Heat-shock responses: systemic and essential ways of malaria parasite survival

Abstract

Fever is a part of the human innate immune response that contributes to limiting microbial growth and development in many infectious diseases. For the parasite Plasmodium falciparum, survival of febrile temperatures is crucial for its successful propagation in human populations as well as a fundamental aspect of malaria pathogenesis. This review discusses recent insights into the biological complexity of the malaria parasite's heat-shock response, which involves many cellular compartments and essential metabolic processes to alleviate oxidative stress and accumulation of damaged and unfolded proteins. We highlight the overlap between heat-shock and artemisinin resistance responses, while also explaining how the malaria parasite adapts its fever response to fight artemisinin treatment. Additionally, we discuss how this systemic and essential fight for survival can also contribute to parasite transmission to mosquitoes.

Figure 1.

Functional assignment of heat-shock and artemisinin resistance response. A). Schematic cell shows the overlap between heat-shock response (Zhang et al 2021) and artemisinin resistance markers (Zhu et al 2022). Figure created with BioRender.com. B). Mutagenesis Index Score (MIS) (Zhang et al 2018) of the main pathways related to heat-shock response and artemisinin resistance, along with gametocytogenesis and AP2-G genes. The plot was generated using R.

Figure 2.

A) Overlap between heat-shock (Zhang et al 2021), artemisinin resistance responses (Zhu et al 2022) and gametogenesis genes (van Biljon et al 2019). Venn diagram shows the number of genes overlapped among three databases: GAM_ART_HS (Zhang et al 2021; Zhu et al 2022; Van Biljon et al 2019). B) Overlapped genes’ representative Gene Ontology terms (GO term), Gene Ontology ID (GO ID) and their associated p values. C) GAM_ART (van Biljon et al 2019 and Zhu et al 2022) and D) GAM_HS (van Biljon et al 2019 and Zhang et al 2021). GO analyses for each overlapped set of genes were performed using the GO enrichment tool in PlasmoDB with a cutoff of p <0.05 (https://plasmodb.org/plasmo/app/).

Figure 3.

Schematic of Plasmodium falciparum physiological nexus highlighting different directions based on the microenvironmental conditions, inherent strain properties, drug treatment and host immune status. Pathways central to these overlapping responses steer the parasite either towards death or sexual development and transmission into the mosquito vector. Figure created with BioRender.com.