AUTHOR=Gupta Anuj , Galinski Mary R. , Voit Eberhard O. 

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

JOURNAL=Frontiers in Molecular Biosciences

VOLUME=8

YEAR=2022

URL=https://www.frontiersin.org/journals/molecular-biosciences/articles/10.3389/fmolb.2021.800721

DOI=10.3389/fmolb.2021.800721

ISSN=2296-889X

ABSTRACT=<p>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 <italic>Plasmodium</italic> pathogen and host species. Previously, we compared the peripheral blood transcriptomes of two macaque species (<italic>Macaca mulatta</italic> and <italic>Macaca fascicularis</italic>) in response to acute primary infection by <italic>Plasmodium knowlesi</italic>. Although these two species are very closely related, the infection in <italic>M. mulatta</italic> is fatal, unless aggressively treated, whereas <italic>M. fascicularis</italic> develops a chronic, but tolerable infection in the blood. As a reason for this stark difference, our analysis suggests delayed pathogen detection in <italic>M. mulatta</italic> followed by extended inflammation that eventually overwhelms this monkey’s immune response. By contrast, the natural host <italic>M. fascicularis</italic> detects the pathogen earlier and controls the inflammation. Additionally, <italic>M. fascicularis</italic> 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. <italic>SICAvar</italic> 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 Ca<sup>2+</sup> homeostasis in inflammation. Additionally, the kynurenine-to-tryptophan ratio, a known inflammatory biomarker, emphasizes higher inflammation in <italic>M. mulatta</italic> 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 <italic>M. fascicularis</italic> and stronger AhR signaling in <italic>M. mulatta</italic>. 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.</p>