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CARD9 Is Required for Classical Macrophage Activation and the Induction of Protective Immunity against Pulmonary Cryptococcosis.
Campuzano, Althea; Castro-Lopez, Natalia; Martinez, Amanda J; Olszewski, Michal A; Ganguly, Anutosh; Leopold Wager, Chrissy; Hung, Chiung-Yu; Wormley, Floyd L.
Afiliação
  • Campuzano A; Department of Biology, South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio, San Antonio, Texas, USA.
  • Castro-Lopez N; Department of Biology, South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio, San Antonio, Texas, USA.
  • Martinez AJ; Department of Biology, South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio, San Antonio, Texas, USA.
  • Olszewski MA; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Michigan Medicine University, Ann Arbor, Michigan, USA.
  • Ganguly A; VA Ann Arbor Healthcare System, Research Service, Ann Arbor, Michigan, USA.
  • Leopold Wager C; VA Ann Arbor Healthcare System, Research Service, Ann Arbor, Michigan, USA.
  • Hung CY; Division of Hepatobiliary Surgery, Department of Surgery, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA.
  • Wormley FL; Department of Biology, South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio, San Antonio, Texas, USA.
mBio ; 11(1)2020 01 07.
Article em En | MEDLINE | ID: mdl-31911495
ABSTRACT
Caspase recruitment domain-containing protein 9 (CARD9) is a critical adaptor molecule triggered by the interaction of C-type lectin receptors (CLRs) with carbohydrate motifs found in fungi. Consequently, clinical and animal studies indicate that CARD9 is an important regulator of protective immunity against fungal pathogens. Previous studies suggest that CARD9 is important for the induction of protection against Cryptococcus neoformans, an opportunistic fungal pathogen that causes life-threatening infections of the central nervous system in immunocompromised patients. However, the effect of CARD9 deficiency on the induction of protective immune responses against C. neoformans is unknown. Immunization with a C. neoformans mutant that overexpresses the transcription factor zinc finger 2, denoted LW10, results in protection against an otherwise lethal challenge with wild-type (WT) C. neoformans Our results showed that CARD9 is essential for the induction of vaccine-mediated immunity against C. neoformans infection. We observed significant decreases in interleukin-17 (IL-17) production and significant increases in Th2-type cytokine (IL-4, IL-5, and IL-13) production in CARD9-deficient mice after inoculation with strain LW10. While leukocyte infiltration to the lungs of CARD9-deficient mice was similar in LW10 and WT C. neoformans-infected mice, macrophages derived from CARD9-deficient mice inherently skewed toward an M2 activation phenotype, were unable to contain the growth of LW10, and failed to produce nitric oxide in response to infection with LW10 or stimulation with lipopolysaccharide. These results suggest that CARD9-mediated signaling is required for M1 macrophage activation and fungicidal activity necessary for the induction of vaccine-mediated immunity against C. neoformansIMPORTANCECryptococcus neoformans is a fungal pathogen that is found throughout the environment and can cause life-threatening infections of the lung and central nervous system in severely immunocompromised individuals. Caspase recruitment domain-containing protein 9 (CARD9) is a critical molecule that is activated after interactions of C-type lectin receptors (CLRs) found on the surfaces of specific immune cells, with carbohydrate structures associated with fungi. Patients with defects in CARD9 are significantly more susceptible to a multitude of fungal infections. C. neoformans contains several carbohydrate structures that interact with CLRs on immune cells and activate CARD9. Consequently, these studies evaluated the necessity of CARD9 for the induction of protective immunity against C. neoformans infection. These results are important, as they advance our understanding of cryptococcal pathogenesis and host factors necessary for the induction of protective immunity against C. neoformans.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Criptococose / Cryptococcus neoformans / Proteínas Adaptadoras de Sinalização CARD / Pneumopatias Fúngicas / Ativação de Macrófagos Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: MBio Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Criptococose / Cryptococcus neoformans / Proteínas Adaptadoras de Sinalização CARD / Pneumopatias Fúngicas / Ativação de Macrófagos Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: MBio Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Estados Unidos