the development of functional decline and mortality in the elderly","volume":"114","author":"Cohen","year":"2003","journal-title":"Am. J. Med."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"1113","DOI":"10.1056\/nejmoa035115","article-title":"Expression of human herpesvirus 8 in primary pulmonary hypertension","volume":"349","author":"Cool","year":"2003","journal-title":"N. Engl. J. Med."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"R1089","DOI":"10.1152\/ajpregu.00373.2009","article-title":"Lymphocyte responses exacerbate angiotensin II-dependent hypertension","volume":"298","author":"Crowley","year":"2010","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"2106","DOI":"10.1161\/01.ATV.0000181743.28028.57","article-title":"Reduced vascular remodeling, endothelial dysfunction, and oxidative stress in resistance arteries of angiotensin II-infused macrophage colony-stimulating factor-deficient mice: evidence for a role in inflammation in angiotensin-induced vascular injury","volume":"25","author":"De Ciuceis","year":"2005","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"1413","DOI":"10.1097\/HJH.0b013e328338cd36","article-title":"Periodontal bacteria and hypertension: the oral infections and vascular disease epidemiology study (INVEST)","volume":"28","author":"Desvarieux","year":"2010","journal-title":"J. Hypertens."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"5106","DOI":"10.1128\/IAI.72.9.5106-5114.2004","article-title":"Senescent BALB\/c mice are able to develop resistance to Leishmania major infection","volume":"72","author":"Ehrchen","year":"2004","journal-title":"Infect. Immun."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1128\/CMR.15.4.631","article-title":"Tularemia","volume":"15","author":"Ellis","year":"2002","journal-title":"Clin. Microbiol. Rev."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1159\/000212361","article-title":"Age-related defense against infection with intracellular pathogens","volume":"25","author":"Emmerling","year":"1979","journal-title":"Gerontology"},{"key":"ref26","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.118.011771","article-title":"Effect of previous exposure to malaria on blood pressure in Kilifi, Kenya: a Mendelian randomization study","volume":"8","author":"Etyang","year":"2019","journal-title":"J. Am. Heart Assoc."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1161\/HYPERTENSIONAHA.118.10893","article-title":"Hypertension in HIV-infected adults: novel pathophysiologic mechanisms","volume":"72","author":"Fahme","year":"2018","journal-title":"Hypertension"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"1627","DOI":"10.1152\/physrev.00038.2017","article-title":"Angiotensin II signal transduction: an update on mechanisms of physiology and pathophysiology","volume":"98","author":"Forrester","year":"2018","journal-title":"Physiol. Rev."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"5769","DOI":"10.4049\/jimmunol.155.12.5769","article-title":"Controlled recruitment of monocytes and macrophages to specific organs through transgenic expression of monocyte chemoattractant protein-1","volume":"155","author":"Fuentes","year":"1995","journal-title":"J. Immunol."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"246","DOI":"10.1097\/01.CCM.0000251639.05135.E0","article-title":"Advanced age exacerbates the pulmonary inflammatory response after lipopolysaccharide exposure","volume":"35","author":"Gomez","year":"2007","journal-title":"Crit. Care Med."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"993","DOI":"10.1161\/CIRCRESAHA.121.318063","article-title":"Oxidative stress and hypertension","volume":"128","author":"Griendling","year":"2021","journal-title":"Circ. Res."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"2449","DOI":"10.1084\/jem.20070657","article-title":"Role of the T cell in the genesis of angiotensin II-induced hypertension and vascular dysfunction","volume":"204","author":"Guzik","year":"2007","journal-title":"J. Exp. Med."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1161\/HYPERTENSIONAHA.110.163576","article-title":"Inflammation, immunity, and hypertension","volume":"57","author":"Harrison","year":"2011","journal-title":"Hypertension"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"659","DOI":"10.1016\/j.cjca.2016.02.070","article-title":"Vascular fibrosis in aging and hypertension: molecular mechanisms and clinical implications","volume":"32","author":"Harvey","year":"2016","journal-title":"Can. J. Cardiol."