Total parasite biomass but not peripheral parasitaemia is associated with endothelial and haematological perturbations in Plasmodium vivax patients

  1. João Luiz Silva-Filho  Is a corresponding author
  2. João CK Dos-Santos
  3. Carla C Judice
  4. Dario Beraldi
  5. Kannan Venugopal
  6. Diogenes De Lima
  7. Helder Nakaya
  8. Erich EV Paula
  9. Stefanie Costa Pinto Lopes
  10. Marcus VG Lacerda
  11. Matthias Marti  Is a corresponding author
  12. Fabio TM Costa  Is a corresponding author
  1. University of Glasgow, United Kingdom
  2. Laboratory of Tropical Diseases, University of Campinas, Brazil
  3. Institute of Biology, University of Campinas, Brazil
  4. Institute of Infection Immunity and Inflammation, University of Glasgow, United Kingdom
  5. 3School of Pharmaceutical Sciences, University of São Paulo, Brazil
  6. University of São Paulo, Brazil
  7. University of Campinas, Brazil
  8. Institute Leônidas and Maria Deane, Brazil
  9. Tropical Medicine Foundation, Brazil

Abstract

Plasmodium vivax is the major cause of human malaria in the Americas. How P. vivax infection can lead to poor clinical outcomes, despite low peripheral parasitaemia remains a matter of intense debate. Estimation of total P. vivax biomass based on circulating markers indicates existence of a predominant parasite population outside of circulation. In this study we investigate associations between both peripheral and total parasite biomass and host response in vivax malaria. We analysed parasite and host signatures in a cohort of uncomplicated vivax malaria patients from Manaus, Brazil, combining clinical and parasite parameters, multiplexed analysis of host responses and ex vivo assays. Patterns of clinical features, parasite burden and host signatures measured in plasma across the patient cohort were highly heterogenous. Further data deconvolution revealed two patient clusters, here termed Vivaxlow and Vivaxhigh. These patient subgroups were defined based on differences in total parasite biomass but not peripheral parasitaemia. Overall Vivaxlow patients clustered with healthy donors and Vivaxhigh patients showed more profound alterations in haematological parameters, endothelial cell (EC) activation and glycocalyx breakdown and levels of cytokines regulating different haematopoiesis pathways compared to Vivaxlow. Vivaxhigh patients presented more severe thrombocytopenia and lymphopenia, along with enrichment of neutrophils in the peripheral blood and increased neutrophil-to-lymphocyte ratio (NLCR). When patients' signatures were combined, high association of total parasite biomass with a subset of markers of EC activation, thrombocytopenia and lymphopenia severity was observed. Finally, machine learning models defined a combination of host parameters measured in the circulation that could predict the extent of parasite infection outside of circulation. Altogether, our data show that total parasite biomass is a better predictor of perturbations in host homeostasis in P. vivax patients than peripheral parasitaemia. This supports the emerging paradigm of a P. vivax tissue reservoir, in particular in the hematopoietic niche of bone marrow and spleen.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Numerical tables and source data files have been provided. Table 1, Figure 2-source data 1 and Figure 2-figure supplement 2-source data 1 contain the numerical data used to generate the figures.

Article and author information

Author details

  1. João Luiz Silva-Filho

    University of Glasgow, Glasgow, United Kingdom
    For correspondence
    joao.dasilvafilho@glasgow.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4762-2205
  2. João CK Dos-Santos

    Laboratory of Tropical Diseases, University of Campinas, Campinas, Brazil
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5916-9845
  3. Carla C Judice

    Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1839-053X
  4. Dario Beraldi

    University of Glasgow, Glasgow, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Kannan Venugopal

    Institute of Infection Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Diogenes De Lima

    3School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  7. Helder Nakaya

    University of São Paulo, São Paulo, Brazil
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5297-9108
  8. Erich EV Paula

    University of Campinas, Campinas, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  9. Stefanie Costa Pinto Lopes

    Institute Leônidas and Maria Deane, Manuas, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  10. Marcus VG Lacerda

    Tropical Medicine Foundation, Manuas, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  11. Matthias Marti

    University of Glasgow, Glasgow, United Kingdom
    For correspondence
    matthias.marti@glasgow.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1040-9566
  12. Fabio TM Costa

    Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil
    For correspondence
    fabiotmc72@gmail.com
    Competing interests
    The authors declare that no competing interests exist.

