RNA-Seq analysis of chikungunya virus infection and identification of granzyme A as a major promoter of arthritic inflammation

Jane A C Wilson; Natalie A. Prow; Wayne A. Schroder; Jonathan J. Ellis; Helen E. Cumming; Linden J. Gearing; Yee Suan Poo; Adam Taylor; Paul J. Hertzog; Francesca Di Giallonardo; Linda Hueston; Roger Le Grand; Bing Tang; Thuy T. Le; Joy Gardner; Suresh Mahalingam; Pierre Roques; Phillip I. Bird; Andreas Suhrbier

doi:10.1371/journal.ppat.1006155

RNA-Seq analysis of chikungunya virus infection and identification of granzyme A as a major promoter of arthritic inflammation

Jane A C Wilson, Natalie A. Prow, Wayne A. Schroder, Jonathan J. Ellis, Helen E. Cumming, Linden J. Gearing, Yee Suan Poo, Adam Taylor, Paul J. Hertzog, Francesca Di Giallonardo, Linda Hueston, Roger Le Grand, Bing Tang, Thuy T. Le, Joy Gardner, Suresh Mahalingam, Pierre Roques, Phillip I. Bird, Andreas Suhrbier

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Abstract

Chikungunya virus (CHIKV) is an arthritogenic alphavirus causing epidemics of acute and chronic arthritic disease. Herein we describe a comprehensive RNA-Seq analysis of feet and lymph nodes at peak viraemia (day 2 post infection), acute arthritis (day 7) and chronic disease (day 30) in the CHIKV adult wild-type mouse model. Genes previously shown to be up-regulated in CHIKV patients were also up-regulated in the mouse model. CHIKV sequence information was also obtained with up to ≈8% of the reads mapping to the viral genome; however, no adaptive viral genome changes were apparent. Although day 2, 7 and 30 represent distinct stages of infection and disease, there was a pronounced overlap in up-regulated host genes and pathways. Type I interferon response genes (IRGs) represented up to ≈50% of up-regulated genes, even after loss of type I interferon induction on days 7 and 30. Bioinformatic analyses suggested a number of interferon response factors were primarily responsible for maintaining type I IRG induction. A group of genes prominent in the RNA-Seq analysis and hitherto unexplored in viral arthropathies were granzymes A, B and K. Granzyme A^-/-and to a lesser extent granzyme K^-/-, but not granzyme B^-/-, mice showed a pronounced reduction in foot swelling and arthritis, with analysis of granzyme A^-/-mice showing no reductions in viral loads but reduced NK and T cell infiltrates post CHIKV infection. Treatment with Serpinb6b, a granzyme A inhibitor, also reduced arthritic inflammation in wild-type mice. In non-human primates circulating granzyme A levels were elevated after CHIKV infection, with the increase correlating with viral load. Elevated granzyme A levels were also seen in a small cohort of human CHIKV patients. Taken together these results suggest granzyme A is an important driver of arthritic inflammation and a potential target for therapy. Trial Registration: ClinicalTrials.gov NCT00281294

Original language	English
Article number	e1006155
Number of pages	32
Journal	PLoS Pathogens
Volume	13
Issue number	2
DOIs	https://doi.org/10.1371/journal.ppat.1006155
Publication status	Published - 16 Feb 2017

Keywords

chikungunya infection
mammalian genomics
lymph nodes
mouse models
chikungunya virus
transcription factors
interferons
viremia

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Wilson, J. A. C., Prow, N. A., Schroder, W. A., Ellis, J. J., Cumming, H. E., Gearing, L. J., Poo, Y. S., Taylor, A., Hertzog, P. J., Di Giallonardo, F., Hueston, L., Le Grand, R., Tang, B., Le, T. T., Gardner, J., Mahalingam, S., Roques, P., Bird, P. I., & Suhrbier, A. (2017). RNA-Seq analysis of chikungunya virus infection and identification of granzyme A as a major promoter of arthritic inflammation. PLoS Pathogens, 13(2), Article e1006155. https://doi.org/10.1371/journal.ppat.1006155

