Only when a microorganism has successfully established a focus of infection in the host does disease occur (see Fig. 11.2). With few exceptions, little damage will be caused unless the pathogen spreads from the original focus or secretes toxins that spread to other parts of the body. Extracellular pathogens spread by direct extension of the infection through the lymphatics or the bloodstream. Spread into the bloodstream usually occurs only after the lymphatic system has been overwhelmed. Obligate intracellular pathogens spread from cell to cell; they do so either by direct transmission from one cell to the next or by release into the extracellular fluid and reinfection of both adjacent and distant cells. Facultative intracellular pathogens can do the same after a period of survival in the extracellular environment. In contrast, some of the bacteria that cause gastroenteritis exert their effects without spreading into the tissues. They establish a site of infection on the luminal surface of the epithelium lining the gut and cause pathology by damaging the epithelium or by secreting toxins that cause damage either in situ or after crossing the epithelial barrier and entering the circulation.
The establishment of a focus of infection in tissues and the response of the innate immune system produce changes in the immediate environment. Many microorganisms are repelled or kept in check at this stage by innate defenses, which are triggered by stimulation of the various germlineencoded pattern recognition receptors expressed by innate sensor cells—such as epithelial cells, tissue-resident mast cells, macrophages, and dendritic cells (see Chapters 2 and 3). Cytokines and chemokines produced by pathogen-activated innate sensor cells initiate local inflammation, and also activate ILCs. These responses are activated within minutes to hours, and are sustained for at least several days. The inflammatory response is induced through activation of the endothelium of local post-capillary venules (see Fig. 3.31). This leads to the recruitment of circulating innate effector cells, particularly neutrophils and monocytes, thereby increasing the numbers of phagocytes available for microbe clearance. As monocytes enter tissue and become activated, additional inflammatory cells are attracted into the infected tissue so that the inflammatory response is maintained and reinforced. Leakiness of the inflamed endothelium also leads to the influx of serum proteins, including complement, activation of which in a primary infection occurs mainly via the alternative and lectin pathways (see Fig. 2.15). This results in the production of the anaphylatoxins C3a and C5a, which further activate the vascular endothelium; and C3b, which opsonizes microbes for more effective clearance by recruited phagocytes. This early phase of the inflammatory response is largely nonspecific for the type of pathogen.