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1.
Viruses ; 13(5)2021 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-34066286

RESUMO

Sub-neutralizing concentrations of antibodies in dengue infected patients is a major risk factor for the development of dengue hemorrhagic fever and dengue shock syndrome. Here, we describe a mouse model with a deficiency in mast cells (MCs) in addition to a deficiency in Type-I and II IFN receptors for studying dengue virus (DENV) infection. We used this model to understand the influence of MCs in a maternal antibody-dependent model of severe dengue, where offspring born to DENV-immune mothers are challenged with a heterologous DENV serotype. Mice lacking both MCs and IFN receptors were found susceptible to primary DENV infection and showed morbidity and mortality. When these mice were immunized, pups born to DENV-immune mothers were found to be protected for a longer duration from a heterologous DENV challenge. In the absence of MCs and type-I interferon signaling, IFN-γ was found to protect pups born to naïve mothers but had the opposite effect on pups born to DENV-immune mothers. Our results highlight the complex interactions between MCs and IFN-signaling in influencing the role of maternal antibodies in DENV-induced disease severity.


Assuntos
Imunidade Materno-Adquirida , Mastócitos/imunologia , Exposição Materna , Efeitos Tardios da Exposição Pré-Natal , Dengue Grave/diagnóstico , Dengue Grave/etiologia , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Vírus da Dengue/imunologia , Modelos Animais de Doenças , Suscetibilidade a Doenças , Feminino , Hospedeiro Imunocomprometido , Mastócitos/metabolismo , Camundongos , Camundongos Knockout , Gravidez , Receptor de Interferon alfa e beta/deficiência , Índice de Gravidade de Doença
2.
Nat Commun ; 10(1): 706, 2019 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-30742008

RESUMO

Japanese encephalitis virus (JEV) is a leading cause of viral encephalitis. However, the mechanisms of JEV penetration of the blood-brain-barrier (BBB) remain poorly understood. Mast cells (MCs) are granulated innate immune sentinels located perivascularly, including at the BBB. Here we show that JEV activates MCs, leading to the release of granule-associated proteases in vivo. MC-deficient mice display reduced BBB permeability during JEV infection compared to congenic wild-type (WT) mice, indicating that enhanced vascular leakage in the brain during JEV infection is MC-dependent. Moreover, MCs promoted increased JEV infection in the central nervous system (CNS), enhanced neurological deficits, and reduced survival in vivo. Mechanistically, chymase, a MC-specific protease, enhances JEV-induced breakdown of the BBB and cleavage of tight-junction proteins. Chymase inhibition reversed BBB leakage, reduced brain infection and neurological deficits during JEV infection, and prolonged survival, suggesting chymase is a novel therapeutic target to prevent JEV encephalitis.


Assuntos
Quimases/metabolismo , Vírus da Encefalite Japonesa (Espécie)/patogenicidade , Encefalite Japonesa/imunologia , Encefalite Japonesa/metabolismo , Mastócitos/metabolismo , Mastócitos/virologia , Animais , Barreira Hematoencefálica/imunologia , Barreira Hematoencefálica/virologia , Encéfalo/patologia , Encéfalo/virologia , Linhagem Celular , Sistema Nervoso Central/patologia , Sistema Nervoso Central/virologia , Quimases/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Encefalite Japonesa/mortalidade , Humanos , Imunidade Inata , Masculino , Mastócitos/imunologia , Mastócitos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Morbidade , Permeabilidade , Análise de Sobrevida , Proteínas de Junções Íntimas
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