Organisms have two mechanisms to survive pathogenic infections: resistance and pathology minimization. Resistance is the ability to eliminate pathogens and we have a strong mechanistic understanding of how immune responses are initiated and executed. Contrary to this, we know of only a few mechanisms by which hosts minimize infection-associated damage irrespective of pathogen load. My goal is to identify and characterize mechanisms by which the host minimizes infection-associated damage. I hypothesize that hosts induce pathology minimization programs in response to pathogen detection and host damage. I will test and characterize how damage to the host (in the form of acute hemolysis) mediates pathology minimization upon subsequent Plasmodium infection. Hemolysis leads to the release of cytotoxic heme, which induces expression of host heme oxygenase-1 (HO-1). When mice are infected with plasmodium subsequent to constitutive low-level or acute hemolysis, these mice exhibit a diminished health impact in a HO-1 dependent manner. I would like to better characterize the reason for this diminished disease severity. I will do this by examining how HO-1-mediated heme catabolism minimizes pathology. I will also test whether the Interferon Regulatory Factor (IRF) proteins, a family of transcription regulators we've found to be induced upon Plasmodium infection, can mediate pathology minimization. We have chosen to focus on IRF proteins because published data suggests that IRFs, as well as IRF regulated genes, can limit the amount of pathology incurred in different types of infections. This will be done using a novel analytical method developed within the lab, termed phase curve analysis, which allows us to evaluate the health impact of microbes on individual hosts during the entire course of the infection. The work proposed here will be the first to systematically identify and characterize novel pathology minimization mechanisms. This proposal also aims to define how these mechanisms are induced. This knowledge may be key in understanding and developing inducible pathology minimization mechanisms as therapeutics for humans experiencing pathogenic infections. As there are many infectious diseases we cannot prevent, it is important that we are able to reduce the amount of damage incurred during these infections. Finally, the work proposed here will serve as a template for identifying mechanisms that may be employed to minimize the severity of unavoidable infections.
The work proposed here will help in understanding how a host minimizes the amount of damage incurred during a microbial infection. A better understanding of damage minimization may aid in the development of treatments to reduce the health costs of unavoidable microbial infections.
