Integrative analysis associates monocytes with insufficient erythropoiesis during acute Plasmodium cynomolgi malaria in rhesus macaques

• Type of Material: Article
• Authors: Yan Tang, Georgia Institute of Technology; Chester J. Joyner, Emory University; Monica Cabrera-Mora, Emory University; Celia L. Saney, Emory University; Stacey A. Lapp, Emory University; Mustafa V. Nural, Emory University; Suman B. Pakala, Emory University; Jeremy D. DeBarry, Emory University; Stephanie Soderberg, Emory University; Jessica C. Kissinger, Emory University; Tracey Lamb, Emory University; Mary Galinski, Emory University; Mark P. Styczynski, Georgia Institute of Technology
• Language: English
• Date: 2017-09-22
• Publisher: BioMed Central
• Publication Version: Final Published Version
• Copyright Statement: © 2017 The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s12936-017-2029-z
• Title of Journal or Parent Work: Malaria Journal
• ISSN: 1475-2875
• Volume: 16
• Start Page: 384
• End Page: 384
• Grant/Funding Information: This project has been funded in whole or in part with Federal funds from the National Institute of Allergy and Infectious Diseases; National Institutes of Health, Department of Health and Human Services [Contract No. HHSN272201200031C] and the National Center for Research Resources [ORIP/OD P51OD011132].
• Keywords: RNA-SEQ EXPERIMENTS; INTERFERON; Systems biology; BLOOD; Tropical Medicine; Bone marrow; Parasitology; GATA1; VIVAX; BONE-MARROW; ANEMIA; Erythropoiesis; Immune response; UNINFECTED ERYTHROCYTES; Nonhuman primates; Science & Technology; Plasmodium vivax; Life Sciences & Biomedicine; Plasmodium cynomolgi; Infectious Diseases; HUMANS; Relapse; COLONY-FORMING-UNITS; Transcriptomics; INFECTION
• Research Categories: Health Sciences, Immunology; Biology, Virology; Engineering, Biomedical

Abstract

Background: Mild to severe anaemia is a common complication of malaria that is caused in part by insufficient erythropoiesis in the bone marrow. This study used systems biology to evaluate the transcriptional and alterations in cell populations in the bone marrow during Plasmodium cynomolgi infection of rhesus macaques (a model of Plasmodium vivax malaria) that may affect erythropoiesis. Results: An appropriate erythropoietic response did not occur to compensate for anaemia during acute cynomolgi malaria despite an increase in erythropoietin levels. During this period, there were significant perturbations in the bone marrow transcriptome. In contrast, relapses did not induce anaemia and minimal changes in the bone marrow transcriptome were detected. The differentially expressed genes during acute infection were primarily related to ongoing inflammatory responses with significant contributions from Type I and Type II Interferon transcriptional signatures. These were associated with increased frequency of intermediate and non-classical monocytes. Recruitment and/or expansion of these populations was correlated with a decrease in the erythroid progenitor population during acute infection, suggesting that monocyte-associated inflammation may have contributed to anaemia. The decrease in erythroid progenitors was associated with downregulation of genes regulated by GATA1 and GATA2, two master regulators of erythropoiesis, providing a potential molecular basis for these findings. Conclusions: These data suggest the possibility that malarial anaemia may be driven by monocyte-associated disruption of GATA1/GATA2 function in erythroid progenitors resulting in insufficient erythropoiesis during acute infection.