{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T23:42:11Z","timestamp":1790638931120,"version":"4.1.0"},"reference-count":44,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2015,10,1]],"date-time":"2015-10-01T00:00:00Z","timestamp":1443657600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Leishmaniasis is a significant neglected tropical disease that is associated with a wide range of clinical presentations and a lifelong persistent infection. Because of the chronic nature of the disease, there is a high risk for coinfection occurring in patients, and how coinfections influence the outcome of leishmaniasis is poorly understood. To address this issue, we infected mice with Leishmania major and 2 wk later with lymphocytic choriomeningitis virus (LCMV) and then monitored the course of infection. Leishmania parasites are controlled by production of IFN-\u03b3, which leads to macrophage-mediated parasite killing. Thus, one might predict that coinfection with LCMV, which induces a strong systemic type 1 response, would accelerate disease resolution. However, we found that infection with LCMV led to significantly enhanced disease in L. major\u2013infected animals. This increased disease correlated with an infiltration into the leishmanial lesions of NKG2D+ CD8+ T cells producing granzyme B, but surprisingly little IFN-\u03b3. We found that depletion of CD8 T cells after viral clearance, as well as blockade of NKG2D, reversed the increased pathology seen in coinfected mice. Thus, this work highlights the impact a secondary infection can have on leishmaniasis and demonstrates that even pathogens known to promote a type 1 response may exacerbate leishmanial infections.<\/jats:p>","DOI":"10.4049\/jimmunol.1500855","type":"journal-article","created":{"date-parts":[[2015,8,20]],"date-time":"2015-08-20T02:00:18Z","timestamp":1440036018000},"page":"3301-3310","source":"Crossref","is-referenced-by-count":55,"title":["Lymphocytic Choriomeningitis Virus Expands a Population of NKG2D+CD8+ T Cells That Exacerbates Disease in Mice Coinfected with <i>Leishmania major<\/i>"],"prefix":"10.1093","volume":"195","author":[{"given":"Erika J","family":"Crosby","sequence":"first","affiliation":[{"name":"Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania , Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan","family":"Clark","sequence":"additional","affiliation":[{"name":"Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania , Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernanda O","family":"Novais","sequence":"additional","affiliation":[{"name":"Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania , Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E John","family":"Wherry","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phillip","family":"Scott","sequence":"additional","affiliation":[{"name":"Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania , Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2015,10,1]]},"reference":[{"key":"2025030704160308800_r1","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1016\/j.chom.2012.10.001","article-title":"Chronic bystander infections and immunity to unrelated antigens","volume":"12","author":"Stelekati","year":"2012","journal-title":"Cell Host Microbe"},{"key":"2025030704160308800_r2","doi-asserted-by":"crossref","first-page":"e35671","DOI":"10.1371\/journal.pone.0035671","article-title":"Leishmaniasis worldwide and global estimates of its incidence","volume":"7","author":"Alvar","year":"2012","journal-title":"PLoS One"},{"key":"2025030704160308800_r3","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1038\/nrmicro2608","article-title":"Leishmaniasis: complexity at the host-pathogen interface","volume":"9","author":"Kaye","year":"2011","journal-title":"Nat. Rev. Microbiol."},{"key":"2025030704160308800_r4","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1086\/509808","article-title":"Influence of helminth infections on the clinical course of and immune response to Leishmania braziliensis cutaneous leishmaniasis","volume":"195","author":"O\u2019Neal","year":"2007","journal-title":"J. Infect. Dis."},{"key":"2025030704160308800_r5","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1046\/j.1365-3024.2002.00473.x","article-title":"Schistosomiasis delays lesion resolution during Leishmania major infection by impairing parasite killing by macrophages","volume":"24","author":"La Flamme","year":"2002","journal-title":"Parasite Immunol."