Pathophysiology of chikungunya virus infection associated with fatal outcomes

William M de Souza; Marcilio J Fumagalli; Shirlene T S de Lima; Pierina L Parise; Deyse C M Carvalho; Cristian Hernandez; Ronaldo de Jesus; Jeany Delafiori; Darlan S Candido; Victor C Carregari; Stefanie P Muraro; Gabriela F Souza; Leda M Simões Mello; Ingra M Claro; Yamilka Díaz; Rodrigo B Kato; Lucas N Trentin; Clauber H S Costa; Ana Carolina B M Maximo; Karene F Cavalcante; Tayna S Fiuza; Vânia A F Viana; Maria Elisabeth L Melo; Clarissa P M Ferraz; Débora B Silva; Larissa M F Duarte; Priscilla P Barbosa; Mariene R Amorim; Carla C Judice; Daniel A Toledo-Teixeira; Mariana S Ramundo; Patricia V Aguilar; Emerson L L Araújo; Fabio T M Costa; Thiago Cerqueira-Silva; Ricardo Khouri; Viviane S Boaventura; Luiz Tadeu M Figueiredo; Rong Fang; Brechla Moreno; Sandra López-Vergès; Liana Perdigão Mello; Munir S Skaf; Rodrigo R Catharino; Fabiana Granja; Daniel Martins-de-Souza; Jessica A Plante; Kenneth S Plante; Ester C Sabino; Michael S Diamond; Eliseo Eugenin; José Luiz Proença-Módena; Nuno R Faria; Scott C Weaver

doi:10.1016/j.chom.2024.02.011

Pathophysiology of chikungunya virus infection associated with fatal outcomes

Cell Host Microbe. 2024 Apr 10;32(4):606-622.e8. doi: 10.1016/j.chom.2024.02.011. Epub 2024 Mar 12.

Authors

William M de Souza¹, Marcilio J Fumagalli², Shirlene T S de Lima³, Pierina L Parise⁴, Deyse C M Carvalho⁵, Cristian Hernandez⁶, Ronaldo de Jesus⁷, Jeany Delafiori⁸, Darlan S Candido⁹, Victor C Carregari¹⁰, Stefanie P Muraro¹¹, Gabriela F Souza¹¹, Leda M Simões Mello¹², Ingra M Claro¹³, Yamilka Díaz¹⁴, Rodrigo B Kato⁷, Lucas N Trentin¹⁵, Clauber H S Costa¹⁵, Ana Carolina B M Maximo¹², Karene F Cavalcante¹², Tayna S Fiuza¹⁶, Vânia A F Viana¹², Maria Elisabeth L Melo¹², Clarissa P M Ferraz¹², Débora B Silva¹², Larissa M F Duarte¹², Priscilla P Barbosa¹¹, Mariene R Amorim¹¹, Carla C Judice¹⁷, Daniel A Toledo-Teixeira¹¹, Mariana S Ramundo¹⁸, Patricia V Aguilar¹⁹, Emerson L L Araújo²⁰, Fabio T M Costa¹⁷, Thiago Cerqueira-Silva²¹, Ricardo Khouri²¹, Viviane S Boaventura²², Luiz Tadeu M Figueiredo²³, Rong Fang²⁴, Brechla Moreno¹⁴, Sandra López-Vergès²⁵, Liana Perdigão Mello¹², Munir S Skaf¹⁵, Rodrigo R Catharino⁸, Fabiana Granja²⁶, Daniel Martins-de-Souza²⁷, Jessica A Plante²⁸, Kenneth S Plante²⁸, Ester C Sabino¹⁸, Michael S Diamond²⁹, Eliseo Eugenin⁶, José Luiz Proença-Módena¹¹, Nuno R Faria⁹, Scott C Weaver³⁰

