Alterations in Phosphorylation of Hepatocyte Ribosomal Protein S6 Control Plasmodium Liver Stage Infection
This week we profile a recent publication in Cell Reports from Drs. Alexis Kaushansky (pictured, above)
and Elizabeth Glennon (pictured, below) at Seattle Children’s Research Institute.
What is your lab’s current research focus?
The Kaushansky Lab in the Center for Global Infectious Disease Research at Seattle Children’s Research Institute focuses on the interactions between pathogens and the humans they infect. A substantial part of the lab focuses on the malaria parasite (Plasmodium) and its human “host”, as well as the development of host-targeted drugs and other therapeutics. One of the major topics of our work is how the malaria parasite selects, invades and manipulates the host cell(s) within the liver. Additional projects in the lab focus on other parasites, bacteria, and viruses to compare how different pathogens interact with their host cells.
What is the significance of the findings in this publication?
The malaria parasite is extremely selective in targeting specific liver cells (hepatocytes). Previous studies show that hepatocytes are not identical, which surfaces the question: What makes a particular hepatocyte attractive to Plasmodium? In the paper just published in Cell Reports, we found that higher levels of a specific protein, Ribosomal Protein S6 (RPS6), is associated with higher levels of susceptibility to Plasmodium infection.
We found that although infected cells exhibited higher levels of RPS6, the protein did not appear to be regulated in a “textbook” fashion. For example, we normally think of this specific signaling pathway as being highly regulated by insulin. While this is true in most cells, and even in cells that are infected with a related pathogen (Toxoplasma – a parasite which is the origin of pregnant women being advised to not clean the cat’s litter box!), in cells that are infected with malaria, insulin does nothing to impact the activation state of RPS6. This suggests that malaria parasites lead to some unusual behavior inside the cells they infect. This has major consequences for drug development – if the normal “rules” don’t apply – using these “rules” to develop drugs is unlikely to be fruitful. Instead, we must figure out what new, malaria-specific rules DO apply – and then target the aspects of the parasite or host cell that are absolutely required for the malaria parasite to survive.
What are the next steps for this research?
While in this paper we described the alteration of a single simple signaling pathway in infected cells, our next steps are to more broadly characterize host cell signaling networks to determine if our observation is generalizable. We will try to identify to what extent signal rewiring is selected for and/or induced in the context of Plasmodium liver stage infection. The implications could be far reaching, with direct implications for drug development and other interventions.