},{"key":"2025030704160308800_r6","doi-asserted-by":"crossref","first-page":"4939","DOI":"10.1128\/IAI.67.9.4939-4944.1999","article-title":"Coinfection with Toxoplasma gondii inhibits antigen-specific Th2 immune responses, tissue inflammation, and parasitism in BALB\/c mice infected with Leishmania major","volume":"67","author":"Santiago","year":"1999","journal-title":"Infect. Immun."},{"key":"2025030704160308800_r7","doi-asserted-by":"crossref","first-page":"e1003970","DOI":"10.1371\/journal.ppat.1003970","article-title":"Engagement of NKG2D on bystander memory CD8 T cells promotes increased immunopathology following Leishmania major infection","volume":"10","author":"Crosby","year":"2014","journal-title":"PLoS Pathog."},{"key":"2025030704160308800_r8","doi-asserted-by":"crossref","first-page":"5841","DOI":"10.4049\/jimmunol.1201679","article-title":"CD8+ T cell-derived IFN-\u03b3 prevents infection by a second heterologous virus","volume":"189","author":"Valentine","year":"2012","journal-title":"J. Immunol."},{"key":"2025030704160308800_r9","doi-asserted-by":"crossref","first-page":"1154","DOI":"10.1128\/IAI.00943-06","article-title":"Virally activated CD8 T cells home to Mycobacterium bovis BCG-induced granulomas but enhance antimycobacterial protection only in immunodeficient mice","volume":"75","author":"Hogan","year":"2007","journal-title":"Infect. Immun."},{"key":"2025030704160308800_r10","doi-asserted-by":"crossref","first-page":"6275","DOI":"10.4049\/jimmunol.175.10.6275","article-title":"Reciprocal immunomodulation in a schistosome and hepatotropic virus coinfection model","volume":"175","author":"Edwards","year":"2005","journal-title":"J. Immunol."},{"key":"2025030704160308800_r11","doi-asserted-by":"crossref","first-page":"e1003243","DOI":"10.1371\/journal.ppat.1003243","article-title":"IL-17 mediates immunopathology in the absence of IL-10 following Leishmania major infection","volume":"9","author":"Gonzalez-Lombana","year":"2013","journal-title":"PLoS Pathog."},{"key":"2025030704160308800_r12","doi-asserted-by":"crossref","first-page":"1675","DOI":"10.1084\/jem.168.5.1675","article-title":"Immunoregulation of cutaneous leishmaniasis. T cell lines that transfer protective immunity or exacerbation belong to different T helper subsets and respond to distinct parasite antigens","volume":"168","author":"Scott","year":"1988","journal-title":"J. Exp. Med."},{"key":"2025030704160308800_r13","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.4049\/jimmunol.166.2.1141","article-title":"The role of IL-10 in promoting disease progression in leishmaniasis","volume":"166","author":"Kane","year":"2001","journal-title":"J. Immunol."},{"key":"2025030704160308800_r14","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1006\/expr.2001.4656","article-title":"A lipophosphoglycan-independent method for isolation of infective Leishmania metacyclic promastigotes by density gradient centrifugation","volume":"99","author":"Sp\u00e4th","year":"2001","journal-title":"Exp. Parasitol."},{"key":"2025030704160308800_r15","doi-asserted-by":"crossref","first-page":"2952","DOI":"10.1128\/iai.61.7.2952-2959.1993","article-title":"Immune responses associated with susceptibility of C57BL\/10 mice to Leishmania amazonensis","volume":"61","author":"Afonso","year":"1993","journal-title":"Infect. Immun."},{"key":"2025030704160308800_r16","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/S0022-1759(98)00204-X","article-title":"An advanced culture method for generating large quantities of highly pure dendritic cells from mouse bone marrow","volume":"223","author":"Lutz","year":"1999","journal-title":"J. Immunol. Methods"},{"key":"2025030704160308800_r17","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1016\/j.immuni.2007.01.017","article-title":"Monocyte-derived dendritic cells formed at the infection site control the induction of protective T helper 1 responses against Leishmania","volume":"26","author":"Le\u00f3n","year":"2007","journal-title":"Immunity"},{"key":"2025030704160308800_r18","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1084\/jem.20101751","article-title":"Platelet activation attracts a subpopulation of effector monocytes to sites of Leishmania major infection","volume":"208","author":"Goncalves","year":"2011","journal-title":"J. Exp. Med."