title: How Many Parameters Does It Take to Describe Disease Tolerance?
abstract: The study of infectious disease has been aided by model organisms, which have helped to elucidate molecular mechanisms and contributed to the development of new treatments; however, the lack of a conceptual framework for unifying findings across models, combined with host variability, has impeded progress and translation. Here, we fill this gap with a simple graphical and mathematical framework to study disease tolerance, the dose response curve relating health to microbe load; this approach helped uncover parameters that were previously overlooked. Using a model experimental system in which we challenged Drosophila melanogaster with the pathogen Listeria monocytogenes, we tested this framework, finding that microbe growth, the immune response, and disease tolerance were all well represented by sigmoid models. As we altered the system by varying host or pathogen genetics, disease tolerance varied, as we would expect if it was indeed governed by parameters controlling the sensitivity of the system (the number of bacteria required to trigger a response) and maximal effect size according to a logistic equation. Though either the pathogen or host immune response or both together could theoretically be the proximal cause of pathology that killed the flies, we found that the pathogen, but not the immune response, drove damage in this model. With this new understanding of the circuitry controlling disease tolerance, we can now propose better ways of choosing, combining, and developing treatments.
authors.affiliation: Department of Microbiology and Immunology, Stanford University, Stanford, California, United States of America.|Program in Immunology, Stanford University, Stanford, California, United States of America.
authors.forename: Alexander
authors.initials: A
authors.lastname: Louie
authors.affiliation: Department of Microbiology and Immunology, Stanford University, Stanford, California, United States of America.
authors.forename: Kyung Han
authors.initials: KH
authors.lastname: Song
authors.affiliation: Department of Microbiology and Immunology, Stanford University, Stanford, California, United States of America.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Hotson
authors.affiliation: Department of Biology and Biochemistry, University of Houston, Houston, Texas, United States of America.
authors.forename: Ann
authors.initials: A
authors.lastname: Thomas Tate
authors.affiliation: Department of Microbiology and Immunology, Stanford University, Stanford, California, United States of America.|Program in Immunology, Stanford University, Stanford, California, United States of America.
authors.forename: David S
authors.initials: DS
authors.lastname: Schneider
mesh_terms: D000818:Animals; D004194:Disease; D004331:Drosophila melanogaster / Q000382:microbiology; D006801:Humans; D008089:Listeria monocytogenes / Q000472:pathogenicity