Research: Acute Models of Malaria to Study Experimental Resilience (THoR’s HAMMER)
A research partnership within DARPA’s THoR (Technologies for Host Resilience) program, the HAMMER project uniquely focuses on malaria and its effects on human and non-human primate hosts. This project will explore the molecular mechanisms of resilience, susceptibility and resistance of non-human primate hosts when challenged with a malaria infection. DARPA contract #W911NF-16-C-0008
The ThoR program seeks to discover biological mechanisms of host tolerance to catalyze the development of novel host-based interventions against emerging pathogens and potential biological threat agents.
Current treatments for infection focus primarily on pathogen inhibition with the premise that increased pathogen load negatively impacts host fitness. This approach frequently relies on a priori knowledge of the pathogen, is limited to a discrete set of pathogens, and has imposed evolutionary pressures leading to the increased prevalence of drug-resistant organisms.
The THoR program’s concept of tolerance is in contrast to host-response mechanisms based on resistance, which refers to the host’s ability to maintain fitness through reduction in pathogen load. Under this program, researchers will seek to develop approaches and methodologies to identify mechanisms of tolerance along with the characterization of the key biological drivers responsible for that response. Furthermore, DARPA aims to recapitulate these pro-tolerance mechanisms in susceptible hosts by applying a single intervention or combination of interventions in order to improve health and reduce mortality to infectious diseases.
THoR is organized into three technical areas:
- Discover Tolerant Populations - perform animal studies to examine intra- and inter-species differences in host fitness; identify sub-populations and species that are tolerant to infection;
- Identify Biological Mechanisms of Tolerance – define and characterize the basis for tolerance across multiple biological scales (i.e., species, tissues, and cells); and
- Identify and Validate Pro-Tolerance Interventions - recapitulate pro-tolerance mechanisms in susceptible hosts using small-animal and large-animal models demonstrating improved survival.
The long term objective of the THoR program is to integrate the aforementioned methods and tools into an end-to-end pipeline for discovering novel host-centric countermeasures against infectious diseases.