2. The host-pathogen interactome model
The use of immunomodulatory therapies to treat infectious disease, such as the recent success of dexamethasone to treat COVID-19, is indicative of the need to consider not only the disease-causing pathogen in therapeutic development, but the contributions of the host too. Casadevall and Pirofski’s seminal damage-response framework is based on the fact that microbial pathogenesis, whether bacterial, fungal, parasitic or viral is the outcome of interactions between the host and a microorganism, and uses host damage as a common principle with which to define and measure this interaction (Fig.1)12. Although it may not always be possible to account for both views in experimental design, conceptual consideration of the contributions of both the host and the microorganism to host damage is important to focus studies of microbial pathogenesis around a common principle, with the potential to unify the field of microbial pathogenesis and allied disciplines of immunology and vaccinology13-15.
Currently, classifications of microorganisms are based on phylogenetic groups (bacteria, fungi, parasites, viruses)16,17. Casadevall and Pirofski argue this system is limited by the fact that most members of any group are not pathogenic in a host; of 150,000 fungal species, for example, only around 150 are pathogenic for humans17. However, classifications based on the perceived capacity of a microorganism to cause disease are equally inadequate as changes in host immune function, ecology, and/or behaviour can render them obsolete18. As discussed later, classifying pathogens based on phylogenetic groups has been mirrored by the antimicrobial lexicon, which currently classifies antimicrobials according to their inhibitory activity against microbial phylogenetic groups (antibiotics, antifungals, antiparasitics, antivirals), encouraging a bias of therapeutic development towards pathogen-killing as opposed to host-pathogen interactome targeting and modulation19.
The use of host damage as the principle with which to categorise pathogens allows them to be classified according to the common denominator of pathogenic outcomes. Pathogens that cause similar types of diseases can be grouped together despite differences in phylogeny and growth characteristics. Pathogens grouped in a single class share similarities with regard to the shape of the damage-response curve as a function of the host immune response20,21. Ultimately, the host-pathogen interactome model crystallises the contemporary view of disease outcome as being determined both by the contributions of the host as well as the pathogen, a marked departure from the classical pathogen-centred view propounded in the early 20thcentury, with ramifications for microbial, immunological, and antimicrobial studies.