{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T15:03:17Z","timestamp":1791558197780,"version":"4.3.4"},"reference-count":61,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2015,6,1]],"date-time":"2015-06-01T00:00:00Z","timestamp":1433116800000},"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":[[2015,6,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Numerous virulence factors expressed by Cryptococcus neoformans modulate host defenses by promoting nonprotective Th2-biased adaptive immune responses. Prior studies demonstrate that the heat shock protein 70 homolog, Ssa1, significantly contributes to serotype D C. neoformans virulence through the induction of laccase, a Th2-skewing and CNS tropic factor. In the present study, we sought to determine whether Ssa1 modulates host defenses in mice infected with a highly virulent serotype A strain of C. neoformans (H99). To investigate this, we assessed pulmonary fungal growth, CNS dissemination, and survival in mice infected with either H99, an SSA1-deleted H99 strain (\u0394ssa1), and a complement strain with restored SSA1 expression (\u0394ssa1::SSA1). Mice infected with the \u0394ssa1 strain displayed substantial reductions in lung fungal burden during the innate phase (days 3 and 7) of the host response, whereas less pronounced reductions were observed during the adaptive phase (day 14) and mouse survival increased only by 5 d. Surprisingly, laccase activity assays revealed that \u0394ssa1 was not laccase deficient, demonstrating that H99 does not require Ssa1 for laccase expression, which explains the CNS tropism we still observed in the Ssa1-deficient strain. Lastly, our immunophenotyping studies showed that Ssa1 directly promotes early M2 skewing of lung mononuclear phagocytes during the innate phase, but not the adaptive phase, of the immune response. We conclude that Ssa1\u2019s virulence mechanism in H99 is distinct and laccase-independent. Ssa1 directly interferes with early macrophage polarization, limiting innate control of C. neoformans, but ultimately has no effect on cryptococcal control by adaptive immunity.<\/jats:p>","DOI":"10.4049\/jimmunol.1402719","type":"journal-article","created":{"date-parts":[[2015,5,14]],"date-time":"2015-05-14T02:42:37Z","timestamp":1431571357000},"page":"5999-6010","source":"Crossref","is-referenced-by-count":56,"title":["Cryptococcal Heat Shock Protein 70 Homolog Ssa1 Contributes to Pulmonary Expansion of <i>Cryptococcus neoformans<\/i> during the Afferent Phase of the Immune Response by Promoting Macrophage M2 Polarization"],"prefix":"10.1093","volume":"194","author":[{"given":"Alison J","family":"Eastman","sequence":"first","affiliation":[{"name":"Graduate Program in Immunology, University of Michigan , Ann Arbor, MI 48109"},{"name":"Veterans Affairs Hospital , Ann Arbor, MI 48105"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiumiao","family":"He","sequence":"additional","affiliation":[{"name":"Veterans Affairs Hospital , Ann Arbor, MI 48105"},{"name":"Division of Pulmonary and Critical Care Medicine, University of Michigan , Ann Arbor, MI 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yafeng","family":"Qiu","sequence":"additional","affiliation":[{"name":"Veterans Affairs Hospital , Ann Arbor, MI 48105"},{"name":"Division of Pulmonary and Critical Care Medicine, University of Michigan , Ann Arbor, MI 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J","family":"Davis","sequence":"additional","affiliation":[{"name":"Veterans Affairs Hospital , Ann Arbor, MI 48105"},{"name":"Division of Pulmonary and Critical Care Medicine, University of Michigan , Ann Arbor, MI 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priya","family":"Vedula","sequence":"additional","affiliation":[{"name":"Veterans Affairs Hospital , Ann Arbor, MI 48105"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel M","family":"Lyons","sequence":"additional","affiliation":[{"name":"Veterans Affairs Hospital , Ann Arbor, MI 48105"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoon-Dong","family":"Park","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah E","family":"Hardison","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Texas at San Antonio , San Antonio, TX 78458"},{"name":"South Texas Center for Emerging Infectious Diseases, University of Texas at San Antonio , San 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