A Molecular Signature in Blood Reveals a Role for p53 in Regulating Malaria-Induced Inflammation

Tuan M. Tran; Rajan Guha; Silvia Portugal; Jeff Skinner; Aissata Ongoiba; Jyoti Bhardwaj; Marcus Jones; Jacqueline Moebius; Pratap Venepally; Safiatou Doumbo; Elizabeth A. DeRiso; Shanping Li; Kamalakannan Vijayan; Sarah L. Anzick; Geoffrey T. Hart; Elise M. O'Connell; Ogobara K. Doumbo; Alexis Kaushansky; Galit Alter; Phillip L. Felgner; Hernan Lorenzi; Kassoum Kayentao; Boubacar Traore; Ewen F. Kirkness; Peter D. Crompton

doi:10.1016/j.immuni.2019.08.009

A Molecular Signature in Blood Reveals a Role for p53 in Regulating Malaria-Induced Inflammation

Tuan M. Tran, Rajan Guha, Silvia Portugal, Jeff Skinner, Aissata Ongoiba, Jyoti Bhardwaj, Marcus Jones, Jacqueline Moebius, Pratap Venepally, Safiatou Doumbo, Elizabeth A. DeRiso, Shanping Li, Kamalakannan Vijayan, Sarah L. Anzick, Geoffrey T. Hart, Elise M. O'Connell, Ogobara K. Doumbo, Alexis Kaushansky, Galit Alter, Phillip L. FelgnerHernan Lorenzi, Kassoum Kayentao, Boubacar Traore, Ewen F. Kirkness, Peter D. Crompton

Medicine - Infectious Disease and International Medicine

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

35 Scopus citations

Abstract

Immunity that controls parasitemia and inflammation during Plasmodium falciparum (Pf) malaria can be acquired with repeated infections. A limited understanding of this complex immune response impedes the development of vaccines and adjunctive therapies. We conducted a prospective systems biology study of children who differed in their ability to control parasitemia and fever following Pf infection. By integrating whole-blood transcriptomics, flow-cytometric analysis, and plasma cytokine and antibody profiles, we demonstrate that a pre-infection signature of B cell enrichment, upregulation of T helper type 1 (Th1) and Th2 cell-associated pathways, including interferon responses, and p53 activation associated with control of malarial fever and coordinated with Pf-specific immunoglobulin G (IgG) and Fc receptor activation to control parasitemia. Our hypothesis-generating approach identified host molecules that may contribute to differential clinical outcomes during Pf infection. As a proof of concept, we have shown that enhanced p53 expression in monocytes attenuated Plasmodium-induced inflammation and predicted protection from fever.

Original language	English (US)
Pages (from-to)	750-765.e10
Journal	Immunity
Volume	51
Issue number	4
DOIs	https://doi.org/10.1016/j.immuni.2019.08.009
State	Published - Oct 15 2019

