Neutrophils use the respiratory burst described above in their role as an early responder to infection. Neutrophils are not tissue-resident cells, and they need to be recruited to a site of infection from the bloodstream. Their sole function is to ingest and kill microorganisms. Although neutrophils are eventually present in much larger numbers than macrophages in some types of acute infection, they are short-lived, dying soon after they have accomplished a round of phagocytosis and used up their primary and secondary granules. Dead and dying neutrophils are a major component of the pus that forms in abscesses and in wounds infected by certain extracellular capsulated bacteria such as streptococci and staphylococci, which are thus known as pus-forming, or pyogenic, bacteria. Macrophages, in contrast, are long-lived cells and continue to generate new lysosomes.
Patients with a disease called chronic granulomatous disease (CGD) have a genetic deficiency of the NADPH oxidase, which means that their phagocytes do not produce the toxic oxygen derivatives characteristic of the respiratory burst and so are less able to kill ingested microorganisms and clear an infection. The most common form of CGD is an X-linked heritable disease that arises from inactivating mutations in the gene encoding the gp91 subunit of cytochrome b558. People with this defect are unusually susceptible to bacterial and fungal infections, especially in infancy, though they remain susceptible for life. One autosomal recessive form of NADPH oxidase deficiency, p47phox deficiency, has very low but detectable activity and causes a milder form of CGD.
Fig. 3.4 Bactericidal agents produced or released by phagocytes after uptake of microorganisms. Most of the agents listed are directly toxic to microbes and can act directly in the phagolysosome. They can also be secreted into the extracellular environment, and many of these substances are toxic to host cells. Other phagocyte products sequester essential nutrients in the extracellular environment, rendering them inaccessible to microbes and hindering microbial growth. Besides being directly bacteriostatic or bactericidal, acidification of lysosomes also activates the many acid hydrolases that degrade the contents of the vacuole.
O2–OCl–H2O2phagosomeprimarygranuleNADPHoxidasesecondarygranulegp91p22Rac2fMLFlysosomeBacterial fMet-Leu-Phe peptides activate Rac2, and bacteria are taken up into phagosomes Phagosomes fuse with primary and secondary granules. Rac2 induces assembly of a functional NADPH oxidase in the phagolysosome membrane, leading to generation of O2 – . Acidifcation as a result of ion infux releases granule proteases from granule matrix p67p47p40Neutrophils engulf and kill the microbes to which they bind primarygranulesecondarygranulemicrobelysosomeK+K+K+SOD