# Host kinase regulation of Plasmodium vivax dormant and replicating liver stages

## TL;DR

The study explores how host kinases regulate both dormant and replicating liver stages of Plasmodium vivax, revealing variability across isolates that may explain differences in relapse patterns.

## Contribution

The study introduces a kinase regression approach to identify host kinase dependencies in P. vivax liver stages across multiple isolates.

## Key findings

- A subset of host kinases regulates the numbers of schizonts and hypnozoites and affects schizont size.
- There is variability in host phosphosignaling dependencies between parasite forms across isolates.
- Parasite isolate differences in host kinase dependencies may contribute to field heterogeneity in relapse patterns.

## Abstract

Upon transmission to the liver, Plasmodium vivax parasites form replicating schizonts, which progress to initiate blood-stage infection, or dormant hypnozoites that reactivate weeks to months after initial infection. P. vivax phenotypes in the field vary significantly, including the time to, and frequency of, relapse. Current evidence suggests that both parasite genetics and environmental factors underly this heterogeneity. Here, we applied an approach called kinase regression to evaluate the extent to which P. vivax liver-stage parasites are susceptible to changes in host kinase activity. We identified a role for a subset of host kinases in regulating the numbers of schizonts and hypnozoites, as well as schizont size, and characterized overlap as well as variability in host phosphosignaling dependencies between parasite forms across multiple patient isolates. Our data point to variability in host dependencies across P. vivax isolates, suggesting one possible origin of the heterogeneity observed in the field.

One of the major hurdles to malaria eradication is the ability of Plasmodium vivax to form dormant liver-stages called hypnozoites, which reside within the liver for weeks to months before being reactivated and causing a new round of blood-stage infection. Due to difficulties in culturing the parasite, little is known about the biology of P. vivax liver stage. Using an approach that combines a small chemical screen and machine learning, we investigate the host kinase dependencies of both dormant and developing liver-stage parasites across multiple P. vivax field isolates. We identify some overlap in host kinase regulation of parasite forms but observe a great deal of variation between isolates, suggesting parasite heterogeneity needs to be taken into consideration in future studies focused on host-parasite interactions within the liver.