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.

Keywords: Leishmania; Plasmodium; cross regulation; cytokine networks; inflammation; manipulation; signalling hubs; system biology.

Figure 1

A hypothetical model summarizing the probable mechanisms of severe inflammation in malaria. Parasite molecules like Haemazoin, Pf AT-rich DNA recruited by TLR and TLR independent (STING) pathways (63, 69). High load of Pf AT rich DNA would lead to increased levels of TRAF3 and of IFN-α. And IFN-α, in turn, suppresses GATA3 expression in Th2 cells resulting in low levels of IL-10 and hence down regulated SOCS3 (68). In addition, low levels of IL-2 and T-bet fail to mediate switch from IFN-γ+/IL-10− to IFN-γ+/IL-10+ Th1 cells that requires T-bet and IL-2 levels, also explain low levels of IL-10. Finally, downregulated SOCS3, which is known to mediate the anti-inflammatory functions of IL-10, fails to regulate an exaggerated proinflammatory response. Another contributory role to severe inflammation in malaria is the high prevalence of IL-8-251T/A, which increases IL-8 expression for enhanced recruitment and activation of inflammatory cells neutrophils resulting in increased activation of NF-κB via IL-1β-mediated pathway.

Figure 2

Immuno-modulation by Leishmania parasite: Leishmania antigens interfere with the signaling cascade of the macrophage and promote the Th-2 non-healing response that helps in the survival of the parasite inside the host.