Bibliographical note

Funding Information:
We thank the residents of Kalifabougou, Mali for participating in this study. This project was supported with federal funds from the National Institute of Allergy and Infectious Diseases (NIAID), NIH, Department of Health and Human Services under contract number HHSN272200900007C, award number U19AI110819, and the Division of Intramural Research. T.M.T. was also supported by K08AI125682 (NIAID) and the Doris Duke Charitable Foundation Clinical Scientist Development Award. Protein microarray experiments were funded by NIAID grants U19AI089686 and R01AI095916 (P.L.F.). Super p53 mice were kindly provided by David G. Kirsch (Duke University). Recombinant Pf antigens were kindly provided by David L. Narum (Laboratory of Malaria Immunology and Vaccinology, NIAID, NIH) and Gavin J. Wright (Wellcome Trust Sanger Institute). T.M.T. and P.D.C. drove the study design, analyzed the data, and wrote the manuscript. R.G. S.P. J.B. and J.M. performed the human cell culture experiments, including flow cytometry studies, and analyzed the data. M.J. P.V. H.L. and E.F.K. were critical in the design and execution of the RNA-seq experiments, including sample processing, sequencing, analysis, and mapping. S.L.A. performed the gene expression confirmation studies and analysis. S.L. performed the PCR studies for parasite detection, quantitation, and microsatellite analysis. P.L.F. E.A.D. and G.A. designed and/or performed the antibody experiments. J.S. assisted with the processing and analysis of the protein array, gene expression, and class prediction data and provided statistical guidance for all experiments. E.M.O. performed the molecular testing for helminth infections. T.M.T. G.T.H. K.V. and A.K. discussed, designed, and conducted the mouse experiments. T.M.T. A.O. S.D. O.K.D. K.K. B.T. and P.D.C. designed, organized, and conducted the field studies in Mali that generated the clinical data and blood samples. All authors reviewed and approved the manuscript. P.L.F. has an equity interest in Antigen Discovery, Inc. which is developing products related to the protein microarray platform used in this study. The University of California reviewed and approved in accordance with its conflict of interest policies.

Funding Information:
We thank the residents of Kalifabougou, Mali for participating in this study. This project was supported with federal funds from the National Institute of Allergy and Infectious Diseases (NIAID), NIH, Department of Health and Human Services under contract number HHSN272200900007C , award number U19AI110819 , and the Division of Intramural Research . T.M.T. was also supported by K08AI125682 ( NIAID ) and the Doris Duke Charitable Foundation Clinical Scientist Development Award. Protein microarray experiments were funded by NIAID grants U19AI089686 and R01AI095916 (P.L.F.). Super p53 mice were kindly provided by David G. Kirsch (Duke University). Recombinant Pf antigens were kindly provided by David L. Narum (Laboratory of Malaria Immunology and Vaccinology, NIAID, NIH) and Gavin J. Wright (Wellcome Trust Sanger Institute).

Publisher Copyright:
© 2019

Keywords

Plasmodium falciparum
RNA sequencing
RNA-seq
antibody profiling
flow cytometry
malaria
malaria immunity
prospective cohort study
systems biology
systems immunology
transcriptomics

PubMed: MeSH publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Intramural
Journal Article
Research Support, N.I.H., Extramural

UN SDGs

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

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10.1016/j.immuni.2019.08.009

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Tran, T. M., Guha, R., Portugal, S., Skinner, J., Ongoiba, A., Bhardwaj, J., Jones, M., Moebius, J., Venepally, P., Doumbo, S., DeRiso, E. A., Li, S., Vijayan, K., Anzick, S. L., Hart, G. T., O'Connell, E. M., Doumbo, O. K., Kaushansky, A., Alter, G., ... Crompton, P. D. (2019). A Molecular Signature in Blood Reveals a Role for p53 in Regulating Malaria-Induced Inflammation. Immunity, 51(4), 750-765.e10. https://doi.org/10.1016/j.immuni.2019.08.009

Tran, TM, Guha, R, Portugal, S, Skinner, J, Ongoiba, A, Bhardwaj, J, Jones, M, Moebius, J, Venepally, P, Doumbo, S, DeRiso, EA, Li, S, Vijayan, K, Anzick, SL, Hart, GT, O'Connell, EM, Doumbo, OK, Kaushansky, A, Alter, G, Felgner, PL, Lorenzi, H, Kayentao, K, Traore, B, Kirkness, EF & Crompton, PD 2019, 'A Molecular Signature in Blood Reveals a Role for p53 in Regulating Malaria-Induced Inflammation', Immunity, vol. 51, no. 4, pp. 750-765.e10. https://doi.org/10.1016/j.immuni.2019.08.009

