{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T07:00:22Z","timestamp":1791961222653,"version":"4.3.4"},"reference-count":43,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2023,10,17]],"date-time":"2023-10-17T00:00:00Z","timestamp":1697500800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI130020-01A1"],"award-info":[{"award-number":["R01AI130020-01A1"]}],"id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["5U19AI142784"],"award-info":[{"award-number":["5U19AI142784"]}],"id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004917","name":"Cancer Prevention and Research Institute of Texas","doi-asserted-by":"publisher","award":["RP200118"],"award-info":[{"award-number":["RP200118"]}],"id":[{"id":"10.13039\/100004917","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000875","name":"Pew Charitable Trusts","doi-asserted-by":"publisher","award":["Pew Scholars Program"],"award-info":[{"award-number":["Pew Scholars Program"]}],"id":[{"id":"10.13039\/100000875","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["R01 DK070855"],"award-info":[{"award-number":["R01 DK070855"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000928","name":"Welch Foundation","doi-asserted-by":"publisher","award":["I-1874"],"award-info":[{"award-number":["I-1874"]}],"id":[{"id":"10.13039\/100000928","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000011","name":"Howard Hughes Medical Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000011","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["T32 AI005284"],"award-info":[{"award-number":["T32 AI005284"]}],"id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Even though gammaherpesvirus and parasitic infections are endemic in parts of the world, there is a lack of understanding about the outcome of coinfection. In humans, coinfections usually occur sequentially, with fluctuating order and timing in different hosts. However, experimental studies in mice generally do not address the variables of order and timing of coinfections. We sought to examine the variable of coinfection order in a system of gammaherpesvirus-helminth coinfection. Our previous work demonstrated that infection with the intestinal parasite, <jats:italic>Heligmosomoides polygyrus<\/jats:italic>, induced transient reactivation from latency of murine gammaherpesvirus-68 (MHV68). In this report, we reverse the order of coinfection, infecting with <jats:italic>H<\/jats:italic>. <jats:italic>polygyrus<\/jats:italic> first, followed by MHV68, and examined the effects of preexisting parasite infection on MHV68 acute and latent infection. We found that preexisting parasite infection increased the propensity of MHV68 to reactivate from latency. However, when we examined the mechanism for reactivation, we found that preexisting parasite infection increased the ability of MHV68 to reactivate in a vitamin A dependent manner, a distinct mechanism to what we found previously with parasite-induced reactivation after latency establishment. We determined that <jats:italic>H<\/jats:italic>. <jats:italic>polygyrus<\/jats:italic> infection increased both acute and latent MHV68 infection in a population of tissue resident macrophages, called large peritoneal macrophages. We demonstrate that this population of macrophages and vitamin A are required for increased acute and latent infection during parasite coinfection.<\/jats:p>","DOI":"10.1371\/journal.ppat.1011691","type":"journal-article","created":{"date-parts":[[2023,10,17]],"date-time":"2023-10-17T17:22:29Z","timestamp":1697563349000},"page":"e1011691","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":9,"title":["Preexisting helminth challenge exacerbates infection and reactivation of gammaherpesvirus in tissue resident macrophages"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6211-5132","authenticated-orcid":true,"given":"Christina M.","family":"Zarek","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaitanya","family":"Dende","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaime","family":"Coronado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mihir","family":"Pendse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phillip","family":"Dryden","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lora V.","family":"Hooper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2325-6546","authenticated-orcid":true,"given":"Tiffany A.","family":"Reese","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,10,17]]},"reference":[{"issue":"9","key":"ppat.1011691.ref001","doi-asserted-by":"crossref","first-page":"2347","DOI":"10.1099\/0022-1317-73-9-2347","article-title":"Virological