Phagocytosis

Several types of cells in the immune system engulf microorganisms via phagocytosis.

• Neutrophils. Neutrophils are abundant in the blood, quickly enter tissues, and phagocytize pathogens in acute inflammation.
• Macrophages. Macrophages are closely related to monocytes in the blood. These longer-lived cells predominate in chronic inflammation. They also release some important inflammatory paracrines. (See below.)
• Dendritic Cells and B Lymphocytes. Phagocytosis in these cells is important for the elaboration of a specific immune response rather than for directly destroying the pathogens. (Much more later.)

Phagocytosis begins with the neutrophil or macrophage flowing around the pathogen and engulfing it so that it winds up enclosed in a phagosome (phagocytic vesicle). But this is only the first step, because the more challenging task of destroying the microorganisms remains. Indeed, some pathogens have special, effective mechanisms for frustrating this destruction step.

The next step is the fusion of lysosomes with the phagosome. The result is called a phagolysosome. Lysosome are derived from the Golgi apparatus, much like secretion vesicles, but their contents are focused on destroying microorganisms.

The following are important factors that help destroy microorganisms within a phagolysosome:

• Oxygen Radicals. A complex of proteins called NADPH oxidase in the membrane of a phagolysosome generates oxygen radicals in the phagosome. These highly reactive molecules react with proteins, lipids and other biological molecules. See the next webpage for details.
• Nitric Oxide. Nitric oxide synthase synthesizes nitric oxide, a reactive substance that reacts with oxygen radicals to create further molecules that damage various biological molecules. (But nitric oxide is also, remarkably enough, an important regulatory molecule elsewhere. More on this later this quarter.)
• Anti-Microbial Proteins. Lysosomes contain several proteases, including a broad spectrum enzyme,elastase, which is important or even essential for killing various bacteria. Another anti-microbial protein is lysozyme, which attacks the cell walls of certain (gram positive) bacteria.
• Anti-Microbial Peptides. Defensins and certain other peptides attack bacterial cell membranes. Similar molecules are found throughout much of the animal kingdom.
• Binding Proteins. Lactoferrin binds iron ions, which are necessary for growth of bacteria. Another protein binds vitamin B12.
• Hydrogen Ion Transport. Transporters for hydrogen ions acidify the phagolysosome, which kills various microorganisms and is important for the action of the proteases described above.

In addition to destroying the microorganism, macrophages also release paracrines that alert other parts of the immune system that an infection is present. (Two important examples are IL-1 and TNF-alpha.) Among other things, these potent paracrines promote inflammation.

Identification of Pathogen

We will go into this topic in more detail later. But here are a few points for now. Neutrophils and macrophages have some ability on their own to recognize microorganisms and begin phagocytosis. This is because such organisms have molecules much different than those found in a human. But phagocytosis is far more effective if microorganisms are labelled as such by special molecules that bind to their surface. (Any molecule that binds to a microorganism and thereby speeds phagocytosis is called an opsonin). Most important here are antibodies (such as IgG), which specifically identify molecules at the surface of specific microorganisms. With this attached to the surface of the microorganisms, phagocytosis is much more effective and rapid.

Difficult Pathogens

But, as mentioned above, sometimes phagocytes have a difficult time with certain pathogens. For example, we discussed in class that Listeria monocytogenes can escape from the phagosome into the cytosol.

Tuberculosis is an especially important example. A macrophage can usually engulf the tuberculosis bacterium, but then the bacterium has a means for preventing the lysosomes from fusing with the phagosome. If the macrophage is not "activated" by paracrines from a specific immune response, the bacteria may remain alive for long periods within the macrophage. In this circumstance, other macrophages surround and wall off the infected macrophages, forming a type of chronic inflammation called a granuloma. Leprosy is another bacterium that is difficult for macrophages to destroy. Again, more on this later.

Some pathogenic bacteria are surrounded by a capsule that make phagocytosis difficult. Anthrax is one example. Anthrax spores entering the body from the lungs or a cut in the skin make their way first to lymph nodes, where they change to their "vegetative form" and begin dividing. But because they are difficult to destroy, they quickly become quite numerous and accumulate in the blood, causing septicemia. Not only do the bacteria release toxins, but also, as is the case in certain other dangerous infections, macrophages respond to the crisis by releasing enough IL-1 and TNF-alpha to cause inflammation systemically, that is, throughout the body. Indeed, this hyperinflammation by itself can quickly be fatal. It can include, for example, widespread formation of small blood clots, which is termed disseminated intravascular coagulation.