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title = "A Molecular Signature in Blood Reveals a Role for p53 in Regulating Malaria-Induced Inflammation",

abstract = "Immunity that controls parasitemia and inflammation during Plasmodium falciparum (Pf) malaria can be acquired with repeated infections. A limited understanding of this complex immune response impedes the development of vaccines and adjunctive therapies. We conducted a prospective systems biology study of children who differed in their ability to control parasitemia and fever following Pf infection. By integrating whole-blood transcriptomics, flow-cytometric analysis, and plasma cytokine and antibody profiles, we demonstrate that a pre-infection signature of B cell enrichment, upregulation of T helper type 1 (Th1) and Th2 cell-associated pathways, including interferon responses, and p53 activation associated with control of malarial fever and coordinated with Pf-specific immunoglobulin G (IgG) and Fc receptor activation to control parasitemia. Our hypothesis-generating approach identified host molecules that may contribute to differential clinical outcomes during Pf infection. As a proof of concept, we have shown that enhanced p53 expression in monocytes attenuated Plasmodium-induced inflammation and predicted protection from fever.",

keywords = "Plasmodium falciparum, RNA sequencing, RNA-seq, antibody profiling, flow cytometry, malaria, malaria immunity, prospective cohort study, systems biology, systems immunology, transcriptomics",

author = "Tran, {Tuan M.} and Rajan Guha and Silvia Portugal and Jeff Skinner and Aissata Ongoiba and Jyoti Bhardwaj and Marcus Jones and Jacqueline Moebius and Pratap Venepally and Safiatou Doumbo and DeRiso, {Elizabeth A.} and Shanping Li and Kamalakannan Vijayan and Anzick, {Sarah L.} and Hart, {Geoffrey T.} and O'Connell, {Elise M.} and Doumbo, {Ogobara K.} and Alexis Kaushansky and Galit Alter and Felgner, {Phillip L.} and Hernan Lorenzi and Kassoum Kayentao and Boubacar Traore and Kirkness, {Ewen F.} and Crompton, {Peter D.}",

note = "Funding Information: We thank the residents of Kalifabougou, Mali for participating in this study. This project was supported with federal funds from the National Institute of Allergy and Infectious Diseases (NIAID), NIH, Department of Health and Human Services under contract number HHSN272200900007C, award number U19AI110819, and the Division of Intramural Research. T.M.T. was also supported by K08AI125682 (NIAID) and the Doris Duke Charitable Foundation Clinical Scientist Development Award. Protein microarray experiments were funded by NIAID grants U19AI089686 and R01AI095916 (P.L.F.). Super p53 mice were kindly provided by David G. Kirsch (Duke University). Recombinant Pf antigens were kindly provided by David L. Narum (Laboratory of Malaria Immunology and Vaccinology, NIAID, NIH) and Gavin J. Wright (Wellcome Trust Sanger Institute). T.M.T. and P.D.C. drove the study design, analyzed the data, and wrote the manuscript. R.G. S.P. J.B. and J.M. performed the human cell culture experiments, including flow cytometry studies, and analyzed the data. M.J. P.V. H.L. and E.F.K. were critical in the design and execution of the RNA-seq experiments, including sample processing, sequencing, analysis, and mapping. S.L.A. performed the gene expression confirmation studies and analysis. S.L. performed the PCR studies for parasite detection, quantitation, and microsatellite analysis. P.L.F. E.A.D. and G.A. designed and/or performed the antibody experiments. J.S. assisted with the processing and analysis of the protein array, gene expression, and class prediction data and provided statistical guidance for all experiments. E.M.O. performed the molecular testing for helminth infections. T.M.T. G.T.H. K.V. and A.K. discussed, designed, and conducted the mouse experiments. T.M.T. A.O. S.D. O.K.D. K.K. B.T. and P.D.C. designed, organized, and conducted the field studies in Mali that generated the clinical data and blood samples. All authors reviewed and approved the manuscript. P.L.F. has an equity interest in Antigen Discovery, Inc. which is developing products related to the protein microarray platform used in this study. The University of California reviewed and approved in accordance with its conflict of interest policies. Funding Information: We thank the residents of Kalifabougou, Mali for participating in this study. This project was supported with federal funds from the National Institute of Allergy and Infectious Diseases (NIAID), NIH, Department of Health and Human Services under contract number HHSN272200900007C , award number U19AI110819 , and the Division of Intramural Research . T.M.T. was also supported by K08AI125682 ( NIAID ) and the Doris Duke Charitable Foundation Clinical Scientist Development Award. Protein microarray experiments were funded by NIAID grants U19AI089686 and R01AI095916 (P.L.F.). Super p53 mice were kindly provided by David G. Kirsch (Duke University). Recombinant Pf antigens were kindly provided by David L. Narum (Laboratory of Malaria Immunology and Vaccinology, NIAID, NIH) and Gavin J. Wright (Wellcome Trust Sanger Institute). Publisher Copyright: {\textcopyright} 2019",

