title: Type I IFN Induction via Poly-ICLC Protects Mice against Cryptococcosis.
abstract: Cryptococcus neoformans is the most common cause of fungal meningoencephalitis in AIDS patients. Depletion of CD4 cells, such as occurs during advanced AIDS, is known to be a critical risk factor for developing cryptococcosis. However, the role of HIV-induced innate inflammation in susceptibility to cryptococcosis has not been evaluated. Thus, we sought to determine the role of Type I IFN induction in host defense against cryptococci by treatment of C. neoformans (H99) infected mice with poly-ICLC (pICLC), a dsRNA virus mimic. Unexpectedly, pICLC treatment greatly extended survival of infected mice and reduced fungal burdens in the brain. Protection from cryptococcosis by pICLC-induced Type I IFN was mediated by MDA5 rather than TLR3. PICLC treatment induced a large, rapid and sustained influx of neutrophils and Ly6Chigh monocytes into the lung while suppressing the development of eosinophilia. The pICLC-mediated protection against H99 was CD4 T cell dependent and analysis of CD4 T cell polyfunctionality showed a reduction in IL-5 producing CD4 T cells, marginal increases in Th1 cells and dramatic increases in RORγt+ Th17 cells in pICLC treated mice. Moreover, the protective effect of pICLC against H99 was diminished in IFNγ KO mice and by IL-17A neutralization with blocking mAbs. Furthermore, pICLC treatment also significantly extended survival of C. gattii infected mice with reduced fungal loads in the lungs. These data demonstrate that induction of type I IFN dramatically improves host resistance against the etiologic agents of cryptococcosis by beneficial alterations in both innate and adaptive immune responses.
authors.affiliation: Molecular Microbiology Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, United States of America.
authors.forename: Edward
authors.initials: E
authors.lastname: Sionov
authors.affiliation: Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, United States of America.
authors.forename: Katrin D
authors.initials: KD
authors.lastname: Mayer-Barber
authors.affiliation: Molecular Microbiology Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, United States of America.
authors.forename: Yun C
authors.initials: YC
authors.lastname: Chang
authors.affiliation: T-Lymphocyte Biology Unit, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, United States of America.
authors.forename: Keith D
authors.initials: KD
authors.lastname: Kauffman
authors.affiliation: Division of Veterinary Resources, Office of Research Services, Office of the Director, National Institutes of Health (NIH), Bethesda, Maryland, United States of America.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Eckhaus
authors.affiliation: Oncovir, Inc., Washington, DC, United States of America.
authors.forename: Andres M
authors.initials: AM
authors.lastname: Salazar
authors.affiliation: T-Lymphocyte Biology Unit, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, United States of America.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Barber
authors.affiliation: Molecular Microbiology Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, United States of America.
authors.forename: Kyung J
authors.initials: KJ
authors.lastname: Kwon-Chung
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002266:Carboxymethylcellulose Sodium / Q000031:analogs & derivatives* / Q000494:pharmacology; D003455:Cryptococcus neoformans; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007369:Interferon Inducers / Q000494:pharmacology*; D007370:Interferon Type I / Q000096:biosynthesis*; D016919:Meningitis, Cryptococcal / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011070:Poly I-C / Q000494:pharmacology*; D011107:Polylysine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D007369:Interferon Inducers; D007370:Interferon Type I; D011107:Polylysine; C019531:poly ICLC; D002266:Carboxymethylcellulose Sodium; D011070:Poly I-C