Comprehensive innate immune profiling of chikungunya virus infection in pediatric cases

Daniela Michlmayr; Theodore R. Pak; Adeeb H. Rahman; El Ad David Amir; Eun Young Kim; Seunghee Kim-Schulze; Maria Suprun; Michael G. Stewart; Guajira P. Thomas; Angel Balmaseda; Li Wang; Jun Zhu; Mayte Suaréz-Fariñas; Steven M. Wolinsky; Andrew Kasarskis; Eva Harris

doi:10.15252/msb.20177862

Comprehensive innate immune profiling of chikungunya virus infection in pediatric cases

Daniela Michlmayr, Theodore R. Pak, Adeeb H. Rahman, El Ad David Amir, Eun Young Kim, Seunghee Kim-Schulze, Maria Suprun, Michael G. Stewart, Guajira P. Thomas, Angel Balmaseda, Li Wang, Jun Zhu, Mayte Suaréz-Fariñas, Steven M. Wolinsky, Andrew Kasarskis, Eva Harris^*

^*Corresponding author for this work

Medicine, Infectious Diseases Division

Research output: Contribution to journal › Article › peer-review

33 Scopus citations

Abstract

Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that causes global epidemics of debilitating disease worldwide. To gain functional insight into the host cellular genes required for virus infection, we performed whole-blood RNA-seq, 37-plex mass cytometry of peripheral blood mononuclear cells (PBMCs), and serum cytokine measurements of acute- and convalescent-phase samples obtained from 42 children naturally infected with CHIKV. Semi-supervised classification and clustering of single-cell events into 57 sub-communities of canonical leukocyte phenotypes revealed a monocyte-driven response to acute infection, with the greatest expansions in “intermediate” CD14 ⁺⁺ CD16 ⁺ monocytes and an activated subpopulation of CD14 ⁺ monocytes. Increases in acute-phase CHIKV envelope protein E2 expression were highest for monocytes and dendritic cells. Serum cytokine measurements confirmed significant acute-phase upregulation of monocyte chemoattractants. Distinct transcriptomic signatures were associated with infection timepoint, as well as convalescent-phase anti-CHIKV antibody titer, acute-phase viremia, and symptom severity. We present a multiscale network that summarizes all observed modulations across cellular and transcriptomic levels and their interactions with clinical outcomes, providing a uniquely global view of the biomolecular landscape of human CHIKV infection.

Original language	English (US)
Article number	e7862
Journal	Molecular Systems Biology
Volume	14
Issue number	8
DOIs	https://doi.org/10.15252/msb.20177862
State	Published - Aug 2018

Keywords

CyTOF
RNA-seq
chikungunya
immune profiling
pediatric

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)
Immunology and Microbiology(all)
Agricultural and Biological Sciences(all)
Applied Mathematics

UN SDGs

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

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10.15252/msb.20177862

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Michlmayr, D., Pak, T. R., Rahman, A. H., Amir, E. A. D., Kim, E. Y., Kim-Schulze, S., Suprun, M., Stewart, M. G., Thomas, G. P., Balmaseda, A., Wang, L., Zhu, J., Suaréz-Fariñas, M., Wolinsky, S. M., Kasarskis, A., & Harris, E. (2018). Comprehensive innate immune profiling of chikungunya virus infection in pediatric cases. Molecular Systems Biology, 14(8), [e7862]. https://doi.org/10.15252/msb.20177862

@article{6c15d38df76a4fe3bd47e2222f1101e6,

title = "Comprehensive innate immune profiling of chikungunya virus infection in pediatric cases",

abstract = " Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that causes global epidemics of debilitating disease worldwide. To gain functional insight into the host cellular genes required for virus infection, we performed whole-blood RNA-seq, 37-plex mass cytometry of peripheral blood mononuclear cells (PBMCs), and serum cytokine measurements of acute- and convalescent-phase samples obtained from 42 children naturally infected with CHIKV. Semi-supervised classification and clustering of single-cell events into 57 sub-communities of canonical leukocyte phenotypes revealed a monocyte-driven response to acute infection, with the greatest expansions in “intermediate” CD14 ++ CD16 + monocytes and an activated subpopulation of CD14 + monocytes. Increases in acute-phase CHIKV envelope protein E2 expression were highest for monocytes and dendritic cells. Serum cytokine measurements confirmed significant acute-phase upregulation of monocyte chemoattractants. Distinct transcriptomic signatures were associated with infection timepoint, as well as convalescent-phase anti-CHIKV antibody titer, acute-phase viremia, and symptom severity. We present a multiscale network that summarizes all observed modulations across cellular and transcriptomic levels and their interactions with clinical outcomes, providing a uniquely global view of the biomolecular landscape of human CHIKV infection.",

keywords = "CyTOF, RNA-seq, chikungunya, immune profiling, pediatric",

author = "Daniela Michlmayr and Pak, {Theodore R.} and Rahman, {Adeeb H.} and Amir, {El Ad David} and Kim, {Eun Young} and Seunghee Kim-Schulze and Maria Suprun and Stewart, {Michael G.} and Thomas, {Guajira P.} and Angel Balmaseda and Li Wang and Jun Zhu and Mayte Suar{\'e}z-Fari{\~n}as and Wolinsky, {Steven M.} and Andrew Kasarskis and Eva Harris",