and pathological features of mice infected with murine gammaherpesvirus 68","volume":"73","author":"NP Sunil-Chandra","year":"1992","journal-title":"J Gen Virol"},{"issue":"1","key":"ppat.1011691.ref002","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/j.virol.2006.05.020","article-title":"A \u03b3-herpesvirus deficient in replication establishes chronic infection in vivo and is impervious to restriction by adaptive immune cells","volume":"353","author":"SA Tibbetts","year":"2006","journal-title":"Virology"},{"issue":"2","key":"ppat.1011691.ref003","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.4049\/jimmunol.165.2.1074","article-title":"Latent Murine \u03b3-Herpesvirus Infection Is Established in Activated B Cells, Dendritic Cells, and Macrophages","volume":"165","author":"E Fla\u00f1o","year":"2000","journal-title":"J Immunol"},{"issue":"13","key":"ppat.1011691.ref004","doi-asserted-by":"crossref","first-page":"7696","DOI":"10.1128\/JVI.77.13.7696-7701.2003","article-title":"Establishment and Maintenance of Gammaherpesvirus Latency Are Independent of Infective Dose and Route of Infection","volume":"77","author":"SA Tibbetts","year":"2003","journal-title":"J Virol"},{"issue":"22","key":"ppat.1011691.ref005","first-page":"12039","article-title":"Histone Deacetylases and the Nuclear Receptor Corepressor Regulate Lytic-Latent Switch Gene 50 in Murine Gammaherpesvirus 68-","volume":"84","author":"MM Goodwin","year":"2010","journal-title":"Infected Macrophages. J Virol"},{"issue":"8","key":"ppat.1011691.ref006","doi-asserted-by":"crossref","first-page":"5227","DOI":"10.1128\/JVI.79.8.5227-5231.2005","article-title":"Ex Vivo Stimulation of B Cells Latently Infected with Gammaherpesvirus 68 Triggers Reactivation from Latency","volume":"79","author":"JM Moser","year":"2005","journal-title":"J Virol"},{"issue":"6196","key":"ppat.1011691.ref007","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1126\/science.1254517","article-title":"Helminth infection reactivates latent \u03b3-herpesvirus via cytokine competition at a viral promoter","volume":"345","author":"TA Reese","year":"2014","journal-title":"Science"},{"issue":"6","key":"ppat.1011691.ref008","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1007\/s00281-012-0347-3","article-title":"Immunity to the model intestinal helminth parasite Heligmosomoides polygyrus","volume":"34","author":"LA Reynolds","year":"2012","journal-title":"Semin Immunopathol"},{"issue":"98","key":"ppat.1011691.ref009","first-page":"52412","article-title":"Cultivation of Heligmosomoides Polygyrus: An Immunomodulatory Nematode Parasite and its Secreted Products.","author":"CJC Johnston","year":"2015","journal-title":"J Vis Exp Jove."},{"issue":"11","key":"ppat.1011691.ref010","doi-asserted-by":"crossref","first-page":"2331","DOI":"10.1084\/jem.20101074","article-title":"Helminth secretions induce de novo T cell Foxp3 expression and regulatory function through the TGF-\u03b2 pathway.","volume":"207","author":"JR Grainger","year":"2010","journal-title":"J Exp Medicine."},{"issue":"4","key":"ppat.1011691.ref011","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1016\/j.immuni.2017.09.015","article-title":"HpARI Protein Secreted by a Helminth Parasite Suppresses Interleukin-33","volume":"47","author":"M Osbourn","year":"2017","journal-title":"Immunity"},{"issue":"5","key":"ppat.1011691.ref012","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1038\/mi.2013.123","article-title":"Blockade of IL-33 release and suppression of type 2 innate lymphoid cell responses by helminth secreted products in airway allergy","volume":"7","author":"HJ McSorley","year":"2014","journal-title":"Mucosal Immunol"},{"issue":"11","key":"ppat.1011691.ref013","doi-asserted-by":"crossref","first-page":"2477","DOI":"10.1084\/jem.20121999","article-title":"IL-4 directly signals tissue-resident macrophages to proliferate beyond homeostatic levels controlled by CSF-1.","volume":"210","author":"SJ Jenkins","year":"2013","journal-title":"J Exp Medicine"},{"issue":"8","key":"ppat.1011691.ref014","doi-asserted-by":"crossref","first-page":"1525","DOI":"10.1084\/jem.20140570","article-title":"Gata6 regulates aspartoacylase expression in resident peritoneal macrophages and controls their survival.","volume":"211","author":"EL Gautier","year":"2014","journal-title":"J Exp Medicine"},{"issue":"3","key":"ppat.1011691.ref015","doi-asserted-by":"crossref","first-page":"409","DOI":"10.4269\/ajtmh.2008.78.409","article-title":"Intestinal parasites in Kaposi sarcoma patients in Uganda: indication of shared risk factors or etiologic