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Mice Infection in Cryptococcus Neoformans Against STAT1 STAT1 Signaling Is Essential for Protection against Cryptococcus neoformans Infection in Mice This information is current as Chrissy M. Leopold Wager, Camaron R. Hole, Karen L. of September 28, 2021. Wozniak, Michal A. Olszewski and Floyd L. Wormley, Jr. J Immunol 2014; 193:4060-4071; Prepublished online 8 September 2014; doi: 10.4049/jimmunol.1400318 http://www.jimmunol.org/content/193/8/4060 Downloaded from References This article cites 93 articles, 34 of which you can access for free at: http://www.jimmunol.org/content/193/8/4060.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 28, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2014 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology STAT1 Signaling Is Essential for Protection against Cryptococcus neoformans Infection in Mice Chrissy M. Leopold Wager,*,† Camaron R. Hole,*,† Karen L. Wozniak,*,† Michal A. Olszewski,‡,x and Floyd L. Wormley, Jr.*,† Nonprotective immune responses to highly virulent Cryptococcus neoformans strains, such as H99, are associated with Th2-type cytokine production, alternatively activated macrophages, and inability of the host to clear the fungus. In contrast, experimental studies show that protective immune responses against cryptococcosis are associated with Th1-type cytokine production and classical macrophage activation. The protective response induced during C. neoformans strain H99g (C. neoformans strain H99 engineered to produce murine IFN-g) infection correlates with enhanced phosphorylation of the transcription factor STAT1 in macrophages; however, the role of STAT1 in protective immunity to C. neoformans is unknown. The current studies examined the effect of STAT1 deletion in murine models of protective immunity to C. neoformans. Survival and fungal burden were evaluated in Downloaded from wild-type and STAT1 knockout (KO) mice infected with either strain H99g or C. neoformans strain 52D (unmodified clinical isolate). Both strains H99g and 52D were rapidly cleared from the lungs, did not disseminate to the CNS, or cause mortality in the wild-type mice. Conversely, STAT1 KO mice infected with H99g or 52D had significantly increased pulmonary fungal burden, CNS dissemination, and 90–100% mortality. STAT1 deletion resulted in a shift from Th1 to Th2 cytokine bias, pronounced lung inflammation, and defective classical macrophage activation. Pulmonary macrophages from STAT1 KO mice exhibited defects in NO production correlating with inefficient inhibition of fungal proliferation. These studies demonstrate that STAT1 signaling is http://www.jimmunol.org/ essential not only for regulation of immune polarization but also for the classical activation of macrophages that occurs during protective anticryptococcal immune responses. The Journal of Immunology, 2014, 193: 4060–4071. ryptococcus neoformans, the predominant etiological therapies are oftentimes rendered ineffective because of the devel- agent of cryptococcosis, is an opportunistic fungal path- opment of drug resistance or an inability of the host’s immune C ogen and frequent cause of life-threatening infection in system to participate in eradicating the pathogen (17–19), necessi- individuals with impaired T cell function (i.e., persons with AIDS, tating new therapeutic strategies that consider the immune status of lymphoid malignancies, and recipients of immunosuppressive the host population commonly impacted by cryptococcal disease. by guest on September 28, 2021 therapies) (1–13). Cryptococcosis is considered an AIDS-defining C. neoformans is ubiquitous in the environment and exposure illness and the most common mycological cause of morbidity and via inhalation of desiccated basidiospores or yeast into the lung mortality among AIDS patients (14). Global estimates show that alveoli often occurs in early childhood (20–22). The over- 1 million cases of cryptococcal meningitis occur in AIDS patients whelming majority of exposures result in asymptomatic disease each year, resulting in ∼625,000 deaths (14). C. neoformans also and possible latency in immunocompetent individuals. However, remains the third most common invasive fungal infection among in immunocompromised individuals, C. neoformans can spread organ transplant recipients (13, 15, 16). Current antifungal drug from the lungs to the CNS, resulting in life-threatening menin- goencephalitis (23). Because