Dynamic Control Balancing Cell Proliferation and Inflammation is Crucial for an Effective Immune Response to Malaria

• Type of Material: Article
• Authors: Anuj Gupta, Georgia Institute of Technology; Mary Galinski, Emory University; Eberhard Voit, Emory University
• Language: English
• Date: 2022-02-15
• Publisher: FRONTIERS MEDIA SA
• Publication Version: Final Published Version
• Copyright Statement: © 2022 Gupta, Galinski and Voit.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3389/fmolb.2021.800721
• Title of Journal or Parent Work: FRONTIERS IN MOLECULAR BIOSCIENCES
• Volume: 8
• Start Page: 800721
• End Page: 800721
• Grant/Funding Information: This project was funded in part by the National Institute of Allergy and Infectious Diseases; National Institutes of Health, Department of Health and Human Services, which established the MaHPIC (Contract Nos. HHSN272201200031C; MG), the NIH Office of Research Infrastructure Programs/OD P51OD011132, the Defense Advanced Research Program Agency and the US Army Research Office via a cooperative agreement (Contract Nos. W911NF16C0008; MG0), which funded the Technologies for Host Resilience - Host Acute Models of Malaria to study Experimental Resilience (THoR’s HAMMER) consortium, and the Georgia Research Alliance.
• Keywords: tryptophan metabolism; antigenic variation; TRYPTOPHAN-METABOLISM; CYNOMOLGUS MACACA-FASCICULARIS; surface antigens; kynurenine metabolism; Plasmodium knowlesi; TISSUE; MULATTA; INTERFERON-GAMMA; EXPRESSION; PLASMODIUM-KNOWLESI; Life Sciences & Biomedicine; ANTIGENIC VARIATION; PRIMATE MODEL; Science & Technology; INDOLEAMINE 2,3-DIOXYGENASE; Biochemistry & Molecular Biology; Macaca fascicularis; Macaca mulatta; AhR signaling
• Research Categories: Engineering, Biomedical

Abstract

Malaria has a complex pathology with varying manifestations and symptoms, effects on host tissues, and different degrees of severity and ultimate outcome, depending on the causative Plasmodium pathogen and host species. Previously, we compared the peripheral blood transcriptomes of two macaque species (Macaca mulatta and Macaca fascicularis) in response to acute primary infection by Plasmodium knowlesi. Although these two species are very closely related, the infection in M. mulatta is fatal, unless aggressively treated, whereas M. fascicularis develops a chronic, but tolerable infection in the blood. As a reason for this stark difference, our analysis suggests delayed pathogen detection in M. mulatta followed by extended inflammation that eventually overwhelms this monkey’s immune response. By contrast, the natural host M. fascicularis detects the pathogen earlier and controls the inflammation. Additionally, M. fascicularis limits cell proliferation pathways during the log phase of infection, presumably in an attempt to control inflammation. Subsequent cell proliferation suggests a cell-mediated adaptive immune response. Here, we focus on molecular mechanisms underlying the key differences in the host and parasite responses and their coordination. SICAvar Type 1 surface antigens are highly correlated with pattern recognition receptor signaling and important inflammatory genes for both hosts. Analysis of pathogen detection pathways reveals a similar signaling mechanism, but with important differences in the glutamate G-protein coupled receptor (GPCR) signaling pathway. Furthermore, differences in inflammasome assembly processes suggests an important role of S100 proteins in balancing inflammation and cell proliferation. Both differences point to the importance of Ca2+ homeostasis in inflammation. Additionally, the kynurenine-to-tryptophan ratio, a known inflammatory biomarker, emphasizes higher inflammation in M. mulatta during log phase. Transcriptomics-aided metabolic modeling provides a functional method for evaluating these changes and understanding downstream changes in NAD metabolism and aryl hydrocarbon receptor (AhR) signaling, with enhanced NAD metabolism in M. fascicularis and stronger AhR signaling in M. mulatta. AhR signaling controls important immune genes like IL6, IFNγ and IDO1. However, direct changes due to AhR signaling could not be established due to complicated regulatory feedback mechanisms associated with the AhR repressor (AhRR). A complete understanding of the exact dynamics of the immune response is difficult to achieve. Nonetheless, our comparative analysis provides clear suggestions of processes that underlie an effective immune response. Thus, our study identifies multiple points of intervention that are apparently responsible for a balanced and effective immune response and thereby paves the way toward future immune strategies for treating malaria.