association","volume":"78","author":"CJ Lin","year":"2008","journal-title":"Am J Tropical Medicine Hyg"},{"issue":"1","key":"ppat.1011691.ref016","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/1750-9378-6-15","article-title":"Parasite infection is associated with Kaposi\u2019s sarcoma associated herpesvirus (KSHV) in Ugandan women.","volume":"6","author":"K Wakeham","year":"2011","journal-title":"Infect Agents Cancer"},{"issue":"8","key":"ppat.1011691.ref017","doi-asserted-by":"crossref","DOI":"10.1128\/JVI.01946-20","article-title":"Th2 Cytokine Modulates Herpesvirus Reactivation in a Cell Type-Specific Manner","volume":"95","author":"G Wang","year":"2021","journal-title":"J Virol"},{"issue":"10","key":"ppat.1011691.ref018","doi-asserted-by":"crossref","first-page":"6775","DOI":"10.1128\/jvi.70.10.6775-6780.1996","article-title":"Mature B cells are required for acute splenic infection, but not for establishment of latency, by murine gammaherpesvirus 68","volume":"70","author":"KE Weck","year":"1996","journal-title":"J Virol"},{"issue":"6","key":"ppat.1011691.ref019","doi-asserted-by":"crossref","first-page":"4651","DOI":"10.1128\/JVI.73.6.4651-4661.1999","article-title":"B Cells Regulate Murine Gammaherpesvirus 68 Latency.","volume":"73","author":"KE Weck","year":"1999","journal-title":"J Virol"},{"issue":"4","key":"ppat.1011691.ref020","doi-asserted-by":"crossref","first-page":"3273","DOI":"10.1128\/JVI.73.4.3273-3283.1999","article-title":"Macrophages are the major reservoir of latent murine gammaherpesvirus 68 in peritoneal cells","volume":"73","author":"KE Weck","year":"1999","journal-title":"J Virol"},{"issue":"11","key":"ppat.1011691.ref021","doi-asserted-by":"crossref","first-page":"6134","DOI":"10.1128\/JVI.00108-07","article-title":"Gamma Interferon Blocks Gammaherpesvirus Reactivation from Latency in a Cell Type-Specific Manner\u25bf","volume":"81","author":"A Steed","year":"2007","journal-title":"J Virol"},{"issue":"1","key":"ppat.1011691.ref022","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1002\/eji.201444806","article-title":"Critical role of p38 MAPK in IL-4-induced alternative activation of peritoneal macrophages","volume":"45","author":"L Jim\u00e9nez-Garcia","year":"2015","journal-title":"Eur J Immunol"},{"issue":"6035","key":"ppat.1011691.ref023","first-page":"1284","article-title":"Local Macrophage Proliferation, Rather than Recruitment from the Blood, Is a Signature of TH2","volume":"332","author":"SJ Jenkins","year":"2011","journal-title":"Inflammation. Science"},{"key":"ppat.1011691.ref024","doi-asserted-by":"crossref","first-page":"656979","DOI":"10.3389\/fmicb.2021.656979","article-title":"Optimized Detection of Acute MHV68 Infection With a Reporter System Identifies Large Peritoneal Macrophages as a Dominant Target of Primary Infection.","volume":"12","author":"JB Riggs","year":"2021","journal-title":"Front Microbiol."},{"issue":"15","key":"ppat.1011691.ref025","doi-asserted-by":"crossref","first-page":"7523","DOI":"10.1128\/JVI.02572-09","article-title":"Use of a Virus-Encoded Enzymatic Marker Reveals that a Stable Fraction of Memory B Cells Expresses Latency-Associated Nuclear Antigen throughout Chronic Gammaherpesvirus Infection\u25bf","volume":"84","author":"MS Nealy","year":"2010","journal-title":"J Virol"},{"issue":"19","key":"ppat.1011691.ref026","doi-asserted-by":"crossref","first-page":"10295","DOI":"10.1128\/JVI.77.19.10295-10303.2003","article-title":"The Gammaherpesvirus 68 Latency-Associated Nuclear Antigen Homolog Is Critical for the Establishment of Splenic Latency","volume":"77","author":"NJ Moorman","year":"2003","journal-title":"J Virol"},{"issue":"19","key":"ppat.1011691.ref027","doi-asserted-by":"crossref","first-page":"10488","DOI":"10.1128\/JVI.77.19.10488-10503.2003","article-title":"Transcription Program of Murine Gammaherpesvirus 68","volume":"77","author":"D Martinez-Guzman","year":"2003","journal-title":"J Virol"},{"key":"ppat.1011691.ref028","article-title":"Expression of factor V by resident macrophages boosts host defense in the peritoneal cavity","author":"N Zhang","year":"2019","journal-title":"J Exp Med"},{"issue":"1","key":"ppat.1011691.ref029","first-page":"14.1.1","article-title":"The Isolation and Characterization of Murine Macrophages","volume":"83","author":"X Zhang","year":"2008","journal-title":"urr Protoc Immunol"},{"issue":"20","key":"ppat.1011691.ref030","doi-asserted-by":"crossref","first-page":"e110","DOI":"10.1182\/blood-2013-08-520619","article-title":"Alternatively activated macrophages derived from monocytes and tissue macrophages are phenotypically and functionally distinct","volume":"123","author":"UM