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

a | The figure depicts the six pathogen classes, as described previously¹. 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 oesophagitis²⁷. Modified with permission from Ref. 1 © (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 ends¹, 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.