Stimulation of dendritic cell functional maturation by capsid protein from chikungunya virus

Document Type: Original Article


1 Department of Pathophysiology, Vietnam Military Medical University, Ha Dong, Hanoi, Vietnam

2 Faculty of Biotechnology, Vietnam National University of Agriculture, Gia Lam, Hanoi, Vietnam

3 Graduate University of Science and Technology, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet, Cau Giay, Ha Noi, Vietnam

4 Institute of Genome Research, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet, Cau Giay, Hanoi, Vietnam



Objective(s): Chikungunya virus (ChikV) infection is characterized by persistent infection in joints and lymphoid organs. The ChikV Capsid protein plays an important role in regulating virus replication. In this study, we hypothesized that capsid protein may stimulate dendritic cell (DC) activation and maturation and trigger an inflammatory response in mice.
Materials and Methods: Mice were intraperitoneally injected with capsid protein and examined for changes in immunophenotype in lymph nodes (LNs). Next, DCs were treated with capsid protein or LPS and then expression of maturation markers, cytokine production, and ability to stimulate CD4+ T cells in allo-MLR were analyzed.
Results: Injection of mice with capsid protein led to recruitment of myeloid cells and increased activation of T lymphocytes in LNs. Importantly, treatment of DCs with capsid protein prolonged the activation of IKB-α and up-regulated the number of CD11c+CD86+DCs and release of TNF-α and IL-12p70 as well as reducing DC apoptosis, all effects were abolished in the presence of Bay 11-7082. In addition, IL-2 production was higher by CD4+ T cells stimulated with capsid-treated as compared with LPS-induced DCs.
Conclusion: The observations revealed that capsid protein participates in the regulation of NF-κB signaling and maturation of DCs.