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title = "RNA-Seq analysis of chikungunya virus infection and identification of granzyme A as a major promoter of arthritic inflammation",

abstract = "Chikungunya virus (CHIKV) is an arthritogenic alphavirus causing epidemics of acute and chronic arthritic disease. Herein we describe a comprehensive RNA-Seq analysis of feet and lymph nodes at peak viraemia (day 2 post infection), acute arthritis (day 7) and chronic disease (day 30) in the CHIKV adult wild-type mouse model. Genes previously shown to be up-regulated in CHIKV patients were also up-regulated in the mouse model. CHIKV sequence information was also obtained with up to ≈8% of the reads mapping to the viral genome; however, no adaptive viral genome changes were apparent. Although day 2, 7 and 30 represent distinct stages of infection and disease, there was a pronounced overlap in up-regulated host genes and pathways. Type I interferon response genes (IRGs) represented up to ≈50% of up-regulated genes, even after loss of type I interferon induction on days 7 and 30. Bioinformatic analyses suggested a number of interferon response factors were primarily responsible for maintaining type I IRG induction. A group of genes prominent in the RNA-Seq analysis and hitherto unexplored in viral arthropathies were granzymes A, B and K. Granzyme A-/-and to a lesser extent granzyme K-/-, but not granzyme B-/-, mice showed a pronounced reduction in foot swelling and arthritis, with analysis of granzyme A-/-mice showing no reductions in viral loads but reduced NK and T cell infiltrates post CHIKV infection. Treatment with Serpinb6b, a granzyme A inhibitor, also reduced arthritic inflammation in wild-type mice. In non-human primates circulating granzyme A levels were elevated after CHIKV infection, with the increase correlating with viral load. Elevated granzyme A levels were also seen in a small cohort of human CHIKV patients. Taken together these results suggest granzyme A is an important driver of arthritic inflammation and a potential target for therapy. Trial Registration: ClinicalTrials.gov NCT00281294",

keywords = "chikungunya infection, mammalian genomics, lymph nodes, mouse models, chikungunya virus, transcription factors, interferons, viremia",

author = "Wilson, {Jane A C} and Prow, {Natalie A.} and Schroder, {Wayne A.} and Ellis, {Jonathan J.} and Cumming, {Helen E.} and Gearing, {Linden J.} and Poo, {Yee Suan} and Adam Taylor and Hertzog, {Paul J.} and {Di Giallonardo}, Francesca and Linda Hueston and {Le Grand}, Roger and Bing Tang and Le, {Thuy T.} and Joy Gardner and Suresh Mahalingam and Pierre Roques and Bird, {Phillip I.} and Andreas Suhrbier",

year = "2017",

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doi = "10.1371/journal.ppat.1006155",

language = "English",

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Wilson, JAC, Prow, NA, Schroder, WA, Ellis, JJ, Cumming, HE, Gearing, LJ, Poo, YS, Taylor, A, Hertzog, PJ, Di Giallonardo, F, Hueston, L, Le Grand, R, Tang, B, Le, TT, Gardner, J, Mahalingam, S, Roques, P, Bird, PI & Suhrbier, A 2017, 'RNA-Seq analysis of chikungunya virus infection and identification of granzyme A as a major promoter of arthritic inflammation', PLoS Pathogens, vol. 13, no. 2, e1006155. https://doi.org/10.1371/journal.ppat.1006155

TY - JOUR

T1 - RNA-Seq analysis of chikungunya virus infection and identification of granzyme A as a major promoter of arthritic inflammation

AU - Wilson, Jane A C

AU - Prow, Natalie A.

AU - Schroder, Wayne A.

AU - Ellis, Jonathan J.

AU - Cumming, Helen E.

AU - Gearing, Linden J.

AU - Poo, Yee Suan

AU - Taylor, Adam

AU - Hertzog, Paul J.

AU - Di Giallonardo, Francesca

AU - Hueston, Linda

AU - Le Grand, Roger

AU - Tang, Bing

AU - Le, Thuy T.

AU - Gardner, Joy

AU - Mahalingam, Suresh

AU - Roques, Pierre

AU - Bird, Phillip I.

