Subversion of early innate antiviral responses during antibody-dependent enhancement of Dengue virus infection induces severe disease in immunocompetent mice.
Dengue is a mosquito-borne disease caused by one of four serotypes of Dengue virus (DENV-1-4). Epidemiologic and observational studies demonstrate that the majority of severe dengue cases, dengue hemorrhagic fever and dengue shock syndrome (DHF/DSS), occurs predominantly in either individuals with cross-reactive immunity following a secondary heterologous infection or in infants with primary DENV infections born from dengue-immune mothers, suggesting that B-cell-mediated and antibody responses impact on disease evolution. We demonstrate here that B cells play a pivotal role in host responses against primary DENV infection in mice. After infection, μMT(-/-) mice showed increased viral loads followed by severe disease manifestation characterized by intense thrombocytopenia, hemoconcentration, cytokine production and massive liver damage that culminated in death. In addition, we show that poly and monoclonal anti-DENV-specific antibodies can sufficiently increase viral replication through a suppression of early innate antiviral responses and enhance disease manifestation, so that a mostly non-lethal illness becomes a fatal disease resembling human DHF/DSS. Finally, treatment with intravenous immunoglobulin containing anti-DENV antibodies confirmed the potential enhancing capacity of subneutralizing antibodies to mediate virus infection and replication and induce severe disease manifestation of DENV-infected mice. Thus, our results show that humoral responses unleashed during DENV infections can exert protective or pathological outcomes and provide insight into the pathogenesis of this important human pathogen.
Laboratório de Interação Microrganismo-Hospedeiro, Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
Vivian V
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Costa
Caio T
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Fagundes
Deborah F
DF
Valadão
Thiago V
TV
Ávila
Daniel
D
Cisalpino
Rebeca F
RF
Rocha
Lucas S
LS
Ribeiro
Fernando R
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Ascenção
Lucas M
LM
Kangussu
M Q
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Celso
Ruiz G
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Astigarraga
Frederico L
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Gouveia
Tarcília A
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Silva
Daniela
D
Bonaventura
Divaldo de Almeida
Dde A
Sampaio
Ana Cristina L
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Leite
Mauro M
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Teixeira
Danielle G
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Souza
D000818:Animals; D019067:Antibody-Dependent Enhancement; D001402:B-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000097:blood; D003643:Death; D003715:Dengue / Q000276:immunology* / Q000473:pathology*; D003716:Dengue Virus / Q000276:immunology*; D007113:Immunity, Innate; D008099:Liver / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013921:Thrombocytopenia; D019562:Viral Load
D016207:Cytokines