Funding

Fundação de Amparo à Pesquisa do Estado de São Paulo (2019/01578-2)

  • João Luiz Silva-Filho

Fundação de Amparo à Pesquisa do Estado de São Paulo (2017/18611-7)

  • João Luiz Silva-Filho

Wellcome Trust (104111)

  • João Luiz Silva-Filho

Fundação de Amparo à Pesquisa do Estado de São Paulo (2016/12855-9)

  • João Luiz Silva-Filho

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: All subjects enrolled in the study were adults. Written informed consent was obtained from all participants and the study was conducted according to the Declaration of Helsinki principles. The study was approved by the local Research Ethics Committee at Fundação de Medicina Tropical Dr. Heitor Vieira Dourado (FMT-HVD, Manaus, Brazil), under #CAAE: 54234216.1.0000.0005.

Reviewing Editor

  1. Urszula Krzych, Walter Reed Army Institute of Research, United States

Publication history

  1. Preprint posted: March 20, 2021 (view preprint)
  2. Received: June 17, 2021
  3. Accepted: September 28, 2021
  4. Accepted Manuscript published: September 29, 2021 (version 1)
  5. Version of Record published: October 22, 2021 (version 2)

Copyright

© 2021, Silva-Filho et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 595
    Page views
  • 117
    Downloads
  • 1
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. João Luiz Silva-Filho
  2. João CK Dos-Santos
  3. Carla C Judice
  4. Dario Beraldi
  5. Kannan Venugopal
  6. Diogenes De Lima
  7. Helder Nakaya
  8. Erich EV Paula
  9. Stefanie Costa Pinto Lopes
  10. Marcus VG Lacerda
  11. Matthias Marti
  12. Fabio TM Costa
(2021)
Total parasite biomass but not peripheral parasitaemia is associated with endothelial and haematological perturbations in Plasmodium vivax patients
eLife 10:e71351.
https://doi.org/10.7554/eLife.71351

Further reading

    1. Biochemistry and Chemical Biology
    2. Microbiology and Infectious Disease
    Lauren C Radlinski, Andreas J Bäumler
    Insight

    Listeria monocytogenes uses respiration to sustain a risky fermentative lifestyle during infection.

    1. Microbiology and Infectious Disease
    Josué Flores-Kim et al.
    Research Article

    Penicillin and related antibiotics disrupt cell wall synthesis in bacteria causing the downstream misactivation of cell wall hydrolases called autolysins to induce cell lysis. Despite the clinical importance of this phenomenon, little is known about the factors that control autolysins and how penicillins subvert this regulation to kill cells. In the pathogen Streptococcus pneumoniae (Sp), LytA is the major autolysin responsible for penicillin-induced bacteriolysis. We recently discovered that penicillin treatment of Sp causes a dramatic shift in surface polymer biogenesis in which cell wall-anchored teichoic acids (WTAs) increase in abundance at the expense of lipid-linked teichoic acids (LTAs). Because LytA binds to both species of teichoic acids, this change recruits the enzyme to its substrate where it cleaves the cell wall and elicits lysis. In this report, we identify WhyD (SPD_0880) as a new factor that controls the level of WTAs in Sp cells to prevent LytA misactivation during exponential growth and premature lysis. We show that WhyD is a WTA hydrolase that restricts the WTA content of the wall to areas adjacent to active PG synthesis. Our results support a model in which the WTA tailoring activity of WhyD during exponential growth directs PG remodeling activity required for proper cell elongation in addition to preventing autolysis by LytA.