Using kinase regression to elucidate host signaling pathways that control infection

Abstract

Intracellular pathogens have extensive needs from their host cells. For example, Plasmodium parasites are dependent on hepatocyte infection for life cycle progression. During their residence within the hepatocyte, malaria parasites rely on their host for protection against cell death and for the acquisition of nutrients that supports their development. Unfortunately, technical hurdles have led to only a sparse knowledge of molecular factors that regulate liver stage malaria infection. Here, we assessed 37 host‐targeted kinase inhibitors for their capacity to eliminate malaria‐infected hepatocytes. We used these data, along with pre‐existing activity profiles of each inhibitor against 300 host kinases, to inform a predictive computational model that identified host kinases which facilitate Plasmodium liver stage infection. Our predictions yielded 49 kinases, including five kinases previously described to impact infection and 44 novel regulators of infection that include multiple Receptor Tyrosine Kinases and members of the Protein Kinase C cascade. Our approach also facilitated the prediction of several novel host‐targeted kinase inhibitors of infection, including multiple compounds which have already been used in humans and are active against Plasmodium parasites in vitro and in vivo. Moreover, this straight‐forward approach facilitates a kinome‐wide assessment of critical host factors involved in infection by a wide range of pathogens. By comparing host regulators of infections by parasites, bacteria and viruses, we hypothesize multiple kinases that regulate cellular processes that underlie infection by a wide variety of pathogens. This suggests that host‐targeted kinase inhibitors could curtail a wide variety of infections.Support or Funding InformationR00AI111785