1. Labadie K, Larcher T, Joubert C, Mannioui A, Delache B, Brochard P, et al. Chikungunya disease in nonhuman primates involves long-term viral persistence in macrophages. J Clin Invest 2010; 120: 894-906.
2. McPherson RL, Abraham R, Sreekumar E, Ong SE, Cheng SJ, Baxter VK, et al. ADP-ribosylhydrolase activity of Chikungunya virus macrodomain is critical for virus replication and virulence. Proc Natl Acad Sci U S A 2017; 114: 1666-1671.
3. Nayak TK, Mamidi P, Kumar A, Singh LP, Sahoo SS, Chattopadhyay S, et al. Regulation of viral replication, apoptosis and pro-inflammatory responses by 17-AAG during chikungunya virus infection in macrophages. Viruses 2017; 9: 1-17.
4. Goh LY, Hobson-Peters J, Prow NA, Gardner J, Bielefeldt-Ohmann H, Suhrbier A, et al. Monoclonal antibodies specific for the capsid protein of chikungunya virus suitable for multiple applications. J Gen Virol 2015; 96: 507-512.
5. Silva LA, Dermody TS. Chikungunya virus: epidemiology, replication, disease mechanisms, and prospective intervention strategies. J Clin Invest 2017; 127: 737-749.
6. Fox JM, Diamond MS. Immune-mediated protection and pathogenesis of chikungunya virus. J Immunol 2016; 197: 4210-4218.
7. Ziegler SA, Lu L, da Rosa AP, Xiao SY, Tesh RB. An animal model for studying the pathogenesis of chikungunya virus infection. Am J Trop Med Hyg 2008; 79: 133-139.
8. Hoarau JJ, Jaffar Bandjee MC, Krejbich Trotot P, Das T, Li-Pat-Yuen G, Dassa B, et al. Persistent chronic inflammation and infection by Chikungunya arthritogenic alphavirus in spite of a robust host immune response. J Immunol 2010; 184: 5914-5927.
9. Her Z, Teng TS, Tan JJ, Teo TH, Kam YW, Lum FM, et al. Loss of TLR3 aggravates CHIKV replication and pathology due to an altered virus-specific neutralizing antibody response. EMBO Mol Med 2015; 7: 24-41.
10.    Partidos CD, Weger J, Brewoo J, Seymour R, Borland EM, Ledermann JP, et al. Probing the attenuation and protective efficacy of a candidate chikungunya virus vaccine in mice with compromised interferon (IFN) signaling. Vaccine 2011; 29: 3067-3073.
11.    Das T, Hoarau JJ, Jaffar Bandjee MC, Maquart M, Gasque P. Multifaceted innate immune responses engaged by astrocytes, microglia and resident dendritic cells against Chikungunya neuroinfection. J Gen Virol 2015; 96: 294-310.
12. Akahata W, Yang ZY, Andersen H, Sun S, Holdaway HA, Kong WP, et al. A virus-like particle vaccine for epidemic Chikungunya virus protects nonhuman primates against infection. Nat Med 2010; 16: 334-338.
13.    Muthumani K, Lankaraman KM, Laddy DJ, Sundaram SG, Chung CW, Sako E, et al. Immunogenicity of novel consensus-based DNA vaccines against Chikungunya virus. Vaccine 2008; 26: 5128-5134.
14.    Brandler S, Ruffie C, Combredet C, Brault JB, Najburg V, Prevost MC, et al. A recombinant measles vaccine expressing chikungunya virus-like particles is strongly immunogenic and protects mice from lethal challenge with chikungunya virus. Vaccine 2013; 31: 3718-3725.
15.    Ramsauer K, Schwameis M, Firbas C, Mullner M, Putnak RJ, Thomas SJ, et al. Immunogenicity, safety, and tolerability of a recombinant measles-virus-based chikungunya vaccine: a randomised, double-blind, placebo-controlled, active-comparator, first-in-man trial. Lancet Infect Dis 2015; 15: 519-527.
16.    Smalley C, Erasmus JH, Chesson CB, Beasley DWC. Status of research and development of vaccines for chikungunya. Vaccine 2016; 34: 2976-2981.
17.    Granucci F, Foti M, Ricciardi-Castagnoli P. Dendritic cell biology. Adv Immunol 2005; 88: 193-233.
18.    Xuan NT, Shumilina E, Matzner N, Zemtsova IM, Biedermann T, Goetz F, et al. Ca2+-dependent functions in peptidoglycan-stimulated mouse dendritic cells. Cell Physiol Biochem 2009; 24: 167-176.
19.    Muller M, Slivinski N, Todd E, Khalid H, Li R, Karwatka M, et al. Chikungunya virus requires cellular chloride channels for efficient genome replication. PLoS Negl Trop Dis 2019; 13: e0007703.
20.    Webster B, Werneke SW, Zafirova B, This S, Coleon S, Decembre E, et al. Plasmacytoid dendritic cells control dengue and Chikungunya virus infections via IRF7-regulated interferon responses. Elife 2018; 7: 1-22.
21.    Long KM, Whitmore AC, Ferris MT, Sempowski GD, McGee C, Trollinger B, et al. Dendritic cell immunoreceptor regulates Chikungunya virus pathogenesis in mice. J Virol 2013; 87: 5697-706.
22.    Sourisseau M, Schilte C, Casartelli N, Trouillet C, Guivel-Benhassine F, Rudnicka D, et al. Characterization of reemerging chikungunya virus. PLoS Pathog 2007; 3: e89.
23.    Damle RG, Jayaram N, Kulkarni SM, Nigade K, Khutwad K, Gosavi S, et al. Diagnostic potential of monoclonal antibodies against the capsid protein of chikungunya virus for detection of recent infection. Arch Virol 2016; 161: 1611-1622.
24.    Sharma R, Fatma B, Saha A, Bajpai S, Sistla S, Dash PK, et al. Inhibition of chikungunya virus by picolinate that targets viral capsid protein. Virology 2016; 498: 265-276.
25.    Hoarau JJ, Gay F, Pelle O, Samri A, Jaffar-Bandjee MC, Gasque P, et al. Identical strength of the T cell responses against E2, nsP1 and capsid CHIKV proteins in recovered and chronic patients after the epidemics of 2005-2006 in La Reunion Island. PLoS One 2013; 8: e84695.
26.    Xuan NT, Wang X, Nishanth G, Waisman A, Borucki K, Isermann B, et al. A20 expression in dendritic cells protects mice from LPS-induced mortality. Eur J Immunol 2015; 45: 818-828.
27.    Kowalzik S, Xuan NV, Weissbrich B, Scheiner B, Schied T, Drosten C, et al. Characterisation of a chikungunya virus from a German patient returning from Mauritius and development of a serological test. Med Microbiol Immunol 2008; 197: 381-386.
28.    Xuan NT, Shumilina E, Nasir O, Bobbala D, Gotz F, Lang F. Stimulation of mouse dendritic cells by Gum Arabic. Cell Physiol Biochem 2010; 25: 641-648.
29.    Garcia-Arriaza J, Cepeda V, Hallengard D, Sorzano CO, Kummerer BM, Liljestrom P, et al. A novel poxvirus-based vaccine, MVA-CHIKV, is highly immunogenic and protects mice against chikungunya infection. J Virol 2014; 88: 3527-3547.
30.    Her Z, Malleret B, Chan M, Ong EK, Wong SC, Kwek DJ, et al. Active infection of human blood monocytes by Chikungunya virus triggers an innate immune response. J Immunol 2010; 184: 5903-5913.
31.    Olagnier D, Scholte FE, Chiang C, Albulescu IC, Nichols C, He Z, et al. Inhibition of dengue and chikungunya virus infections by RIG-I-mediated type I interferon-independent stimulation of the innate antiviral response. J Virol 2014; 88: 4180-4194.
32.    Davenport BJ, Bullock C, McCarthy MK, Hawman DW, Murphy KM, Kedl RM, et al. Chikungunya virus evades antiviral CD8(+) T cell responses to establish persistent infection in joint-associated tissues. J Virol 2020; 94:e02036-19.
33.    Lee WW, Teo TH, Her Z, Lum FM, Kam YW, Haase D, et al. Expanding regulatory T cells alleviates chikungunya virus-induced pathology in mice. J Virol 2015; 89:7893-7904.