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

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.

Plasmodium knowlesi Cytoadhesion Involves SICA Variant Proteins

“…Interestingly, in stark contrast, the BM response was timely in kra monkeys infected with P. knowlesi , with the kra monkey BM responding naturally to the infection without treatment ( Peterson et al., 2021 ). This is consistent with their faster overall recovery from infection compared to the rhesus, as indicated by transcriptomics ( Gupta et al., 2021 ; Peterson et al., 2021 ; Gupta et al., 2022 ). Future determinations of the mechanism(s) by which hemoglobin levels in rhesus monkeys stabilize after subcurative treatment may lead to a better understanding of malarial anemia in relation to patient care.…”

Discrete Biochemical Systems Theory

“…The aryl-hydrocarbon receptor (AhR) is a highly conserved sensor for specific cues during development and normal physiology ( Stockinger et al, 2014 ; Brinkmann et al, 2019 ; Zhu et al, 2019 ), as well as for external, xenobiotic compounds ( Stevens et al, 2009 ; Simon et al, 2015 ) or danger signals derived from the invasion of parasites, which are mediated through compounds like the tryptophan-derivative kynurenine ( Julliard et al, 2014 ; Gupta et al, 2022 ). In response to such signals, the AhR signal transduction system triggers the upregulation of a host of genes, most prominently those coding for cytochrome P450 enzymes that metabolize toxicants.…”

Systems biology of malaria explored with nonhuman primates

“…Transcriptomics and metabolomics data were integrated by Gardinassi et al from a P. vivax CHMI trial to define specific immune responses [ 484 ], and by Cordy et al to define metabolic signatures associated with acute and chronic disease caused by P. coatneyi and P. falciparum [ 131 ]. Gupta et al recently used systems approaches, including transcriptomic and metabolic modelling, to show distinctive relationships between longitudinal P. knowlesi infections in M. mulatta and M. fascicularis, which highlight mechanisms of resilience in the latter species [ 396 , 413 ]. Systems vaccinology approaches were used to study an RTS,S candidate vaccine, demonstrating NK cell responses as correlates of protection associated with RTS,S vaccination [ 414 ].…”

“…Furthermore, M. fascicularis responded to the parasite as early as 3 days after inoculation with sporozoites, unlike M. mulatta , showing early cytokine signaling along with interferon responses while the parasites were still in the liver. Among other findings, Gupta and colleagues also report pre-infection differences in neutrophils and naïve CD4+T cells that lead to differences in Ca 2+ homeostasis, which ultimately balances inflammation and cell proliferation during the log phase of parasitaemia expansion [ 413 ]. These P. knowlesi infection experiments also incorporated unique telemetry measurements generated from implanted devices that continuously tracked temperature, blood pressure, heart rate and activity levels (Brady et al pers.…”