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

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

The mechanisms that protect from febrile malaria remain unclear. Tran et al. applied a systems-based approach to a longitudinal pediatric study to identify immune signatures that associate with control of malaria fever and parasitemia, revealing that p53 upregulation in monocytes attenuates malaria-induced inflammation and predicts protection from fever.

Original languageEnglish (US)
Pages (from-to)750-765.e10
JournalImmunity
Volume51
Issue number4
DOIs
StatePublished - 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

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