Innate immunity

Phagocytosis looks like a single act but is a fixed sequence of steps, and each step can be named, measured and, in a patient, blocked. The first step is margination: neutrophils slow down along the endothelial lining of the vessel, because inflammatory mediators make the vessel wall sticky. They then roll, tethering and releasing adhesion molecules called selectins, until chemokines activate integrins on the neutrophil surface and it sticks firmly. The third step is transmigration, or diapedesis: the cell squeezes between endothelial cells and crosses the basement membrane into the tissue. It then follows chemotaxis, moving up a chemical gradient of bacterial peptides, complement fragment C5a and the chemokine interleukin-8 released at the site. Recognition comes next, and it is far more efficient when the microbe is coated with complement fragment C3b or with antibody, a process called opsonisation. The neutrophil extends pseudopodia around the coated particle, closes them and traps it in a vesicle called a phagosome. The phagosome fuses with lysosomal granules to form a phagolysosome, and killing occurs in two waves: the granules release defensins, proteases and lysozyme, while the respiratory burst assembles an enzyme complex called NADPH oxidase that converts oxygen into superoxide, then into hydrogen peroxide, and finally, with myeloperoxidase, into hypochlorous acid. If the organism is too large to swallow, the neutrophil can also expel webs of DNA called extracellular traps. Neutrophils die after a few hours of this work, which is why pus follows a successful defence; macrophages survive, digest more slowly and display fragments of what they destroyed to the lymphocytes of the adaptive response, which is the bridge between section 7.2 and section 7.3.

Interferon is neither an antibody nor a toxin; it is a warning signal, and its value lies in the fact that it is broadcast before the infection spreads. When a virus enters a cell and begins to replicate, it produces double-stranded RNA and other structures that human cells never make. Receptors such as TLR3 and the cytoplasmic sensors RIG-I and MDA5 detect these patterns and switch on transcription of the interferon genes. The infected cell then secretes type I interferon — interferon-alpha, made mainly by leukocytes, and interferon-beta, made mainly by fibroblasts — and dies, but it dies having sent the message. The interferon binds a receptor called IFNAR on the surface of neighbouring cells and triggers the JAK-STAT signalling pathway, which switches on a set of antiviral proteins. Protein kinase R blocks translation, so the cell stops making proteins and the virus finds no machinery to use; 2´-5´ oligoadenylate synthetase activates an enzyme, RNase L, that cuts viral RNA; and Mx proteins trap viral components before they can assemble. The neighbour is now refractory to infection by many different viruses at once. Interferon also increases the display of MHC class I molecules, marking infected cells so that natural killer cells and cytotoxic lymphocytes can destroy them. Two consequences matter clinically. First, because the sensor recognises general viral features rather than one antigen, interferon is antiviral without being virus specific: a single signal protects against unrelated viruses, which is why the notes can say it prevents replication of the infecting virus and why the same molecule works in hepatitis B, hepatitis C and some cancers. Second, the fever, muscle aching and fatigue you feel during influenza are largely the effect of interferon acting on the whole body, not the effect of the virus on the nose alone. Interferon therapy therefore produces a deliberate, uncomfortable imitation of that state, and nurses who give it must warn the patient about it. The supplied notes state only that infected cells produce interferon which prevents viral replication; the mechanism and the clinical points above go beyond them.

Innate immunity is fast but it is also predictable, and successful pathogens have evolved ways around each of its steps. The commonest is the capsule, a thick layer of polysaccharide outside the cell wall, whose slippery, water-loving surface prevents complement from being deposited and stops the phagocyte from gripping the microbe; Klebsiella pneumoniae, Streptococcus pneumoniae and Neisseria meningitidis all rely on it, and the structure of the capsule itself belongs to section 3.4. A related trick is to look like the host: some capsules contain sialic acid, a sugar normally found on human cells, so the phagocyte hesitates. Others attack the effector molecules directly. Staphylococcus aureus makes protein A, which binds the tail of antibody molecules and holds them the wrong way round, so they cannot mark the bacterium for engulfment, while Streptococcus pyogenes uses M protein to bind factors that switch complement off. Organisms that make the enzyme catalase, including Staphylococcus aureus and Mycobacterium tuberculosis, destroy the hydrogen peroxide produced during the respiratory burst, so the chemical weapon is neutralised before it can act. The most difficult group survives inside the very cells sent to kill it: Mycobacterium tuberculosis prevents the phagosome from fusing with the lysosome, Listeria monocytogenes escapes into the cytoplasm, and Legionella pneumophila blocks the maturation of the phagosome, so each organism lives in a protected compartment. Where a surface is available, many bacteria form a biofilm, a matrix of polysaccharide and protein that shields the community, blocks antibodies and phagocytes and keeps them away from the cells underneath; Pseudomonas aeruginosa growing on a catheter or a wound is the standard example. These strategies explain nursing decisions that otherwise look arbitrary. A biofilm on an indwelling device will not be cleared by antibiotics alone, so the device is removed. An encapsulated organism requires specific antibody for efficient killing, which is why conjugate vaccines against pneumococcus, meningococcus and Haemophilus influenzae type b are given before exposure. A patient with tuberculosis needs several drugs for many months because some organisms sit inside macrophages where drugs penetrate poorly. And a patient whose neutrophils have been destroyed by chemotherapy has lost the first line of cellular defence altogether, so fever must be treated as an emergency rather than observed.