Approach to the Patient with an Infectious Disease
Molecular Mechanisms of Microbial Pathogenesis
Over the past five decades, molecular studies of the pathogenesis of microorganisms have yielded a torrent of information about the various microbial and host molecules that contribute to the processes of infection and disease. These processes can be classified into several stages: microbial encounter with and entry into the host; microbial growth after entry; avoidance of innate host defenses; tissue invasion and tropism; tissue damage; and transmission to new hosts. Virulence is the measure of an organism’s capacity to cause disease and is a function of the pathogenic factors elaborated by microbes. These factors promote colonization (the simple presence of potentially pathogenic microbes in or on a host), infection (attachment and growth of pathogens and avoidance of host defenses), and disease (often, but not always, the result of activities of secreted toxins or toxic metabolites). In addition, the host’s inflammatory response to infection greatly contributes to disease and its attendant clinical signs and symptoms. A recent explosion of interest in the microbiome (the collection of microbial genomes present in or on mammalian organisms) and the microbiota (the collection of microbes residing in and on mammalian organisms) and their impact on physiology of, susceptibility to, and response to infection and on immune system development has greatly expanded our understanding of host–pathogen interactions. Furthermore, investigations in this field have documented effects of the microbiome on all aspects of animal—and even plant—physiology, greatly increasing our knowledge of the everyday influence of host–microbe interactions on life.
MICROBIAL ENTRY AND ADHERENCE
We now know that the indigenous microbial organisms living in close association with almost all animals and plants are organized into complex communities that strongly modulate overall host physiology, including the ability of pathogenic microbes to establish themselves in or on host surfaces. The sheer numbers of these microbes and their genomic variability often exceed the numbers of host cells and the variability of host genes in a typical animal. Changes and differences in microbiomes within and between individuals, currently characterized by high-throughput DNA sequencing techniques and bioinformatic analysis, impact such diverse conditions as obesity; type 1 diabetes; cognition; neurologic states; autoimmune diseases; skin, gastrointestinal, respiratory, and vaginal infectious diseases; and development and control of the immune system. It has been difficult to directly associate specific types of microbiomes with pathophysiologic states, and our understanding of the degree to which microbial species are conserved or variable within human and other animal microbiotas is evolving. Experimental studies in laboratory animals, particularly in germ-free mammals, show the potent ability of changes in the microbiota to manipulate health status and outcomes. One of the clearest functions of the microbiota is to influence and mature the cells of the immune system, thereby exerting a major effect on susceptibility and resistance to microbial infection. The degree to ...