Towards Using Host Targeted Interventions Against Infectious Diseases

C.E. Credits: P.A.C.E. CE Florida CE
  • Alexis Kaushansky, PhD

    Associate Professor of Pediatrics, University of Washington, Adjunct Associate Professor of Global Health, Center for Global Infectious Disease Research, Seattle Children's Hospital


Parasitic infection alters the host in many ways.  Intracellular parasites have extensive needs of their host cells and exploit properties of host cell signaling networks to facilitate their own survival and proliferation. Parasites alter surrounding cells by cell-cell contact and by promoting inflammation, creating differences in and around infected cells.  Some of these changes are required for infection and thus could create a therapeutic index for targeting infection without damaging uninfected cells. Yet, a systematic methodology to identify key infection-associated host targets and translate these targets into interventions is not yet available.  I will present our work towards creating this framework for the malaria-causing parasite Plasmodium.  Plasmodium parasites undergo multiple complex life cycle transitions and interact with a variety of host cell types.  Upon transmission to the mammalian host, Plasmodium parasites are carried through the bloodstream to the liver, where they infect a single hepatocyte.  This represents a first critical stage of infection, as clearance of the parasite during this stage would eliminate all disease and subsequent transmission.  We have also focused on host-targeted interventions that strengthen the blood-brain endothelial barrier, as breakdown of the blood-brain barrier has been implicated in cerebral malaria and adjunctive therapy that restores normal brain function could improve survival rates.  To systematically identify relevant host targets for each of these stages, we utilized existing, and built new, machine-learning driven tools.  These tools include kinase regression and a newly developed tool, Temporally Resolved Kinase Network Generation (TREKING). In each case, we aim to identify critical kinases and/or phosphosignaling networks that drive infection and/or pathogenesis but do not eliminate uninfected cells. These strategies have led us to kinase inhibitors that both eliminate most liver stage parasites and protect the blood brain barrier during inflammation.  While we have taken a malaria-focused approach, our strategies are disease state agnostic and could be used to interrogate multiple diseases either independently or in combination. 

Learning Objectives:

1. Interpret the life cycle of the malaria causing parasite, Plasmodium.

2. Consolidate new approaches to identifying host regulators of infection.

3. Describe advantages and disadvantages to targeting infectious diseases with host targeted interventions.

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