Is It Time To Kill the Survival Curve? A Case for Disease Progression Factors in Microbial Pathogenesis and Host Defense Research.

Robert A Cramer,Caitlin H Kowalski,J Andrew Alspaugh

doi:10.1128/mbio.03483-20

Abstract

The molecular mechanisms of microbial virulence and host defense are most often studied using animal models and Koch's molecular postulates. A common rationale for these types of experiments is to identify therapeutic targets based on the assumption that microbial or host factors that confer extreme animal model survival phenotypes represent critical virulence and host defense factors. Yet null mutant strains of microbial (or host) factors often yield extreme survival curve phenotypes because they fail to establish an infection. The lack of infection and disease establishment prevents true assessment of the given factor's role(s) in disease progression. Here, we posit that the emphasis on extreme survival curve phenotypes in fungal infectious disease models is leading to missed opportunities to identify new fungal and host factors critical for disease progression. We simply do not yet have a sufficient understanding of fungal virulence and host defense mechanisms throughout the temporal course of an infection. We propose that there is a need to develop new approaches and to revisit tried and true methods to define infection site biology beyond the analysis of survival curve phenotypes. To stimulate these new approaches, we propose the (new) terms "disease initiation factor" and "disease progression factor" to distinguish functional roles at distinct temporal stages of an infection and give us targets to foster new discoveries.

Highlights

The molecular mechanisms of microbial virulence and host defense are most often studied using animal models and Koch’s molecular postulates
While our focus here is on human fungal infections, the general concept and terminology apply to other infectious diseases, and we provide an illustration of its broad relevance below
Current approaches that rely on animal model survival curve results often fail to address the importance of a given microbial or host factor in an established infection microenvironment

Summary

Introduction

The molecular mechanisms of microbial virulence and host defense are most often studied using animal models and Koch’s molecular postulates. While studies identifying fungal virulence and host defense response factors and mechanisms have undoubtedly yielded enormous insights into mycoses, it remains mbio.asm.org 2 Unclear if the majority of fungal virulence and host defense factors identified to date contribute to disease progression beyond the initiation of the infection.

Results

Conclusion