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

Recent studies suggest differential activation of immune cells and biochemical pathways during infection with distinct etiological agents of human malaria, <i>Plasmodium falciparum</i> or <i>Plasmodium vivax</i>. Rhesus monkeys infected with <i>Plasmodium coatneyi</i> develop pathology comparable to <i>P. falciparum</i> infection in humans, whereas <i>P. vivax</i> is modeled by infection with <i>Plasmodium cynomolgi</i>. 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 <i>HMOX1</i> 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 <i>P. cynomolgi</i> and <i>P. vivax</i>. 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 <i>Plasmodium</i> 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 <i>Plasmodium</i> from those that are caused by factors beyond the infection.