AU - Suhrbier, Andreas

PY - 2017/2/16

Y1 - 2017/2/16

N2 - Chikungunya virus (CHIKV) is an arthritogenic alphavirus causing epidemics of acute and chronic arthritic disease. Herein we describe a comprehensive RNA-Seq analysis of feet and lymph nodes at peak viraemia (day 2 post infection), acute arthritis (day 7) and chronic disease (day 30) in the CHIKV adult wild-type mouse model. Genes previously shown to be up-regulated in CHIKV patients were also up-regulated in the mouse model. CHIKV sequence information was also obtained with up to ≈8% of the reads mapping to the viral genome; however, no adaptive viral genome changes were apparent. Although day 2, 7 and 30 represent distinct stages of infection and disease, there was a pronounced overlap in up-regulated host genes and pathways. Type I interferon response genes (IRGs) represented up to ≈50% of up-regulated genes, even after loss of type I interferon induction on days 7 and 30. Bioinformatic analyses suggested a number of interferon response factors were primarily responsible for maintaining type I IRG induction. A group of genes prominent in the RNA-Seq analysis and hitherto unexplored in viral arthropathies were granzymes A, B and K. Granzyme A-/-and to a lesser extent granzyme K-/-, but not granzyme B-/-, mice showed a pronounced reduction in foot swelling and arthritis, with analysis of granzyme A-/-mice showing no reductions in viral loads but reduced NK and T cell infiltrates post CHIKV infection. Treatment with Serpinb6b, a granzyme A inhibitor, also reduced arthritic inflammation in wild-type mice. In non-human primates circulating granzyme A levels were elevated after CHIKV infection, with the increase correlating with viral load. Elevated granzyme A levels were also seen in a small cohort of human CHIKV patients. Taken together these results suggest granzyme A is an important driver of arthritic inflammation and a potential target for therapy. Trial Registration: ClinicalTrials.gov NCT00281294

AB - Chikungunya virus (CHIKV) is an arthritogenic alphavirus causing epidemics of acute and chronic arthritic disease. Herein we describe a comprehensive RNA-Seq analysis of feet and lymph nodes at peak viraemia (day 2 post infection), acute arthritis (day 7) and chronic disease (day 30) in the CHIKV adult wild-type mouse model. Genes previously shown to be up-regulated in CHIKV patients were also up-regulated in the mouse model. CHIKV sequence information was also obtained with up to ≈8% of the reads mapping to the viral genome; however, no adaptive viral genome changes were apparent. Although day 2, 7 and 30 represent distinct stages of infection and disease, there was a pronounced overlap in up-regulated host genes and pathways. Type I interferon response genes (IRGs) represented up to ≈50% of up-regulated genes, even after loss of type I interferon induction on days 7 and 30. Bioinformatic analyses suggested a number of interferon response factors were primarily responsible for maintaining type I IRG induction. A group of genes prominent in the RNA-Seq analysis and hitherto unexplored in viral arthropathies were granzymes A, B and K. Granzyme A-/-and to a lesser extent granzyme K-/-, but not granzyme B-/-, mice showed a pronounced reduction in foot swelling and arthritis, with analysis of granzyme A-/-mice showing no reductions in viral loads but reduced NK and T cell infiltrates post CHIKV infection. Treatment with Serpinb6b, a granzyme A inhibitor, also reduced arthritic inflammation in wild-type mice. In non-human primates circulating granzyme A levels were elevated after CHIKV infection, with the increase correlating with viral load. Elevated granzyme A levels were also seen in a small cohort of human CHIKV patients. Taken together these results suggest granzyme A is an important driver of arthritic inflammation and a potential target for therapy. Trial Registration: ClinicalTrials.gov NCT00281294

KW - chikungunya infection

KW - mammalian genomics

KW - lymph nodes

KW - mouse models

KW - chikungunya virus

KW - transcription factors

KW - interferons

KW - viremia

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U2 - 10.1371/journal.ppat.1006155

DO - 10.1371/journal.ppat.1006155

M3 - Article

AN - SCOPUS:85014084189

SN - 1553-7366

VL - 13

JO - PLoS Pathogens

JF - PLoS Pathogens

IS - 2

M1 - e1006155

ER -

RNA-Seq analysis of chikungunya virus infection and identification of granzyme A as a major promoter of arthritic inflammation

Abstract

Keywords

UN SDGs

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