Chikungunya Virus and Its Envelope Protein E2 Induce Hyperalgesia in Mice: Inhibition by Anti-E2 Monoclonal Antibodies and by Targeting TRPV1

Carina Z Segato-Vendrameto; Camila Zanluca; Amanda Z Zucoloto; Tiago H Zaninelli; Mariana M Bertozzi; Telma Saraiva-Santos; Camila R Ferraz; Larissa Staurengo-Ferrari; Stephanie Badaro-Garcia; Marília F Manchope; Amanda M Dionisio; Felipe A Pinho-Ribeiro; Sergio M Borghi; Ana Luiza Pamplona Mosimann; Rubia Casagrande; Juliano Bordignon; Victor Fattori; Claudia N Duarte Dos Santos; Waldiceu A Verri

doi:10.3390/cells12040556

Chikungunya Virus and Its Envelope Protein E2 Induce Hyperalgesia in Mice: Inhibition by Anti-E2 Monoclonal Antibodies and by Targeting TRPV1

Cells. 2023 Feb 9;12(4):556. doi: 10.3390/cells12040556.

Authors

Carina Z Segato-Vendrameto¹, Camila Zanluca², Amanda Z Zucoloto¹, Tiago H Zaninelli¹, Mariana M Bertozzi¹, Telma Saraiva-Santos¹, Camila R Ferraz¹, Larissa Staurengo-Ferrari¹, Stephanie Badaro-Garcia¹, Marília F Manchope¹, Amanda M Dionisio¹, Felipe A Pinho-Ribeiro^{1

3}, Sergio M Borghi^{1

4}, Ana Luiza Pamplona Mosimann², Rubia Casagrande⁵, Juliano Bordignon², Victor Fattori^{1

6}, Claudia N Duarte Dos Santos², Waldiceu A Verri¹

Affiliations

¹ Laboratory of Pain, Inflammation, Neuropathy, and Cancer, Department of Pathology, Londrina State University, Londrina 86057-970, PR, Brazil.
² Laboratory of Molecular Virology, Carlos Chagas Institute/Fiocruz PR, Curitiba 81310-020, PR, Brazil.
³ Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
⁴ Center for Research in Health Sciences, University of Northern Paraná, Londrina 86041-140, PR, Brazil.
⁵ Department of Pharmaceutical Sciences, University Hospital (Health Science Centre), Londrina State University, Londrina 86057-970, PR, Brazil.
⁶ Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, 1 Blackfan Circle, Karp Research Building 11.006C, Boston, MA 02115, USA.

Abstract

Chikungunya virus is an arthropod-borne infectious agent that causes Chikungunya fever disease. About 90% of the infected patients experience intense polyarthralgia, affecting mainly the extremities but also the large joints such as the knees. Chronic disease symptoms persist for months, even after clearance of the virus from the blood. Envelope proteins stimulate the immune response against the Chikungunya virus, becoming an important therapeutic target. We inactivated the Chikungunya virus (iCHIKV) and produced recombinant E2 (rE2) protein and three different types of anti-rE2 monoclonal antibodies. Using these tools, we observed that iCHIKV and rE2 protein induced mechanical hyperalgesia (electronic aesthesiometer test) and thermal hyperalgesia (Hargreaves test) in mice. These behavioral results were accompanied by the activation of dorsal root ganglia (DRG) neurons in mice, as observed by calcium influx. Treatment with three different types of anti-rE2 monoclonal antibodies and absence or blockade (AMG-9810 treatment) of transient receptor potential vanilloid 1 (TRPV1) channel diminished mechanical and thermal hyperalgesia in mice. iCHIKV and rE2 activated TRPV1+ mouse DRG neurons in vitro, demonstrating their ability to activate nociceptor sensory neurons directly. Therefore, our mouse data demonstrate that targeting E2 CHIKV protein with monoclonal antibodies and inhibiting TRPV1 channels are reasonable strategies to control CHIKV pain.

Keywords: Chikungunya virus; E2 envelope protein; TRPV1; joint pain; monoclonal antibody.

Publication types

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

MeSH terms

Animals
Antibodies, Monoclonal* / pharmacology
Antibodies, Viral
Antineoplastic Agents
Chikungunya Fever* / drug therapy
Chikungunya virus*
Hyperalgesia* / drug therapy
Mice
TRPV Cation Channels
Viral Envelope Proteins* / metabolism

Substances

Antibodies, Monoclonal
Antibodies, Viral
Antineoplastic Agents
TRPV Cation Channels
TRPV1 protein, mouse
Viral Envelope Proteins

Grants and funding

This work was supported by Brazilian grants from the Coordination for the Improvement of Higher Education Personnel (CAPES; finance code #001), National Council for Scientific and Technological Development (CNPq; #405027/2021-4; #427946/2018-2; #309633/2021-4; #307852/2019-9), Department of Science and Technology from the Science, Technology and Strategic Inputs Secretariat of the Ministry of Health (Decit/SCTIE/MS, Brazil) intermediated by the National Council for Scientific and Technological Development (CNPq, Brazil) with support from Araucária Foundation and State Health Secretariat, Paraná (SESA-PR, Brazil; PPSUS Grant agreement #041/2017, protocol 48,095); Support Program for Excellence Groups (PRONEX) grant supported by SETI/Araucaria Foundation and MCTI/CNPq; and Paraná State Government (agreement #014/2017, protocol 46,843). The authors also thank the support of CMLP-UEL (Central Multiuser de Laboratorios de Pesquisa—Universidade Estadual de Londrina). C.Z.S.-V., C.Z., A.Z.Z., V.F., L.S.-F., S.B.-G., T.H.Z., M.M.B., T.S.-S.; C.R.F., M.F.M. and F.A.P.-R. acknowledge CAPES fellowships (finance code #001). S.M.B. acknowledges the FUNADESP fellowship (#5301159). R.C., CNDS, and WAVJ acknowledge the Senior Research CNPq fellowship.