Systems Biological Analysis of Immune-Metabolic Host Responses to Distinct Malaria Parasites

TL;DR

This paper compares immune and metabolic responses in malaria infections caused by different Plasmodium species using data from monkeys and humans.

Contribution

It identifies conserved and species-specific host responses to Plasmodium infections using multimodal data integration.

Findings

Conserved dynamics of dendritic cells and CD8+ T cells were observed across simian malaria infections.

Gene modules related to coagulation and complement activation were upregulated in rhesus monkeys and humans.

Metabolite regulation, including kynurenine and sex hormone-derived metabolites, was conserved across species.

Abstract

Recent studies suggest differential activation of immune cells
and biochemical pathways during infection with distinct etiological
agents of human malaria, Plasmodium falciparum or Plasmodium vivax. Rhesus monkeys
infected with Plasmodium coatneyi develop
pathology comparable to P. falciparum infection in humans, whereas P. vivax is modeled by infection with Plasmodium cynomolgi. To investigate host immune and metabolic responses, we analyzed
and integrated public blood flow cytometry, transcriptomics, and untargeted
metabolomics data from simian infection models and human malaria.
We found conserved dynamics of blood dendritic cells, effector memory
CD8+ T cells, and PD-1+ effector memory CD8+ T cells in simian infections;
increased expression of HMOX1 and coagulation-related
genes was conserved in simian infections, while the complement activation
gene module was upregulated in rhesus and humans. Myeloid cell transcriptional
responses were enriched in all infections, but gene modules reflecting
chemokine responses and T cell differentiation were mostly associated
with P. cynomolgi and P. vivax. Untargeted metabolomics analysis suggests
conserved regulation of metabolites such as kynurenine and androgen-
and estrogen-derived metabolites, and metabolic modules indicate tyrosine
metabolism activity. Multimodal data integration from rhesus monkeys
revealed distinct interacting network models. In conclusion, we identified
conserved cellular, transcriptional, and metabolic responses between
simian models and human malaria. Moreover, many significant variables
were associated with one determined Plasmodium species, suggesting a significant impact of parasite biology on
immune and metabolic host responses. However, systematic experimental
comparisons are needed to distinguish species-specific host responses
to Plasmodium from those that are caused
by factors beyond the infection.

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