Identifying host regulators and inhibitors of liver stage malaria infection using kinase activity profiles

Abstract

Plasmodium parasites have extensive needs from their host hepatocytes during the obligate liver stage of infection, yet there remains sparse knowledge of specific host regulators. Here we assess 34 host-targeted kinase inhibitors for their capacity to eliminate Plasmodium yoeliiinfected hepatocytes. Using pre-existing activity profiles of each inhibitor, we generate a predictive computational model that identifies host kinases, which facilitate Plasmodium yoelii liver stage infection. We predict 47 kinases, including novel and previously described kinases that impact infection. The impact of a subset of kinases is experimentally validated, including Receptor Tyrosine Kinases, members of the MAP Kinase cascade, and WEE1. Our approach also predicts host-targeted kinase inhibitors of infection, including compounds already used in humans. Three of these compounds, VX-680, Roscovitine and Sunitinib, each eliminate >85% of infection. Our approach is well-suited to uncover key host determinants of infection in difficult model systems, including field-isolated parasites and/or emerging pathogens.

Alterations in Phosphorylation of Hepatocyte Ribosomal Protein S6 Control Plasmodium Liver Stage Infection

“…Optimal maintenance of LS infection is dependent on the activity of a large number of host kinases regulating processes such as cytoskeletal organization and apoptosis (Arang et al, 2017). These observations are consistent with the hypothesis that the parasite rewires a portion of host cell signaling in a manner that disrupts canonical signal transduction cascades.…”

“…Once a parasite is inside a hepatocyte, its survival is also influenced by host cell factors, including levels of the tumor suppressor p53 (Douglass et al, 2015; Kaushansky et al, 2013), the degree of endoplasmic reticulum (ER) stress (Inácio et al, 2015; Kaushansky and Kappe, 2015), and regulation of an extensive network of kinases (Arang et al, 2017; Prudêncio et al, 2008; Ruivo et al, 2016). Interestingly, a large portion of the hepatocyte kinome regulates LS infection (Arang et al, 2017), suggesting that phosphosignaling in the cell might be globally altered in the context of infection. Consistent with this hypothesis, a variety of signaling pathways are disrupted by Plasmodium infection on the transcriptional, protein, and post-translational levels (Albuquerque et al, 2009; Kaushansky et al, 2013; Posfai et al, 2018).…”

A screen forPlasmodium falciparumsporozoite surface protein binding to human hepatocyte surface receptors identifies novel host-pathogen interactions

“…FGFR4 has previously been implicated in liver stage development of P. yoelii in Hepa1-6 cells, as one among a number of ‘hits’ in a screen investigating the role of host kinases in EEF development. [25], although negative results were obtained in a similar screen investigating P. berghei [26].…”

“…The possibility that interactions between Pf34 and FGFR4 could contribute to a functionally-important invasion complex is supported by FGFR4’s role in liver-specific signalling pathways, and evidence of reduced EEF formation in the absence of FGFR4 [24, 25, 29]. Investigation of the effect of disruption of these interactions upon sporozoite invasion is a priority.…”

Ferroptosis-like signaling facilitates a potent innate defense againstPlasmodiuminfection

“…S6). Neither Erastin nor Sorafenib impacted the growth of Plasmodium-infected erythrocytes 21 , further minimizing the likelihood that these drugs directly target parasite pathways ( Fig. S5b).…”