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

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.

Combined Pan-, Population-, and Phylo-Genomic Analysis of Aspergillus fumigatus Reveals Population Structure and Lineage-Specific Diversity

“…The genes defining the thee primary clades are enriched for diverse metabolic functions, hinting that population structure may be shaped by environmental niche occupation or substrate specificity. If niche occupation translates to realized differences in nutrient usage or stress tolerance, it may have disease initiation and/or progression implications (Cramer & Kowalski, 2021). Finally, as evidenced by the numerous gene families identified here which have no homologue in Af293, the under-characterization and inability to assign annotations to approximately 20% of the accessory genome, and variant scans which identified clear cases where Af293 was the exception, rather than the rule for the population (and therefore inappropriate to define mutations against).…”

Host Lung Environment Limits Aspergillus fumigatus Germination through an SskA-Dependent Signaling Response

“…After entering the airways of a mammalian host, conidia are typically removed by mucociliary clearance or innate phagocytotic responses ( 1 – 3 , 42 ). It has been proposed that fungal disease is driven by two types of virulence traits: (i) disease initiating factors, which are factors that either promote the initiation of infection or disease pathology; and (ii) disease progressing factors, which facilitate microbe persistence, host damage, and disease progression in an established infection microenvironment ( 43 ). Our previous work has demonstrated early fungal germination within the airway space is a disease initiating trait in a model of A. fumigatus -induced bronchopneumonia ( 4 ).…”

A hyper-immunogenic and slow-growing fungal strain induces a murine granulomatous response to cryptococcal infection

“…Virulence potential is a notable difference between the strains. The gcs1 mutant strain is unable to initiate infection and disease via the inhalation route of infection (18), categorizing GCS1 as a disease initiation factor (61). In contrast, the mar1 mutant strain can establish infection and cause fatal disease in nearly half of the infected mice (23), making MAR1 a disease progression factor (61).…”

“…The gcs1 mutant strain is unable to initiate infection and disease via the inhalation route of infection (18), categorizing GCS1 as a disease initiation factor (61). In contrast, the mar1 mutant strain can establish infection and cause fatal disease in nearly half of the infected mice (23), making MAR1 a disease progression factor (61). This may be related to the fact that GCS1 orthologs are found in many pathogenic fungi (18), while MAR1 appears to be a Cryptococcus-specific gene (23).…”