note = "Funding Information: This work was supported by NIH/NIAID grants U19AI118610 (DM, TRP, AR, E-YK, SK-S, AB, MS-F, SW, AK, EH), R33AI100186 (AB, EH), and F30AI122673 (TRP), and in part by the resources and expertise of the Department of Scientific Computing at the Icahn School of Medicine at Mount Sinai. We thank Jesse Waggoner for advice regarding quantifying CHIKV viremia in patient samples. We thank study personnel at the HIMJR and the National Virology Laboratory of the Ministry of Health in Managua, Nicaragua, for enrolling patients, collecting blood samples and clinical data, maintaining databases and a high level of quality control, and preparing PBMCs. We are grateful to the study participants and their families. Publisher Copyright: {\textcopyright} 2018 The Authors. Published under the terms of the CC BY 4.0 license",

year = "2018",

month = aug,

doi = "10.15252/msb.20177862",

language = "English (US)",

volume = "14",

journal = "Molecular Systems Biology",

issn = "1744-4292",

publisher = "Nature Publishing Group",

number = "8",

}

Michlmayr, D, Pak, TR, Rahman, AH, Amir, EAD, Kim, EY, Kim-Schulze, S, Suprun, M, Stewart, MG, Thomas, GP, Balmaseda, A, Wang, L, Zhu, J, Suaréz-Fariñas, M, Wolinsky, SM, Kasarskis, A & Harris, E 2018, 'Comprehensive innate immune profiling of chikungunya virus infection in pediatric cases', Molecular Systems Biology, vol. 14, no. 8, e7862. https://doi.org/10.15252/msb.20177862

TY - JOUR

T1 - Comprehensive innate immune profiling of chikungunya virus infection in pediatric cases

AU - Michlmayr, Daniela

AU - Pak, Theodore R.

AU - Rahman, Adeeb H.

AU - Amir, El Ad David

AU - Kim, Eun Young

AU - Kim-Schulze, Seunghee

AU - Suprun, Maria

AU - Stewart, Michael G.

AU - Thomas, Guajira P.

AU - Balmaseda, Angel

AU - Wang, Li

AU - Zhu, Jun

AU - Suaréz-Fariñas, Mayte

AU - Wolinsky, Steven M.

AU - Kasarskis, Andrew

AU - Harris, Eva

N1 - Funding Information: This work was supported by NIH/NIAID grants U19AI118610 (DM, TRP, AR, E-YK, SK-S, AB, MS-F, SW, AK, EH), R33AI100186 (AB, EH), and F30AI122673 (TRP), and in part by the resources and expertise of the Department of Scientific Computing at the Icahn School of Medicine at Mount Sinai. We thank Jesse Waggoner for advice regarding quantifying CHIKV viremia in patient samples. We thank study personnel at the HIMJR and the National Virology Laboratory of the Ministry of Health in Managua, Nicaragua, for enrolling patients, collecting blood samples and clinical data, maintaining databases and a high level of quality control, and preparing PBMCs. We are grateful to the study participants and their families. Publisher Copyright: © 2018 The Authors. Published under the terms of the CC BY 4.0 license

PY - 2018/8

Y1 - 2018/8

N2 - Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that causes global epidemics of debilitating disease worldwide. To gain functional insight into the host cellular genes required for virus infection, we performed whole-blood RNA-seq, 37-plex mass cytometry of peripheral blood mononuclear cells (PBMCs), and serum cytokine measurements of acute- and convalescent-phase samples obtained from 42 children naturally infected with CHIKV. Semi-supervised classification and clustering of single-cell events into 57 sub-communities of canonical leukocyte phenotypes revealed a monocyte-driven response to acute infection, with the greatest expansions in “intermediate” CD14 ++ CD16 + monocytes and an activated subpopulation of CD14 + monocytes. Increases in acute-phase CHIKV envelope protein E2 expression were highest for monocytes and dendritic cells. Serum cytokine measurements confirmed significant acute-phase upregulation of monocyte chemoattractants. Distinct transcriptomic signatures were associated with infection timepoint, as well as convalescent-phase anti-CHIKV antibody titer, acute-phase viremia, and symptom severity. We present a multiscale network that summarizes all observed modulations across cellular and transcriptomic levels and their interactions with clinical outcomes, providing a uniquely global view of the biomolecular landscape of human CHIKV infection.

AB - Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that causes global epidemics of debilitating disease worldwide. To gain functional insight into the host cellular genes required for virus infection, we performed whole-blood RNA-seq, 37-plex mass cytometry of peripheral blood mononuclear cells (PBMCs), and serum cytokine measurements of acute- and convalescent-phase samples obtained from 42 children naturally infected with CHIKV. Semi-supervised classification and clustering of single-cell events into 57 sub-communities of canonical leukocyte phenotypes revealed a monocyte-driven response to acute infection, with the greatest expansions in “intermediate” CD14 ++ CD16 + monocytes and an activated subpopulation of CD14 + monocytes. Increases in acute-phase CHIKV envelope protein E2 expression were highest for monocytes and dendritic cells. Serum cytokine measurements confirmed significant acute-phase upregulation of monocyte chemoattractants. Distinct transcriptomic signatures were associated with infection timepoint, as well as convalescent-phase anti-CHIKV antibody titer, acute-phase viremia, and symptom severity. We present a multiscale network that summarizes all observed modulations across cellular and transcriptomic levels and their interactions with clinical outcomes, providing a uniquely global view of the biomolecular landscape of human CHIKV infection.

KW - CyTOF

KW - RNA-seq

KW - chikungunya

KW - immune profiling

KW - pediatric

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UR - http://www.scopus.com/inward/citedby.url?scp=85052535804&partnerID=8YFLogxK

U2 - 10.15252/msb.20177862

DO - 10.15252/msb.20177862

M3 - Article

C2 - 30150281

AN - SCOPUS:85052535804

SN - 1744-4292

VL - 14

JO - Molecular Systems Biology

JF - Molecular Systems Biology

IS - 8

M1 - e7862

ER -

Comprehensive innate immune profiling of chikungunya virus infection in pediatric cases

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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