inhalation is the principal route of *Department of Biology, University of Texas, San Antonio, TX 78249; †South Texas entry, the host is dependent on resident pulmonary phagocytes, Center for Emerging Infectious Diseases, University of Texas, San Antonio, TX 78249; such as macrophages, to contain the pathogen and prevent dis- ‡Veterans Affairs Ann Arbor Health System, University of Michigan Health System, Ann Arbor, MI 48109; and xDivision of Pulmonary and Critical Care Medicine, De- semination from the lungs. Studies using various experimental partment of Internal Medicine, University of Michigan Health System, Ann Arbor, models of pulmonary cryptococcosis indicate that protection MI 48109 against C. neoformans infection is associated with the induction of Received for publication February 4, 2014. Accepted for publication August 6, 2014. Th1-type cytokine responses (IL-2, IL-12, IFN-g, and TNF-a), This work was supported by Research Grant 2RO1 AI071752 from the National increased lymphocyte infiltration, and classical macrophage (M1) Institute of Allergy and Infectious Diseases of the National Institutes of Health (to F.L.W.), Grant W911NF-11-1-0136 from the Army Research Office of the Depart- activation (24–30). In contrast, Th2-type cytokine responses (IL-4, ment of Defense (to F.L.W.), and Department of Veterans Affairs Merit Review IL-5, and IL-13) are detrimental to the host and are associated Grant 1I01BX000656 (to M.A.O.). with alternative macrophage (M2) activation (31–33). M1 mac- The content of this article is solely the responsibility of the authors and does not rophages are known for their capacity to efficiently kill phago- necessarily represent the official views of the National Institute of Allergy and Infectious Diseases, the National Institutes of Health, or the University of Texas at cytized organisms through the production of reactive oxygen and San Antonio. nitrogen species (25, 31, 34–36). M2 macrophages, however, are Address correspondence and reprint requests to Dr. Floyd L. Wormley, Jr., Depart- associated with wound healing and are not efficiently microbicidal ment of Biology, University of Texas at San Antonio, One UTSA Circle, San Antonio, TX 78249-0062. E-mail address: fl[email protected] against C. neoformans (25, 31, 34–36). M1 macrophages produce L Abbreviations used in this article: Arg1, arginase 1; FIZZ1, found in inflammatory NO and -citrulline via inducible NO synthase (iNOS) by acting zone 1; H99g,IFN-g–producing Cryptococcus neoformans strain; iNOS, inducible on the substrate L-arginine. Arginase-1 (Arg1) in M2 macrophages NO synthase; KO, knockout; ROS, reactive oxygen species; WT, wild-type; YM1, competes with iNOS for L-arginine to produce L-ornithine and chitinase 3-like 3; YPD, yeast extract/peptone/dextrose. urea (37), which is not fungicidal against C. neoformans (38, 39). Copyright Ó 2014 by The American Association of Immunologists, Inc. 0022-1767/14/$16.00 Therefore, macrophage polarization toward an M2 phenotype, www.jimmunol.org/cgi/doi/10.4049/jimmunol.1400318 The Journal of Immunology 4061 which occurs during infection with wild-type (WT) C. neoformans inoculation with 1 3 104 CFU C. neoformans strains H99g or 52D in 50 ml strain H99, results in uncontrolled fungal growth, dissemination, sterile PBS. The inocula used for nasal inhalation were verified by quan- and exacerbation of disease (31, 35, 40, 41). titative culture on YPD agar. Mice were euthanized on predetermined days by CO2 inhalation, followed by cervical dislocation, and lung tissues were Experimental pulmonary infection in mice with a C. neoformans excised using aseptic technique. For survival analyses, mice were inoculated strain engineered to express IFN-g, designated H99g, results in as stated above and monitored twice daily for up to 60 d postinoculation. Th1-type and IL-17A cytokine responses, M1 macrophage acti- Fungal burden vation, and resolution of the acute infection (26, 42). In addition, mice protectively immunized with C. neoformans strain H99g For fungal burden analysis, the left lobe of the lung was removed and developed an M1 macrophage activation phenotype during sec- homogenized in 1 ml sterile PBS. A 50-ml aliquot was removed, serially diluted in sterile PBS, and plated on YPD agar supplemented with chlor- ondary challenge with a non–IFN-g–producing WT C. neofor- amphenicol. Plates were incubated for 48 h at 30˚C, and
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