Integrative Approaches to Understand the Mastery in Manipulation of Host Cytokine Networks by Protozoan Parasites with Emphasis on Plasmodium and Leishmania Species

Abstract

Diseases by protozoan pathogens pose a significant public health concern, particularly in tropical and subtropical countries, where these are responsible for significant morbidity and mortality. Protozoan pathogens tend to establish chronic infections underscoring their competence at subversion of host immune processes, an important component of disease pathogenesis and of their virulence. Modulation of cytokine and chemokine levels, their crosstalks and downstream signaling pathways, and thereby influencing recruitment and activation of immune cells is crucial to immune evasion and subversion. Many protozoans are now known to secrete effector molecules that actively modulate host immune transcriptome and bring about alterations in host epigenome to alter cytokine levels and signaling. The complexity of multi-dimensional events during interaction of hosts and protozoan parasites ranges from microscopic molecular levels to macroscopic ecological and epidemiological levels that includes disrupting metabolic pathways, cell cycle (Toxoplasma and Theileria sp.), respiratory burst, and antigen presentation (Leishmania spp.) to manipulation of signaling hubs. This requires an integrative systems biology approach to combine the knowledge from all these levels to identify the complex mechanisms of protozoan evolution via immune escape during host–parasite coevolution. Considering the diversity of protozoan parasites, in this review, we have focused on Leishmania and Plasmodium infections. Along with the biological understanding, we further elucidate the current efforts in generating, integrating, and modeling of multi-dimensional data to explain the modulation of cytokine networks by these two protozoan parasites to achieve their persistence in host via immune escape during host–parasite coevolution.

The parasites caught in-action: Imaging at the host–Parasite interface

“…Millions are infected annually with substantial morbidity, mortality, and economic loss. [ 17 ] Some of these protozoans, such as Plasmodium, Leishmania, and Toxoplasma , typically initiate a chronic intracellular existence justifying their abilities in manipulating host immune defenses and hijacking its metabolic machinery for survival, proliferation, and transmission. The intracellular niche also confers a shield from host's immunity.…”

Host-Malaria Parasite Interactions and Impacts on Mutual Evolution

“…There are other approaches for studying host-parasite interaction such as analysis of genome diversity and genetic association (Early et al, 2018;Damena et al, 2019;Malaria Genomic Epidemiology Network, 2019), computational prediction of host-parasite interactomes (Wuchty, 2011;Cuesta-Astroz et al, 2019), metabolite profiling to investigate transcriptomic changes during malaria infection (Tang et al, 2018), and systems biology/integrative approaches to study host immune responses (Mahanta et al, 2018). These are just few emerging and promising examples using -omics data to study host-parasite interactions.…”

Leishmania-Host Interactions—An Epigenetic Paradigm

“…Natural killer (NK) cells have also been reported to differentiate into memory NK cells with distinct epigenetic profile (64). However, the epigenetic signatures of innate immune cells during Leishmania infection are limited (65).…”

“…Epigenetic reprograming at cytokine gene loci is reported to influence its gene expression. A growing body of data suggests that differential cytokine microenvironment modulates T helper (Th) cell polarization, macrophage phenotype differentiation and cytokine-inflammasome crosstalk for optimal immune response (65). Signal transducers and activators of transcription (STAT)-4 and−6 have also been reported to play antagonistic roles in epigenetic tuning for Th cell differentiation (66).…”

“…Following infection with L. major and L. donovani , miRNA expression was down modulated through MAP kinase, JAK-STAT, and TGF-β signaling pathways (31). H3K27 has been found to suppress toll-interacting protein that negatively regulates TLR, thereby promoting TLR-mediated inflammatory cytokine production, and activation of innate immune response against the invading pathogens (65).…”