},{"key":"2025030704160308800_r19","doi-asserted-by":"crossref","first-page":"1288","DOI":"10.1093\/infdis\/jiu013","article-title":"Human classical monocytes control the intracellular stage of Leishmania braziliensis by reactive oxygen species","volume":"209","author":"Novais","year":"2014","journal-title":"J. Infect. Dis."},{"key":"2025030704160308800_r20","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1016\/S0952-7915(06)80031-2","article-title":"Virally induced immunosuppression","volume":"4","author":"Zinkernagel","year":"1992","journal-title":"Curr. Opin. Immunol."},{"key":"2025030704160308800_r21","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1007\/s00281-015-0475-7","article-title":"CD8+ T cells in cutaneous leishmaniasis: the good, the bad, and the ugly","volume":"37","author":"Novais","year":"2015","journal-title":"Semin. Immunopathol."},{"key":"2025030704160308800_r22","doi-asserted-by":"crossref","first-page":"e1003504","DOI":"10.1371\/journal.ppat.1003504","article-title":"Cytotoxic T cells mediate pathology and metastasis in cutaneous leishmaniasis","volume":"9","author":"Novais","year":"2013","journal-title":"PLoS Pathog."},{"key":"2025030704160308800_r23","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.1038\/jid.2013.4","article-title":"CD8(+) granzyme B(+)-mediated tissue injury vs. CD4(+)IFN\u03b3(+)-mediated parasite killing in human cutaneous leishmaniasis","volume":"133","author":"Santos","year":"2013","journal-title":"J. Invest. Dermatol."},{"key":"2025030704160308800_r24","doi-asserted-by":"crossref","first-page":"4467","DOI":"10.4049\/jimmunol.159.9.4467","article-title":"Parasite-driven in vitro human lymphocyte cytotoxicity against autologous infected macrophages from mucosal leishmaniasis","volume":"159","author":"Brodskyn","year":"1997","journal-title":"J. Immunol."},{"key":"2025030704160308800_r25","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1111\/j.1365-3024.2009.01125.x","article-title":"Recruitment of CD8(+) T cells expressing granzyme A is associated with lesion progression in human cutaneous leishmaniasis","volume":"31","author":"Faria","year":"2009","journal-title":"Parasite Immunol."},{"key":"2025030704160308800_r26","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/S1074-7613(02)00333-3","article-title":"The role of the NKG2D immunoreceptor in immune cell activation and natural killing","volume":"17","author":"Jamieson","year":"2002","journal-title":"Immunity"},{"key":"2025030704160308800_r27","doi-asserted-by":"crossref","first-page":"1922","DOI":"10.4049\/jimmunol.174.4.1922","article-title":"Engagement of NKG2D by cognate ligand or antibody alone is insufficient to mediate costimulation of human and mouse CD8+ T cells","volume":"174","author":"Ehrlich","year":"2005","journal-title":"J. Immunol."},{"key":"2025030704160308800_r28","doi-asserted-by":"crossref","first-page":"2825","DOI":"10.4049\/jimmunol.175.5.2825","article-title":"Costimulation through NKG2D enhances murine CD8+ CTL function: similarities and differences between NKG2D and CD28 costimulation","volume":"175","author":"Markiewicz","year":"2005","journal-title":"J. Immunol."},{"key":"2025030704160308800_r29","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/S0022-1759(03)00265-5","article-title":"Sensitive and viable identification of antigen-specific CD8+ T cells by a flow cytometric assay for degranulation","volume":"281","author":"Betts","year":"2003","journal-title":"J. Immunol. Methods"},{"key":"2025030704160308800_r30","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1126\/science.1256942","article-title":"Coinfection. Virus-helminth coinfection reveals a microbiota-independent mechanism of immunomodulation","volume":"345","author":"Osborne","year":"2014","journal-title":"Science"},{"key":"2025030704160308800_r31","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1126\/science.1254517","article-title":"Coinfection. Helminth infection reactivates latent \u03b3-herpesvirus via cytokine competition at a viral promoter","volume":"345","author":"Reese","year":"2014","journal-title":"Science"},{"key":"2025030704160308800_r32","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1016\/j.nano.2013.04.003","article-title":"PLGA nanoparticles loaded with KMP-11 stimulate innate immunity and induce the killing of Leishmania","volume":"9","author":"Santos","year":"2013","journal-title":"Nanomedicine (Lond.)"