Affiliations

¹ Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, College of Medicine, Lexington, KY, USA; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA; World Reference Center for Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston, TX, USA; Global Virus Network, Baltimore, MD, USA. Electronic address: [email protected].
² Laboratory of Molecular Immunology, The Rockefeller University, New York, NY, USA.
³ Laboratório Central de Saúde Pública do Ceará, Fortaleza, Ceará, Brazil; Laboratory of Emerging Viruses, Department of Genetics, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, São Paulo, Brazil.
⁴ Laboratory of Emerging Viruses, Department of Genetics, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, São Paulo, Brazil; Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA.
⁵ Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA; Laboratory of Immunobiotechnology, Biotechnology Center, Federal University of Paraíba, João Pessoa, Paraíba, Brazil.
⁶ Department of Neurobiology, University of Texas Medical Branch, Galveston, TX, USA.
⁷ Coordenação Geral dos Laboratórios de Saúde Pública, Secretaria de Vigilância em Saúde, Ministério da Saúde, Brasília, Brazil; Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
⁸ Innovare Biomarkers Laboratory, School of Pharmaceutical Sciences, University of Campinas, Campinas, São Paulo, Brazil.
⁹ MRC Centre for Global Infectious Disease Analysis, Department of Infectious Disease Epidemiology, School of Public Health, Imperial College London, London, UK; Department of Zoology, University of Oxford, Oxford, UK; Instituto de Medicina Tropical, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
¹⁰ Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, São Paulo, Brazil.
¹¹ Laboratory of Emerging Viruses, Department of Genetics, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, São Paulo, Brazil.
¹² Laboratório Central de Saúde Pública do Ceará, Fortaleza, Ceará, Brazil.
¹³ MRC Centre for Global Infectious Disease Analysis, Department of Infectious Disease Epidemiology, School of Public Health, Imperial College London, London, UK; Instituto de Medicina Tropical, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil; Departamento de Moléstias Infecciosas e Parasitárias, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
¹⁴ Department of Research in Virology and Biotechnology, Gorgas Memorial Institute of Health Studies, Panama, Panama.
¹⁵ Institute of Chemistry and Center for Computing in Engineering and Sciences, University of Campinas, Campinas, São Paulo, Brazil.
¹⁶ Laboratório Central de Saúde Pública do Ceará, Fortaleza, Ceará, Brazil; Programa de Pós Graduação em Bioinformática, Instituto Metrópole Digital, Universidade Federal do Rio Grande do Norte, Natal, Rio Grande do Norte, Brazil.
¹⁷ Laboratory of Tropical Diseases, Institute of Biology, University of Campinas, Campinas, São Paulo, Brazil.
¹⁸ Instituto de Medicina Tropical, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil; Departamento de Moléstias Infecciosas e Parasitárias, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
¹⁹ Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA; Center for Tropical Diseases, Institute for Human Infection and Immunity, University of Texas Medical Branch, Galveston, TX, USA.
²⁰ Coordenação Geral de Atenção às Doenças Transmissíveis na Atenção Primária, Departamento de Gestão ao cuidado Integral, Secretaria de Atenção Primária à Saúde, Ministério da Saúde, Brasília, Brazil.
²¹ Universidade Federal da Bahia, Faculdade de Medicina, Salvador, Bahia, Brazil; Fundação Oswaldo Cruz, Instituto Gonçalo Muniz, Laboratório de Medicina e Saúde Pública de Precisão, Salvador, Bahia, Brazil.
²² Universidade Federal da Bahia, Faculdade de Medicina, Salvador, Bahia, Brazil; Fundação Oswaldo Cruz, Instituto Gonçalo Muniz, Laboratório de Medicina e Saúde Pública de Precisão, Salvador, Bahia, Brazil; Hospital Santa Izabel, Santa Casa de Misericórdia da Bahia, Serviço de Otorrinolaringologia, Salvador, Bahia, Brazil.
²³ Virology Research Centre, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
²⁴ Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA.
²⁵ Department of Research in Virology and Biotechnology, Gorgas Memorial Institute of Health Studies, Panama, Panama; Sistema Nacional de Investigación from SENACYT, Panama, Panama.
²⁶ Laboratory of Emerging Viruses, Department of Genetics, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, São Paulo, Brazil; Biodiversity Research Centre, Federal University of Roraima, Boa Vista, Roraima, Brazil.
²⁷ Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, São Paulo, Brazil; D'Or Institute for Research and Education, São Paulo, São Paulo, Brazil; Experimental Medicine Research Cluster, University of Campinas, Campinas, São Paulo, Brazil.
²⁸ Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA; World Reference Center for Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston, TX, USA.
²⁹ Departments of Medicine, Molecular Microbiology, Pathology & Immunology, Washington University School of Medicine, Saint Louis, MO, USA.
³⁰ Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA; World Reference Center for Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston, TX, USA; Global Virus Network, Baltimore, MD, USA; Institute for Human Infection and Immunity, University of Texas Medical Branch, Galveston, TX, USA.

Abstract

Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that causes acute, subacute, and chronic human arthritogenic diseases and, in rare instances, can lead to neurological complications and death. Here, we combined epidemiological, virological, histopathological, cytokine, molecular dynamics, metabolomic, proteomic, and genomic analyses to investigate viral and host factors that contribute to chikungunya-associated (CHIK) death. Our results indicate that CHIK deaths are associated with multi-organ infection, central nervous system damage, and elevated serum levels of pro-inflammatory cytokines and chemokines compared with survivors. The histopathologic, metabolite, and proteomic signatures of CHIK deaths reveal hemodynamic disorders and dysregulated immune responses. The CHIKV East-Central-South-African lineage infecting our study population causes both fatal and survival cases. Additionally, CHIKV infection impairs the integrity of the blood-brain barrier, as evidenced by an increase in permeability and altered tight junction protein expression. Overall, our findings improve the understanding of CHIK pathophysiology and the causes of fatal infections.

Keywords: alphavirus; arbovirus; central nervous system infection; chikungunya death; chikungunya virus; hemodynamic disorders; inflammation; mosquito-borne virus; pathophysiology.

MeSH terms

Animals
Chikungunya Fever* / complications
Chikungunya virus* / genetics
Cytokines / metabolism
Humans
Proteomics

Substances

Cytokines

Abstract

MeSH terms

Substances

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