What Is a Host? Attributes of Individual Susceptibility

Abstract

In every epidemic some individuals become sick and some may die, whereas others recover from illness and still others show no signs or symptoms of disease. These differences highlight a fundamental question of microbial pathogenesis: why are some individuals susceptible to infectious diseases while others who acquire the same microbe remain well? For most of human history, the answer assumed the hand of providence. With the advent of the germ theory of disease, the focus on disease causality became the microbe, but this did not explain how there can be different outcomes of infection in different individuals with the same microbe. Here we examine the attributes of susceptibility in the context of the "damage-response framework" of microbial pathogenesis. We identify 11 attributes that, although not independent, are sufficiently distinct to be considered separately: microbiome, inoculum, sex, temperature, environment, age, chance, history, immunity, nutrition, and genetics. We use the first letter of each to create the mnemonic MISTEACHING, underscoring the need for caution in accepting dogma and attributing disease causality to any single factor. For both populations and individuals, variations in the attributes that assemble into MISTEACHING can create an enormity of combinations that can in turn translate into different outcomes of host-microbe encounters. Combinatorial diversity among the 11 attributes makes identifying "signatures" of susceptibility possible. However, with their inevitable uncertainties and propensity to change, there may still be a low likelihood for prediction with regard to individual host-microbe interactions, although probabilistic prediction may be possible.

Keywords: host resistance; pathogenesis; virulence.

FIG 1

DRF parabolic curves representative of populations. We consider three host-microbe interactions involving humans and propose that in each case the curve emerges from the points contributed by individuals manifesting certain damage from their responses. In this idealized formulation, each point on the curve represents one individual. The position of the apex of the parabola differs in that the asymptomatic condition is accompanied by different degrees of host damage in each interaction, ranging from none to minimal with S. cerevisiae colonization to local granuloma damage in latent tuberculosis to chronic hepatitis in asymptomatic HCV infection. The line for disease threshold (DT) denotes a point at which host damage is sufficient to affect homeostasis, with those above and below the line colored red and blue, respectively, to denote those with and without clinical symptoms.

FIG 2

DRF parabolic curves representative of individuals. We consider three hosts infected with M. tuberculosis to illustrate how events and medical interventions can move the position of an individual along the parabola. Host 1 has latent infection characterized by a positive tuberculin test and is asymptomatic. Infection with HIV results in a damaged immune system that cannot contain the latent infection, which disseminates. Treatment with antiretroviral therapy restores immunity, which then attacks host tissues where residual mycobacterial antigens are found to cause the immune reconstitution syndrome. Host 2 has miliary tuberculosis but is treated with antimicrobial agents, which reduce burden, and adjunctive gamma interferon, which stimulates cellular immunity. The treatment enhances the host response and moves the individual to the right, resulting in cure. Host 3 has tuberculous meningitis, a condition where the inflammatory response is a major contributor to brain damage. This host is treated with a combination of antimicrobial agents that lower the bacterial burden and corticosteroids to reduce inflammation. The treatment reduces the host response and moves the individual to the left, resulting in cure. DT, disease threshold.

FIG 3

Different host-microbe interactions result in different damage-response relationships, idealized as parabolic curves. The three curves (A to C) can denote the damage-response relationships of a single microbe with three hosts or those of a single host with three different microbes. During intermediate responses, none of these interactions is sufficient to cause diseases, since the amount of damage incurred by the host is insufficient to affect homeostasis. However, in the setting of weak or strong responses, each of these host-microbe interactions has the potential to cause sufficient damage to cross the disease threshold. The position of the parabola vertex is determined by the particular combination of MISTEACHING factors that applies for the host-microbe interaction and a particular time. For curve A, the interaction results in some host damage at all response intensities, but in intermediate responses the vertex lies below the disease threshold. For curve B, the vertex lies on the axis during intermediate responses, resulting in an interaction where no damage occurs in the state of commensalism. For curve C, the vertex lies below the axis, representing an interaction that is potentially symbiotic in some MISTEACHING combinations with the potential for host virulence when the combination results in weak or strong responses.