Pathogens have, however, developed a variety of strategies to avoid immediate destruction by macrophages and neutrophils. Many extracellular pathogenic bacteria coat themselves with a thick polysaccharide capsule that is not recognized by any phagocytic receptor. In such cases, however, the complement system can recognize microbial surfaces and coat them with C3b, thereby flagging them for phagocytosis via complement receptors, as described in Chapter 2. Other pathogens, for example, mycobacteria, have evolved ways to grow inside macrophage phagosomes by inhibiting their acidification and fusion with lysosomes. Without such devices, a microorganism must enter the body in sufficient numbers to overwhelm the immediate innate host defenses and to establish a focus of infection.
3-3 Microbial recognition and tissue damage initiate an inflammatory response.
An important effect of the interaction between microbes and tissue macrophages is the activation of macrophages and other immune cells to release small proteins called cytokines and chemokines, and other chemical mediators. Collectively, these proteins induce a state of inflammation in the tissue, attract monocytes and neutrophils to the infection, and allow plasma proteins to enter the tissue from the blood. An inflammatory response is usually initiated within hours of infection or wounding. Macrophages are stimulated to secrete pro-inflammatory cytokines, such as TNF-α, and chemokines by interactions between microbes and microbial products and specific receptors expressed by the macrophage. We will examine how the cytokines interact with pathogens later in the chapter, but first we describe some general aspects of inflammation and how it contributes to host defense.
Inflammation has three essential roles in combating infection. The first is to deliver additional effector molecules and cells from the blood into sites of infection, and so increase the destruction of invading microorganisms. The second is to induce local blood clotting, which provides a physical barrier to the spread of the infection in the bloodstream. The third is to promote the repair of injured tissue.
Inflammatory responses are characterized by pain, redness, heat, and swelling at the site of an infection, reflecting four types of change in the local blood vessels, as shown in Fig. 3.7. The first is an increase in vascular diameter, leading to increased local blood flow—hence the heat and redness—and a reduction in the velocity of blood flow, especially along the inner walls of small blood vessels. The second change is the activation of endothelial cells lining the blood vessel to express cell-adhesion molecules that promote the binding of circulating leukocytes. The combination of slowed blood flow and adhesion molecules allows leukocytes to attach to the endothelium and migrate into the tissues, a process known as extravasation. All these changes are initiated by the pro-inflammatory cytokines and chemokines produced by activated macrophages and parenchymal cells.
Once inflammation has begun, the first white blood cells attracted to the site are neutrophils. These are followed by monocytes (Fig. 3.8), which upon activation are called inflammatory monocytes and can produce various pro-inflammatory cytokines, but are distinguishable from macrophages by their lack of expression of the adhesion G-protein-coupled receptor E1, commonly
Fig. 3.6 Neutrophil extracellular traps (NETs) can trap bacteria and fungi.
This scanning electron micrograph of activated human neutrophils infected with a virulent strain of Shigella flexneri (pink rods) shows the stimulated neutrophils forming NETs (blue, indicated by arrows). Bacteria trapped within NETs are visible (lower arrow). Photo courtesy of Arturo Zychlinsky.