Granzyme A in Chikungunya and Other Arboviral Infections

Alessandra S Schanoski; Thuy T Le; Dion Kaiserman; Caitlin Rowe; Natalie A Prow; Diego D Barboza; Cliomar A Santos; Paolo M A Zanotto; Kelly G Magalhães; Luigi Aurelio; David Muller; Paul Young; Peishen Zhao; Phillip I Bird; Andreas Suhrbier

doi:10.3389/fimmu.2019.03083

Granzyme A in Chikungunya and Other Arboviral Infections

Front Immunol. 2020 Jan 14:10:3083. doi: 10.3389/fimmu.2019.03083. eCollection 2019.

Authors

Alessandra S Schanoski¹, Thuy T Le², Dion Kaiserman³, Caitlin Rowe³, Natalie A Prow^{2

4}, Diego D Barboza¹, Cliomar A Santos⁵, Paolo M A Zanotto⁶, Kelly G Magalhães⁷, Luigi Aurelio⁸, David Muller⁹, Paul Young⁹, Peishen Zhao⁸, Phillip I Bird³, Andreas Suhrbier^{2

4}

Affiliations

¹ Bacteriology Laboratory, Butantan Institute, São Paulo, Brazil.
² QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
³ Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia.
⁴ Australian Infectious Disease Research Centre, University of Queensland, Brisbane, QLD, Australia.
⁵ Health Foundation Parreiras Horta, Central Laboratory of Public Health, State Secretary for Health, Aracajú, Brazil.
⁶ Laboratory of Molecular Evolution and Bioinformatics, Department of Microbiology, Biomedical Sciences Institute, University of São Paulo, São Paulo, Brazil.
⁷ Laboratory of Immunology and Inflammation, University of Brasilia, Brasilia, Brazil.
⁸ Drug Discovery Biology and Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia.
⁹ School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD, Australia.

Abstract

Granzyme A (GzmA) is secreted by cytotoxic lymphocytes and has traditionally been viewed as a mediator of cell death. However, a growing body of data suggests the physiological role of GzmA is promotion of inflammation. Here, we show that GzmA is significantly elevated in the sera of chikungunya virus (CHIKV) patients and that GzmA levels correlated with viral loads and disease scores in these patients. Serum GzmA levels were also elevated in CHIKV mouse models, with NK cells the likely source. Infection of mice deficient in type I interferon responses with CHIKV, Zika virus, or dengue virus resulted in high levels of circulating GzmA. We also show that subcutaneous injection of enzymically active recombinant mouse GzmA was able to mediate inflammation, both locally at the injection site as well as at a distant site. Protease activated receptors (PARs) may represent targets for GzmA, and we show that treatment with PAR antagonist ameliorated GzmA- and CHIKV-mediated inflammation.

Keywords: NK cell; arbovirus; arthritis; chikungunya; granzyme A.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Arbovirus Infections / immunology*
Chikungunya Fever / immunology*
Granzymes / blood
Granzymes / immunology*
Humans
Inflammation / immunology*
Killer Cells, Natural / immunology*
Mice
Mice, Inbred C57BL

Substances

Granzymes