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"867","DOI":"10.1111\/j.1474-9726.2012.00851.x","article-title":"Aging is associated with chronic innate immune activation and dysregulation of monocyte phenotype and function","volume":"11","author":"Hearps","year":"2012","journal-title":"Aging Cell"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"37048","DOI":"10.1074\/jbc.M113.520023","article-title":"A haplotype of angiotensin receptor type 1 associated with human hypertension increases blood pressure in transgenic mice","volume":"288","author":"Jain","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1093\/ajh\/hpx176","article-title":"Metabolic syndrome induces over expression of the human AT1R: A haplotype-dependent effect with implications on cardio-renal function","volume":"31","author":"Jain","year":"","journal-title":"Am. J. Hypertens."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"1234","DOI":"10.1093\/ajh\/hpy121","article-title":"Age-related expression of human AT1R variants and associated renal dysfunction in transgenic mice","volume":"31","author":"Jain","year":"","journal-title":"Am. J. Hypertens."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"777","DOI":"10.1016\/j.humimm.2009.07.005","article-title":"Aging is associated with a numerical and functional decline in plasmacytoid dendritic cells, whereas myeloid dendritic cells are relatively unaltered in human peripheral blood","volume":"70","author":"Jing","year":"2009","journal-title":"Hum. Immunol."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"1269","DOI":"10.1172\/JCI5208","article-title":"Chronic inflammation upregulates chemokine receptors and induces neutrophil migration to monocyte chemoattractant protein-1","volume":"103","author":"Johnston","year":"1999","journal-title":"J. Clin. Investig."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"4642","DOI":"10.1172\/JCI74084","article-title":"DC isoketal-modified proteins activate T cells and promote hypertension","volume":"124","author":"Kirabo","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.mib.2015.11.003","article-title":"Infection in an aging population","volume":"29","author":"Kline","year":"2016","journal-title":"Curr. Opin. Microbiol."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"342","DOI":"10.1016\/j.smim.2012.04.004","article-title":"B cell maintenance and function in aging","volume":"24","author":"Kogut","year":"2012","journal-title":"Semin. Immunol."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"14988","DOI":"10.1073\/pnas.232308999","article-title":"Transcriptional profiles associated with aging and middle age-onset caloric restriction in mouse hearts","volume":"99","author":"Lee","year":"2002","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"ref45","doi-asserted-by":"publisher","first-page":"59","DOI":"10.3109\/03009742.2013.834963","article-title":"Hypertension is associated with serologically active disease in patients with systemic lupus erythematosus: role of increased Th1\/Th2 ratio and oxidative stress","volume":"43","author":"Lozovoy","year":"2014","journal-title":"Scand. J. Rheumatol."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"e0224094","DOI":"10.1371\/journal.pone.0224094","article-title":"Stringent response governs the oxidative stress resistance and virulence of Francisella tularensis","volume":"14","author":"Ma","year":"2019","journal-title":"PLoS One"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"500","DOI":"10.1161\/HYPERTENSIONAHA.109.145094","article-title":"Interleukin 17 promotes angiotensin II-induced hypertension and vascular dysfunction","volume":"55","author":"Madhur","year":"2010","journal-title":"Hypertension"},{"key":"ref48","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.exger.2009.10.004","article-title":"Aged mice display an altered pulmonary host response to Francisella tularensis live vaccine strain (LVS) infections","volume":"45","author":"Mares","year":"","journal-title":"Exp. Gerontol."