},{"key":"2025030704160308800_r33","doi-asserted-by":"crossref","first-page":"3992","DOI":"10.4049\/jimmunol.168.8.3992","article-title":"CD8+ T cells are required for primary immunity in C57BL\/6 mice following low-dose, intradermal challenge with Leishmania major","volume":"168","author":"Belkaid","year":"2002","journal-title":"J. Immunol."},{"key":"2025030704160308800_r34","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1038\/jid.2014.305","article-title":"Genomic profiling of human Leishmania braziliensis lesions identifies transcriptional modules associated with cutaneous immunopathology","volume":"135","author":"Novais","year":"2015","journal-title":"J. Invest. Dermatol."},{"key":"2025030704160308800_r35","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1038\/nri3399","article-title":"Neutrophil recruitment and function in health and inflammation","volume":"13","author":"Kolaczkowska","year":"2013","journal-title":"Nat. Rev. Immunol."},{"key":"2025030704160308800_r36","doi-asserted-by":"crossref","first-page":"1749","DOI":"10.1084\/jem.167.5.1749","article-title":"Virus-triggered immune suppression in mice caused by virus-specific cytotoxic T cells","volume":"167","author":"Leist","year":"1988","journal-title":"J. Exp. Med."},{"key":"2025030704160308800_r37","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1128\/jvi.69.2.1059-1070.1995","article-title":"Virus-induced immunosuppression: immune system-mediated destruction of virus-infected dendritic cells results in generalized immune suppression","volume":"69","author":"Borrow","year":"1995","journal-title":"J. Virol."},{"key":"2025030704160308800_r38","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1038\/nri3581","article-title":"Regulation of type I interferon responses","volume":"14","author":"Ivashkiv","year":"2014","journal-title":"Nat. Rev. Immunol."},{"key":"2025030704160308800_r39","doi-asserted-by":"crossref","first-page":"5929","DOI":"10.1128\/JVI.02516-10","article-title":"Virus-induced transient immune suppression and the inhibition of T cell proliferation by type I interferon","volume":"85","author":"Marshall","year":"2011","journal-title":"J. Virol."},{"key":"2025030704160308800_r40","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1126\/science.1235208","article-title":"Blockade of chronic type I interferon signaling to control persistent LCMV infection","volume":"340","author":"Wilson","year":"2013","journal-title":"Science"},{"key":"2025030704160308800_r41","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1126\/science.1235214","article-title":"Persistent LCMV infection is controlled by blockade of type I interferon signaling","volume":"340","author":"Teijaro","year":"2013","journal-title":"Science"},{"key":"2025030704160308800_r42","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1172\/JCI20243","article-title":"Viral targeting of hematopoietic progenitors and inhibition of DC maturation as a dual strategy for immune subversion","volume":"113","author":"Sevilla","year":"2004","journal-title":"J. Clin. Invest."},{"key":"2025030704160308800_r43","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1126\/science.1144830","article-title":"Regulation of homeostatic chemokine expression and cell trafficking during immune responses","volume":"317","author":"Mueller","year":"2007","journal-title":"Science"},{"key":"2025030704160308800_r44","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/j.immuni.2012.05.029","article-title":"Inflammatory monocytes activate memory CD8(+) T and innate NK lymphocytes independent of cognate antigen during microbial pathogen invasion","volume":"37","author":"Soudja","year":"2012","journal-title":"Immunity"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/195\/7\/3301\/62252136\/1500855.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/195\/7\/3301\/62252136\/1500855.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,7]],"date-time":"2025-03-07T04:33:28Z","timestamp":1741322008000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/195\/7\/3301\/7973384"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,10,1]]},"references-count":44,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2015,10,1]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.1500855","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2015,10]]},"published":{"date-parts":[[2015,10,1]]}}}