Transcriptomic evidence for modulation of host inflammatory responses during febrile Plasmodium falciparum malaria

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Abstract

Identifying molecular predictors and mechanisms of malaria disease is important for understanding how Plasmodium falciparum malaria is controlled. Transcriptomic studies in humans have so far been limited to retrospective analysis of blood samples from clinical cases. In this prospective, proof-of-principle study, we compared whole-blood RNA-seq profiles at pre-and post-infection time points from Malian adults who were either asymptomatic (n = 5) or febrile (n = 3) during their first seasonal PCR-positive P. falciparum infection with those from malaria-naïve Dutch adults after a single controlled human malaria infection (n = 5). Our data show a graded activation of pathways downstream of pro-inflammatory cytokines, with the highest activation in malaria-naïve Dutch individuals and significantly reduced activation in malaria-experienced Malians. Newly febrile and asymptomatic infections in Malians were statistically indistinguishable except for genes activated by pro-inflammatory cytokines. The combined data provide a molecular basis for the development of a pyrogenic threshold as individuals acquire immunity to clinical malaria.

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Most cited references 18

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Gamma-globulin and acquired immunity to human malaria.

S. Cohen, I A McGregor, S Carrington (1961)

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Global analyses of human immune variation reveal baseline predictors of postvaccination responses.

John Tsang, Pamela Schwartzberg, Yuri Kotliarov … (2014)

A major goal of systems biology is the development of models that accurately predict responses to perturbation. Constructing such models requires the collection of dense measurements of system states, yet transformation of data into predictive constructs remains a challenge. To begin to model human immunity, we analyzed immune parameters in depth both at baseline and in response to influenza vaccination. Peripheral blood mononuclear cell transcriptomes, serum titers, cell subpopulation frequencies, and B cell responses were assessed in 63 individuals before and after vaccination and were used to develop a systematic framework to dissect inter- and intra-individual variation and build predictive models of postvaccination antibody responses. Strikingly, independent of age and pre-existing antibody titers, accurate models could be constructed using pre-perturbation cell populations alone, which were validated using independent baseline time points. Most of the parameters contributing to prediction delineated temporally stable baseline differences across individuals, raising the prospect of immune monitoring before intervention.

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Parasitologic and clinical human response to immunoglobulin administration in falciparum malaria.

Arunee Sabchareon, Hasnaa Bouharoun-Tayoun, Tan Chongsuphajaisiddhi … (1991)

The protective effect of African IgG antibodies against Plasmodium falciparum malaria was investigated by passive transfer in Thai patients. Sera from 333 African adults were collected in the Cote d'Ivoire and subjected to extensive screening. One hundred fifty-three samples were discarded for safety reasons, and IgG was extracted from those remaining under conditions allowing their use by the intravenous (iv) route. Eight Thai patients with P. falciparum parasitemia were treated by iv inoculation of the IgG: six with a 100 mg/kg dose given over three days, one with a single 20 mg/kg dose, and one with a single 200 mg/kg dose. To ensure a safety margin of at least 48 hours, subjects were chosen among patients having a recrudescent parasitemia following quinine treatment failure at the RI level. At that stage, symptoms were mild or absent and parasitemia was low but increasing (range 4, 200-9,000/microliters). The IgG pool exerted a profound, stage-specific, but non-sterilizing effect on each of the strains tested, and proved to be safe. Asexual parasitemia decreased by a mean 728-fold (range 46-1,086), while gametocytes were unaffected. Clearance of parasites and symptoms was as fast or faster than with drugs, and was consistent in the eight patients treated, suggesting that target antigens were equally expressed in geographically remote isolates. In peripheral blood smears, no mature forms were seen at any time during the followup, which does not support the hypothesis that reversal of cytoadherence occurred. After the disappearance of the transferred antibodies, recrudescent parasites from three patients were found to be susceptible to the same extent (mean decrease of 1,310-fold) to the same IgG preparation, indicating that selection of parasites able to escape the effect of antibodies had not occurred. No adverse side-effects were detected during the followup, which lasted one year.

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Author and article information

Journal

Journal ID (nlm-ta): Sci Rep

Journal ID (iso-abbrev): Sci Rep

Title: Scientific Reports

Publisher: Nature Publishing Group

ISSN (Electronic): 2045-2322

Publication date (Electronic): 10 August 2016

Publication date Collection: 2016

Volume: 6

Electronic Location Identifier: 31291

Affiliations

[1 ]Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Rockville, MD, USA

[2 ]Division of Infectious Diseases, Department of Medicine, Indiana University School of Medicine , Indianapolis, IN, USA

[3 ]Genomic Medicine Group, J. Craig Venter Institute , Rockville, Maryland, USA

[4 ]Mali International Center of Excellence in Research, University of Sciences, Technique and Technology of Bamako , Bamako, Mali

[5 ]Department of Medical Microbiology, Radboud University Medical Center , Nijmegen, The Netherlands

[6 ]Department of Infectious Diseases, Leiden University Medical Center , Leiden, The Netherlands

[7 ]Systems Immunology Division, Benaroya Research Institute , Seattle, WA, USA

[8 ]Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, MD, USA

[9 ]Sidra Medical and Research Center , Doha, Qatar

[10 ]Infectious Diseases Group, J. Craig Venter Institute , Bethesda, Maryland, USA

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[a ] tuantran@ 123456iu.edu

Article

Publisher Item ID: srep31291

DOI: 10.1038/srep31291

PMC ID: 4978957

PubMed ID: 27506615

SO-VID: efe6d576-3f44-4092-a856-14d5dd2ec4a6

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Transcriptomic evidence for modulation of host inflammatory responses during febrile Plasmodium falciparum malaria

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Biomarkers for Inflammatory Lung Disease

Most cited references 18

Gamma-globulin and acquired immunity to human malaria.

Global analyses of human immune variation reveal baseline predictors of postvaccination responses.

Parasitologic and clinical human response to immunoglobulin administration in falciparum malaria.

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