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month = oct,

day = "15",

doi = "10.1016/j.immuni.2019.08.009",

language = "English (US)",

volume = "51",

pages = "750--765.e10",

journal = "Immunity",

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T1 - A Molecular Signature in Blood Reveals a Role for p53 in Regulating Malaria-Induced Inflammation

AU - Tran, Tuan M.

AU - Guha, Rajan

AU - Portugal, Silvia

AU - Skinner, Jeff

AU - Ongoiba, Aissata

AU - Bhardwaj, Jyoti

AU - Jones, Marcus

AU - Moebius, Jacqueline

AU - Venepally, Pratap

AU - Doumbo, Safiatou

AU - DeRiso, Elizabeth A.

AU - Li, Shanping

AU - Vijayan, Kamalakannan

AU - Anzick, Sarah L.

AU - Hart, Geoffrey T.

AU - O'Connell, Elise M.

AU - Doumbo, Ogobara K.

AU - Kaushansky, Alexis

AU - Alter, Galit

AU - Felgner, Phillip L.

AU - Lorenzi, Hernan

AU - Kayentao, Kassoum

AU - Traore, Boubacar

AU - Kirkness, Ewen F.

AU - Crompton, Peter D.

N1 - Funding Information: We thank the residents of Kalifabougou, Mali for participating in this study. This project was supported with federal funds from the National Institute of Allergy and Infectious Diseases (NIAID), NIH, Department of Health and Human Services under contract number HHSN272200900007C, award number U19AI110819, and the Division of Intramural Research. T.M.T. was also supported by K08AI125682 (NIAID) and the Doris Duke Charitable Foundation Clinical Scientist Development Award. Protein microarray experiments were funded by NIAID grants U19AI089686 and R01AI095916 (P.L.F.). Super p53 mice were kindly provided by David G. Kirsch (Duke University). Recombinant Pf antigens were kindly provided by David L. Narum (Laboratory of Malaria Immunology and Vaccinology, NIAID, NIH) and Gavin J. Wright (Wellcome Trust Sanger Institute). T.M.T. and P.D.C. drove the study design, analyzed the data, and wrote the manuscript. R.G. S.P. J.B. and J.M. performed the human cell culture experiments, including flow cytometry studies, and analyzed the data. M.J. P.V. H.L. and E.F.K. were critical in the design and execution of the RNA-seq experiments, including sample processing, sequencing, analysis, and mapping. S.L.A. performed the gene expression confirmation studies and analysis. S.L. performed the PCR studies for parasite detection, quantitation, and microsatellite analysis. P.L.F. E.A.D. and G.A. designed and/or performed the antibody experiments. J.S. assisted with the processing and analysis of the protein array, gene expression, and class prediction data and provided statistical guidance for all experiments. E.M.O. performed the molecular testing for helminth infections. T.M.T. G.T.H. K.V. and A.K. discussed, designed, and conducted the mouse experiments. T.M.T. A.O. S.D. O.K.D. K.K. B.T. and P.D.C. designed, organized, and conducted the field studies in Mali that generated the clinical data and blood samples. All authors reviewed and approved the manuscript. P.L.F. has an equity interest in Antigen Discovery, Inc. which is developing products related to the protein microarray platform used in this study. The University of California reviewed and approved in accordance with its conflict of interest policies. Funding Information: We thank the residents of Kalifabougou, Mali for participating in this study. This project was supported with federal funds from the National Institute of Allergy and Infectious Diseases (NIAID), NIH, Department of Health and Human Services under contract number HHSN272200900007C , award number U19AI110819 , and the Division of Intramural Research . T.M.T. was also supported by K08AI125682 ( NIAID ) and the Doris Duke Charitable Foundation Clinical Scientist Development Award. Protein microarray experiments were funded by NIAID grants U19AI089686 and R01AI095916 (P.L.F.). Super p53 mice were kindly provided by David G. Kirsch (Duke University). Recombinant Pf antigens were kindly provided by David L. Narum (Laboratory of Malaria Immunology and Vaccinology, NIAID, NIH) and Gavin J. Wright (Wellcome Trust Sanger Institute). Publisher Copyright: © 2019

