A systems biological view of intracellular pathogens
As biomedical research becomes increasingly data-intensive, it is increasingly essential to integrate genomic-scale datasets, so as to generate a more holistic picture of complex biological processes. The systems biology paradigm may differ in strategy from traditional reductionist scientific methods, but the goal remains the same: to generate tenable hypotheses driving the experimental elucidation of biological mechanisms. Intracellular pathogens provide an excellent opportunity for systems
... lysis, as many of these organisms are amenable to genetic manipulation, allowing their biology to be played off against that of the host. Moreover, many of the most fundamental biological properties of these microbes (host cell invasion, immune escape, intracellular replication, long-term persistence) are directly linked to pathogenesis and readily quantifiable using genomic-scale technologies. In this review, we summarize and discuss some of the available and foreseeable functional genomics datasets pertaining to host-pathogen interactions and suggest that the host-pathogen interface represents a promising, tractable challenge for systems biological analysis. Success will require developing and leveraging new technologies, expanding data acquisition, and increasing public access to comprehensive datasets, in order to assemble quantitative and testable models of the host-pathogen relationship. Pathogens as biological 'systems': open, robust, modular, and stochastic Systems biology has enjoyed a recent surge in attention, but the discipline is rooted in general systems theory, exemplified by the work of Ludwig von Bertalanffy, who noted that biological systems are open, i.e. they exchange information with the surrounding environment (1). Intracellular pathogens can be viewed as the ultimate open system: they are constantly interacting with the infected cell and modulating both the host and the pathogen so as to establish a viable physical/temporal niche. These organisms typically exhibit specific auxotrophies, relying on host metabolic processes for essential nucleotides, amino acids, lipids, sugars, vitamins, etc. In addition to taking in host nutrients for their own use, bacterial, fungal, and protozoan pathogens also deploy an arsenal of secreted proteins (the 'secretome'), including many factors that interact with host cell components. This openness means that biological systems cannot simply be described as the sum of their parts (a characteristic termed 'emergence' by Bertalanffy).