Disrupted human-pathogen co-evolution: a model for disease

Abstract

A major goal in infectious disease research is to identify the human and pathogenic genetic variants that explain differences in microbial pathogenesis. However, neither pathogenic strain nor human genetic variation in isolation has proven adequate to explain the heterogeneity of disease pathology. We suggest that disrupted co-evolution between a pathogen and its human host can explain variation in disease outcomes, and that genome-by-genome interactions should therefore be incorporated into genetic models of disease caused by infectious agents. Genetic epidemiological studies that fail to take both the pathogen and host into account can lead to false and misleading conclusions about disease etiology. We discuss our model in the context of three pathogens, Helicobacter pylori, Mycobacterium tuberculosis and human papillomavirus, and generalize the conditions under which it may be applicable.

Keywords: Helicobacter pylori; Mycobacterium tuberculosis; genome–genome interactions; host–pathogen co-evolution; human disease; human papillomavirus.

FIGURE 1

Gastric histopathology as a function of Amerindian human and African H. pylori ancestry in a Colombian population (N = 121, age > 39). Histopathology was scored on a continuous scale, with 2 (blue) representing gastritis and 5 (red) representing dysplasia. Data from Kodaman et al. (2014). Reference samples from the 1000 Genomes Project (Abecasis et al., 2012), HapMap (The International HapMap Consortium, 2005), and the Human Genome Diversity Project (Cavalli-Sforza, 2005) were used to calculate human ancestry, and from the MLST database (Maiden et al., 1998) to calculate H. pylori ancestry.