Gundra","year":"2014","journal-title":"Blood"},{"issue":"98","key":"ppat.1011691.ref031","first-page":"e52749","article-title":"Isolation of Murine Peritoneal Macrophages to Carry Out Gene Expression Analysis Upon Toll-like Receptors Stimulation.","author":"A Layoun","year":"2015","journal-title":"J Vis Exp"},{"issue":"5","key":"ppat.1011691.ref032","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1093\/jn\/117.5.857","article-title":"Impaired Immunity in Vitamin A-Deficient Mice.","volume":"117","author":"SM Smith","year":"1987","journal-title":"J Nutrition"},{"issue":"6","key":"ppat.1011691.ref033","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1038\/ni.3734","article-title":"Vitamin A mediates conversion of monocyte-derived macrophages into tissue-resident macrophages during alternative activation","volume":"18","author":"UM Gundra","year":"2017","journal-title":"Nat Immunol"},{"issue":"4","key":"ppat.1011691.ref034","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1016\/j.cell.2014.04.016","article-title":"Tissue-Specific Signals Control Reversible Program of Localization and Functional Polarization of Macrophages","volume":"157","author":"Y Okabe","year":"2014","journal-title":"Cell"},{"issue":"5","key":"ppat.1011691.ref035","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1016\/j.immuni.2017.10.006","article-title":"Tissue-Resident Macrophages Are Locally Programmed for Silent Clearance of Apoptotic Cells","volume":"47","author":"AW Roberts","year":"2017","journal-title":"Immunity"},{"issue":"1","key":"ppat.1011691.ref036","doi-asserted-by":"crossref","first-page":"438","DOI":"10.4049\/jimmunol.180.1.438","article-title":"TLR9 Contributes to Antiviral Immunity during Gammaherpesvirus Infection","volume":"180","author":"S Guggemoos","year":"2008","journal-title":"J Immunol"},{"issue":"2","key":"ppat.1011691.ref037","doi-asserted-by":"crossref","first-page":"887","DOI":"10.4049\/jimmunol.1003737","article-title":"Suppression of TLR9 Immunostimulatory Motifs in the Genome of a Gammaherpesvirus","volume":"187","author":"AC Pezda","year":"2011","journal-title":"J Immunol"},{"issue":"2","key":"ppat.1011691.ref038","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.it.2022.12.002","article-title":"Gata6+ large peritoneal macrophages: an evolutionarily conserved sentinel and effector system for infection and injury","volume":"44","author":"L Salm","year":"2023","journal-title":"Trends Immunol"},{"issue":"48","key":"ppat.1011691.ref039","article-title":"Rate of replenishment and microenvironment contribute to the sexually dimorphic phenotype and function of peritoneal macrophages.","volume":"5","author":"CC Bain","year":"2020","journal-title":"Sci Immunol."},{"issue":"3","key":"ppat.1011691.ref040","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/S1074-7613(00)80439-2","article-title":"Stat6 Is Required for Mediating Responses to IL-4 and for the Development of Th2 Cells.","volume":"4","author":"MH Kaplan","year":"1996","journal-title":"Immunity."},{"issue":"1","key":"ppat.1011691.ref041","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/1471-213X-6-19","article-title":"Generation of mice harbouring a conditional loss-of-function allele of Gata6","volume":"6","author":"CP Sodhi","year":"2006","journal-title":"Bmc Dev Biol"},{"issue":"7355","key":"ppat.1011691.ref042","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1038\/nature10138","article-title":"CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis","volume":"475","author":"BZ Qian","year":"2011","journal-title":"Nature"},{"issue":"10","key":"ppat.1011691.ref043","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1038\/s41590-020-0768-4","article-title":"Limited proliferation capacity of aortic intima resident macrophages requires monocyte recruitment for atherosclerotic plaque progression","volume":"21","author":"JW Williams","year":"2020","journal-title":"Nat Immunol"}],"container-title":["PLOS Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1011691","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,17]],"date-time":"2023-10-17T17:22:56Z","timestamp":1697563376000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1011691"}},"subtitle":[],"editor":[{"given":"Blossom","family":"Damania","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2023,10,17]]},"references-count":43,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2023,10,17]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.ppat.1011691","relation":{},"ISSN":["1553-7374"],"issn-type":[{"value":"1553-7374","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,17]]}}}