},{"key":"ref49","doi-asserted-by":"publisher","first-page":"3001","DOI":"10.1128\/IAI.00215-08","article-title":"Initial delay in the immune response to Francisella tularensis is followed by hypercytokinemia characteristic of severe sepsis and correlating with upregulation and release of damage-associated molecular patterns","volume":"76","author":"Mares","year":"2008","journal-title":"Infect. Immun."},{"key":"ref50","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0014088","article-title":"Attenuated response of aged mice to respiratory Francisella novicida is characterized by reduced cell death and absence of subsequent hypercytokinemia","volume":"5","author":"Mares","year":"","journal-title":"PLoS One"},{"key":"ref51","doi-asserted-by":"publisher","first-page":"e0018521","DOI":"10.1128\/JB.00185-21","article-title":"An AraC\/XylS family transcriptional regulator modulates the oxidative stress response of Francisella tularensis","volume":"203","author":"Marghani","year":"2021","journal-title":"J. Bacteriol."},{"key":"ref52","doi-asserted-by":"publisher","first-page":"C82","DOI":"10.1152\/ajpcell.00287.2006","article-title":"Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system","volume":"292","author":"Mehta","year":"2007","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref53","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0004619","article-title":"NTD and NCD co-morbidities: the example of dengue fever","volume":"10","author":"Mehta","year":"2016","journal-title":"PLoS Negl. Trop. Dis."},{"key":"ref54","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1038\/s41581-019-0244-2","article-title":"The global epidemiology of hypertension","volume":"16","author":"Mills","year":"2020","journal-title":"Nat. Rev. Nephrol."},{"key":"ref55","doi-asserted-by":"publisher","first-page":"107680","DOI":"10.1016\/j.exer.2019.05.020","article-title":"The renin-angiotensin-aldosterone system and its therapeutic targets","volume":"186","author":"Mirabito Colafella","year":"2019","journal-title":"Exp. Eye Res."},{"key":"ref560","doi-asserted-by":"publisher","first-page":"R1","DOI":"10.1530\/VB-20-0014","article-title":"Aging- and gender-related modulation of RAAS: potential implications in COVID-19 disease","volume":"3","author":"Monteonofrio","year":"2021","journal-title":"Vasc. Biol."},{"key":"ref56","doi-asserted-by":"publisher","first-page":"7977","DOI":"10.4049\/jimmunol.181.11.7977","article-title":"Aging mice exhibit a functional defect in mucosal dendritic cell response against an intracellular pathogen","volume":"181","author":"Moretto","year":"2008","journal-title":"J. Immunol."},{"key":"ref57","doi-asserted-by":"publisher","first-page":"613","DOI":"10.1111\/j.1439-0450.1993.tb00184.x","article-title":"Identification and classification of different isolates of Francisella tularensis","volume":"40","author":"M\u00f6rner","year":"1993","journal-title":"J. Veterinary Med. Ser. B"},{"key":"ref58","doi-asserted-by":"publisher","first-page":"797","DOI":"10.3390\/ijms17070797","article-title":"Role of the renin-angiotensin-aldosterone system beyond blood pressure regulation: molecular and cellular mechanisms involved in end-organ damage during arterial hypertension","volume":"17","author":"Mu\u00f1oz-Durango","year":"2016","journal-title":"Int. J. Mol. Sci."},{"key":"ref59","doi-asserted-by":"publisher","first-page":"e427","DOI":"10.1371\/journal.pbio.0020427","article-title":"A transcriptional profile of aging in the human kidney","volume":"2","author":"Rodwell","year":"2004","journal-title":"PLoS Biol."},{"key":"ref60","doi-asserted-by":"publisher","first-page":"404","DOI":"10.1016\/j.phrs.2017.02.026","article-title":"The role of chemokines in hypertension and consequent target organ damage","volume":"119","author":"Rudemiller","year":"2017","journal-title":"Pharmacol. Res."},{"key":"ref61","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1186\/1471-2172-11-30","article-title":"Age-dependent alterations of monocyte subsets and monocyte-related chemokine pathways in healthy adults","volume":"11","author":"Seidler","year":"2010","journal-title":"BMC Immunol."},{"key":"ref62","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/j.micpath.2011.03.007","article-title":"Features of sepsis caused by pulmonary infection with Francisella tularensis type A strain","volume":"51","author":"Sharma","year":"2011","journal-title":"Microb. Pathog."