The damage-response framework of microbial pathogenesis

Abstract

The late twentieth century witnessed the emergence of numerous infectious diseases that are caused by microorganisms that rarely cause disease in normal, healthy immunocompetent hosts. The emergence of these diseases shows that the existing concepts of pathogenicity and virulence do not take into account the fact that both the microorganism and the host contribute to microbial pathogenesis. To address this impediment to studies of host-microorganism interactions, we propose a new theoretical approach to understanding microbial pathogenesis, known as the 'damage-response' framework.

Figure 1. Basic parabolic curve of the damage-response framework.

All other curves are derived from this basic curve. The arrow indicates that the position of the curve is variable, and depends on the particular host–microorganism interaction. The y-axis denotes host damage as a function of the host response. In this scheme, host damage can occur throughout the host response, but is magnified at both extremes. The host response is represented by a continuum from 'weak' to 'strong'. 'Weak' and 'strong' are terms that can encompass both quantitative and qualitative characteristics of the host response and are used as the best available terms to denote the spectrum of host response as more precise terms are limiting. Weak responses are those that are insufficient, poor or inappropriate — that is, they are not strong enough to benefit the host. Strong responses are those that are excessive, overly robust or inappropriate — that is, they are too strong and can damage the host. When a threshold amount of damage is reached, the host can become symptomatic and if damage is severe, death can ensue. Green, yellow and purple represent health, disease and severe disease, respectively.

Figure 2. The six classes of pathogenic microorganisms according to the damage-response framework.

a | The figure depicts the six pathogen classes, as described previously. The extension of the curve below the x-axis represents the beneficial effect that interactions with Class 1 microorganisms can produce in normal hosts, whereby the host response prevents significant damage and commensalism confers a benefit to the host. Examples of pathogens classified by the six damage-response curves are listed in Table 2. We have previously suggested that Helicobacter pylori should be placed in Class 6 (Ref. 2). The dashed line below the x-axis in the panel for Class 6 reflects recent evidence that H. pylori can confer a benefit in certain hosts, based on the observation of an inverse correlation between colonization with this organism and reflux oesophagitis. Modified with permission from Ref. © (1999) AmericanSociety for Microbiology. b | The figure denotes a situation where a microbial factor is entirely responsible for host damage — for example, a toxin that causes damage irrespective of the host response because toxin action is so rapid and/or the amount of toxin is insufficient to trigger an immune response. Previously, we have proposed that toxin-producing microorganisms are a variant of Class 3 where the curve is flat at both ends, but here we suggest that this type of interaction might be unique and warrants a separate panel. As shown here, the damage-response classification scheme is flexible and makes it possible to postulate the existence of pathogens for which there are no known examples at present. Such pathogens could be recognized in the future as 'emerging' pathogens as shown in c and d. c | The Class 4 curve is extended below the x-axis. Such a theoretical microorganism would be a commensal in the setting of intermediate host responses, but pathogenic in hosts with either weak or strong responses. d | The inverted parabola represents a putative host–microorganism interaction that induces damage over a narrow and limited range of responses, but not in the presence of either strong or weak host responses. One example of such a phenomenon would be an antibody response to a hypothetical microorganism, whereby host damage is caused by antigen–antibody complexes. Although we cannot think of a specific microorganism that fits this description at this time, examples of this type of host damage are the host–microorganism interactions characterized by the Herxheimer reaction following treatment of syphilis, the similar reaction that can occur after the initiation of therapy for Pneumocystis carinii pneumonia, and serum sickness following the injection of foreign protein.

Figure 3. Plotting host damage as a function of time.

The host–microorganism interaction can be depicted by plotting host damage as a function of time. Panels a–d show how plotting damage versus time can be used to denote the states of the host–microorganism interaction for four different pathogens. Infection represents the acquisition of the microorganism by the host and is followed by the states of commensalism, colonization, latency and disease, depending on the amount of damage to the host^,. These plots highlight the fact that for certain pathogens there is continuity between the various states. The colours green, yellow and purple denote health, disease and severe disease, respectively, and the relevant states for each host–microorganism interaction are highlighted in bold.