PY - 2019/10/15

Y1 - 2019/10/15

N2 - Immunity that controls parasitemia and inflammation during Plasmodium falciparum (Pf) malaria can be acquired with repeated infections. A limited understanding of this complex immune response impedes the development of vaccines and adjunctive therapies. We conducted a prospective systems biology study of children who differed in their ability to control parasitemia and fever following Pf infection. By integrating whole-blood transcriptomics, flow-cytometric analysis, and plasma cytokine and antibody profiles, we demonstrate that a pre-infection signature of B cell enrichment, upregulation of T helper type 1 (Th1) and Th2 cell-associated pathways, including interferon responses, and p53 activation associated with control of malarial fever and coordinated with Pf-specific immunoglobulin G (IgG) and Fc receptor activation to control parasitemia. Our hypothesis-generating approach identified host molecules that may contribute to differential clinical outcomes during Pf infection. As a proof of concept, we have shown that enhanced p53 expression in monocytes attenuated Plasmodium-induced inflammation and predicted protection from fever.

AB - Immunity that controls parasitemia and inflammation during Plasmodium falciparum (Pf) malaria can be acquired with repeated infections. A limited understanding of this complex immune response impedes the development of vaccines and adjunctive therapies. We conducted a prospective systems biology study of children who differed in their ability to control parasitemia and fever following Pf infection. By integrating whole-blood transcriptomics, flow-cytometric analysis, and plasma cytokine and antibody profiles, we demonstrate that a pre-infection signature of B cell enrichment, upregulation of T helper type 1 (Th1) and Th2 cell-associated pathways, including interferon responses, and p53 activation associated with control of malarial fever and coordinated with Pf-specific immunoglobulin G (IgG) and Fc receptor activation to control parasitemia. Our hypothesis-generating approach identified host molecules that may contribute to differential clinical outcomes during Pf infection. As a proof of concept, we have shown that enhanced p53 expression in monocytes attenuated Plasmodium-induced inflammation and predicted protection from fever.

KW - Plasmodium falciparum

KW - RNA sequencing

KW - RNA-seq

KW - antibody profiling

KW - flow cytometry

KW - malaria

KW - malaria immunity

KW - prospective cohort study

KW - systems biology

KW - systems immunology

KW - transcriptomics

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U2 - 10.1016/j.immuni.2019.08.009

DO - 10.1016/j.immuni.2019.08.009

M3 - Article

C2 - 31492649

AN - SCOPUS:85072768557

SN - 1074-7613

VL - 51

SP - 750-765.e10

JO - Immunity

JF - Immunity

IS - 4

ER -

A Molecular Signature in Blood Reveals a Role for p53 in Regulating Malaria-Induced Inflammation

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

UN SDGs

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