Systems analysis of subjects acutely infected with the Chikungunya virus

Soares‐Schanoski, Alessandra; Cruz, Natália Baptista; Castro-Jorge, Luíza Antunes de; Carvalho, Roberto Gameiro de; Santos, Cliomar Alves dos; Rós, Nancy da; Oliveira, Úrsula; Costa, Danuza Duarte; Santos, Cecília Luiza Simões; Cunha, Marielton dos Passos; Oliveira, Maria Leonor S.; Alves, Juliana Cardoso; Océa, Regina Adalva de Lucena Couto; Ribeiro, Danielle Rodrigues; Gonçalves, André Nicolau Aquime; Gonzalez-Dias, Patrícia; Suhrbier, Andreas; Zanotto, Paolo Marinho de Andrade; Junqueira-de-Azevedo, Inácio L.M.; Zamboni, Dario S.; Almeida, Roque Pacheco de; Ho, Paulo Lee; Kalil, Jorge; Nishiyama-Jr, Milton Yutaka; Nakaya, Helder I.

doi:10.1371/journal.ppat.1007880

Cited by 39 publications

(28 citation statements)

References 65 publications

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“…No mouse models have so far been developed that measure polyarthralgia. The adult wild-type CHIKV mouse model recapitulates many aspects of human disease [ 42 , 57 ], with recent RNA-Seq comparisons further illustrating that this mouse model shares many inflammatory processes with those seen in humans [ 105 , 106 ]. However, such comparisons are not yet available for ONNV, MAYV or RRV.…”

Section: Discussionmentioning

confidence: 99%

Arthritogenic Alphavirus Vaccines: Serogrouping Versus Cross-Protection in Mouse Models

et al. 2020

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Chikungunya virus (CHIKV), Ross River virus (RRV), o’nyong nyong virus (ONNV), Mayaro virus (MAYV) and Getah virus (GETV) represent arthritogenic alphaviruses belonging to the Semliki Forest virus antigenic complex. Antibodies raised against one of these viruses can cross-react with other serogroup members, suggesting that, for instance, a CHIKV vaccine (deemed commercially viable) might provide cross-protection against antigenically related alphaviruses. Herein we use human alphavirus isolates (including a new human RRV isolate) and wild-type mice to explore whether infection with one virus leads to cross-protection against viremia after challenge with other members of the antigenic complex. Persistently infected Rag1-/- mice were also used to assess the cross-protective capacity of convalescent CHIKV serum. We also assessed the ability of a recombinant poxvirus-based CHIKV vaccine and a commercially available formalin-fixed, whole-virus GETV vaccine to induce cross-protective responses. Although cross-protection and/or cross-reactivity were clearly evident, they were not universal and were often suboptimal. Even for the more closely related viruses (e.g., CHIKV and ONNV, or RRV and GETV), vaccine-mediated neutralization and/or protection against the intended homologous target was significantly more effective than cross-neutralization and/or cross-protection against the heterologous virus. Effective vaccine-mediated cross-protection would thus likely require a higher dose and/or more vaccinations, which is likely to be unattractive to regulators and vaccine manufacturers.

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Section: Discussionmentioning

confidence: 99%

Arthritogenic Alphavirus Vaccines: Serogrouping Versus Cross-Protection in Mouse Models

et al. 2020

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“…The mechanisms whereby the high fiber diet would mediate the neutrophil-promoting changes during CHIKV arthritis are likely to be complex given the interaction of various SCFAs with multiple cell types (10, 18, 24, 66, 113), the infection of different cell types by CHIKV, and the complex interplay of anti-viral and inflammatory responses seen post infection (36, 41, 42, 51). Nevertheless, a likely key contributing mechanism highlighted herein is the down-modulation in the rM gene signature seen in feet during peak CHIKV arthritis in mice fed a high fiber diet (compared with peak CHIKV arthritis in mice fed a no fiber diet) (Figure 5).…”

Section: Discussionmentioning

confidence: 99%

“…CD4 T cells are important for driving CHIKV arthritis (36), with Tregs associated with disease amelioration (49, 50). Macrophages/monocytes also play an important role in the arthritic immunopathology (36), with the pro-inflammatory response to CHIKV infection in peripheral blood shown to be monocyte centric (41, 51). However, macrophages are also required for resolution of inflammation, both generally (52–54) and specifically for CHIKV arthritic inflammation (45).…”

Section: Introductionmentioning

confidence: 99%

Exacerbation of Chikungunya Virus Rheumatic Immunopathology by a High Fiber Diet and Butyrate

et al. 2019

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Chikungunya virus (CHIKV) is a mosquito transmitted alphavirus associated with a robust systemic infection and an acute inflammatory rheumatic disease. A high fiber diet has been widely promoted for its ability to ameliorate inflammatory diseases. Fiber is fermented in the gut into short chain fatty acids such as acetate, propionate, and butyrate, which enter the circulation providing systemic anti-inflammatory activities. Herein we show that mice fed a high fiber diet show a clear exacerbation of CHIKV arthropathy, with increased edema and neutrophil infiltrates. RNA-Seq analyses illustrated that a high fiber diet, in this setting, promoted a range of pro-neutrophil responses including Th17/IL-17. Gene Set Enrichment Analyses demonstrated significant similarities with mouse models of inflammatory psoriasis and significant depression of macrophage resolution phase signatures in the CHIKV arthritic lesions from mice fed a high fiber diet. Supplementation of the drinking water with butyrate also increased edema after CHIKV infection. However, the mechanisms involved were different, with modulation of AP-1 and NF-κB responses identified, potentially implicating deoptimization of endothelial barrier repair. Thus, neither fiber nor short chain fatty acids provided benefits in this acute infectious disease setting, which is characterized by widespread viral cytopathic effects and a need for tissue repair.

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“…Human serum samples were collected in the Brazilian states of Sergipe, São Paulo, and Brasília (52,53). Clinical and sociodemographic data was collected through a questionnaire that participants were asked to complete.…”

Section: Human Sera Collection Diagnosis and Patient Informationmentioning

confidence: 99%

Granzyme A in Chikungunya and Other Arboviral Infections

Soares‐Schanoski

Kaiserman

et al. 2020

Front. Immunol.

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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.

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Systems analysis of subjects acutely infected with the Chikungunya virus

Cited by 39 publications

References 65 publications

Arthritogenic Alphavirus Vaccines: Serogrouping Versus Cross-Protection in Mouse Models

Arthritogenic Alphavirus Vaccines: Serogrouping Versus Cross-Protection in Mouse Models

Exacerbation of Chikungunya Virus Rheumatic Immunopathology by a High Fiber Diet and Butyrate

Granzyme A in Chikungunya and Other Arboviral Infections

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