},{"key":"ref63","doi-asserted-by":"publisher","first-page":"875","DOI":"10.1038\/nri3547","article-title":"Age-dependent dysregulation of innate immunity","volume":"13","author":"Shaw","year":"2013","journal-title":"Nat. Rev. Immunol."},{"key":"ref64","doi-asserted-by":"publisher","first-page":"17056","DOI":"10.1038\/cddiscovery.2017.56","article-title":"Necroptotic debris including damaged mitochondria elicits sepsis-like syndrome during late-phase tularemia","volume":"3","author":"Singh","year":"2017","journal-title":"Cell Death Discov."},{"key":"ref65","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1196\/annals.1409.009","article-title":"Tularemia: history, epidemiology, pathogen physiology, and clinical manifestations","volume":"1105","author":"Sj\u00f6stedt","year":"2007","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref66","doi-asserted-by":"publisher","first-page":"420","DOI":"10.1016\/j.ijcard.2005.05.039","article-title":"Seropositivity to Chlamydia pneumoniae or Helicobacter pylori and coronary artery disease","volume":"109","author":"Sotiropoulos","year":"2006","journal-title":"Int. J. Cardiol."},{"key":"ref67","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1007\/978-1-0716-1488-4_8","article-title":"Francisella tularensis infection of mice as a model of sepsis","volume":"2321","author":"Spencer","year":"2021","journal-title":"Methods Mol. Biol."},{"key":"ref68","doi-asserted-by":"publisher","first-page":"725572","DOI":"10.3389\/fmicb.2021.725572","article-title":"Nlrp3 increases the Host\u2019s susceptibility to tularemia","volume":"12","author":"Suresh","year":"2021","journal-title":"Front. Microbiol."},{"key":"ref69","doi-asserted-by":"publisher","first-page":"159","DOI":"10.2174\/187152812800392805","article-title":"The IL23\/Th17 pathway as a therapeutic target in chronic inflammatory diseases","volume":"11","author":"Toussirot","year":"2012","journal-title":"Inflamm. Allergy Drug Targets"},{"key":"ref700","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1007\/s11906-022-01207-3","article-title":"Renin\u2013Angiotensin\u2013Aldosterone Inhibitors and COVID-19 Infection","volume":"24","author":"Tsampasian","year":"2022","journal-title":"Curr. Hypertens Rep."},{"key":"ref70","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1002\/kjm2.12237","article-title":"Two hits to the renin-angiotensin system may play a key role in severe COVID-19","volume":"36","author":"Tseng","year":"2020","journal-title":"Kaohsiung J. Med. Sci."},{"key":"ref71","doi-asserted-by":"publisher","first-page":"1307","DOI":"10.1097\/01.hjh.0000234111.31239.c3","article-title":"Deregulated expression of monocyte chemoattractant protein-1 (MCP-1) in arterial hypertension: role in endothelial inflammation and atheromasia","volume":"24","author":"Tucci","year":"2006","journal-title":"J. Hypertens."},{"key":"ref72","doi-asserted-by":"publisher","first-page":"4628","DOI":"10.1128\/IAI.70.8.4628-4637.2002","article-title":"Old mice express a transient early resistance to pulmonary tuberculosis that is mediated by CD8 T cells","volume":"70","author":"Turner","year":"2002","journal-title":"Infect. Immun."},{"key":"ref73","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/j.mad.2006.11.015","article-title":"Inflammatory networks in ageing, age-related diseases and longevity","volume":"128","author":"Vasto","year":"2007","journal-title":"Mech. Ageing Dev."},{"key":"ref74","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1002\/jlb.67.1.40","article-title":"Effect of age on human neutrophil function","volume":"67","author":"Wenisch","year":"2000","journal-title":"J. Leukoc. Biol."}],"container-title":["Frontiers in Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2023.1173577\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,17]],"date-time":"2023-05-17T05:34:06Z","timestamp":1684301646000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2023.1173577\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,17]]},"references-count":76,"alternative-id":["10.3389\/fmicb.2023.1173577"],"URL":"https:\/\/doi.org\/10.3389\/fmicb.2023.1173577","relation":{},"ISSN":["1664-302X"],"issn-type":[{"value":"1664-302X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,17]]},"article-number":"1173577"}}