AUTHOR=Schanoski Alessandra S. , Le Thuy T. , Kaiserman Dion , Rowe Caitlin , Prow Natalie A. , Barboza Diego D. , Santos Cliomar A. , Zanotto Paolo M. A. , Magalhães Kelly G. , Aurelio Luigi , Muller David , Young Paul , Zhao Peishen , Bird Phillip I. , Suhrbier Andreas TITLE=Granzyme A in Chikungunya and Other Arboviral Infections JOURNAL=Frontiers in Immunology VOLUME=10 YEAR=2020 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.03083 DOI=10.3389/fimmu.2019.03083 ISSN=1664-3224 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.