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Pathogen Recognition

Pathogen Recognition

An infection may be intracellular or extracellular, depending on the pathogen. All viruses infect cells and replicate within those cells (intracellularly), whereas bacteria and other parasites may replicate intracellularly or extracellularly, depending on the species. The innate immune system must respond accordingly: by identifying the extracellular pathogen and/or by identifying host cells that have already been infected. When a pathogen enters the body, cells in the blood and lymph detect the specific pathogen-associated molecular patterns (PAMPs) on the pathogen’s surface.

PAMPs are carbohydrate, polypeptide, and nucleic acid “signatures” that are expressed by viruses, bacteria, and parasites but which differ from molecules on host cells. The immune system has specific cells, described in the figure below and shown in the figure below, with receptors that recognize these PAMPs. A macrophage is a large phagocytic cell that engulfs foreign particles and pathogens. Macrophages recognize PAMPs via complementary pattern recognition receptors (PRRs). PRRs are molecules on macrophages and dendritic cells which are in contact with the external environment.

A monocyte is a type of white blood cell that circulates in the blood and lymph and differentiates into macrophages after it moves into infected tissue. Dendritic cells bind molecular signatures of pathogens and promote pathogen engulfment and destruction. Toll-like receptors (TLRs) are a type of PRR that recognizes molecules that are shared by pathogens but distinguishable from host molecules). TLRs are present in invertebrates as well as vertebrates, and appear to be one of the most ancient components of the immune system. TLRs have also been identified in the mammalian nervous system.

 Table shows various types of white blood cells and describes their function. Mast cells, natural killer cells, neutrophils, basophils and eosinophils are all filled with granules and have a horseshoe-shaped nucleus. Macrophages are irregular in shape, with a round nucleus. Dendrites have star-like projections and a small horseshoe shaped nucleus. Mast cells dilate blood vessels and induce inflammation through release of histamines and heparin. They also recruit macrophages and neutrophils, and are involved in wound healing and defense against pathogens, but can also be responsible for allergic reactions. They are found in connective tissue and mucous membranes. Macrophages are phagocytic cells that consume foreign pathogens and cancer cells. They stimulate response of other immune cells and migrate from blood vessels into tissues. Natural killer cells kill tumor cells and virus-infected cells. They circulate in blood and migrate into tissues. Dendritic cells present antigens on their surface, thereby triggering adaptive immunity. They are present in tissues in epithelial tissue, including skin, lung and tissues of the digestive tract. Migrate to lymph nodes upon activation. Monocytes differentiate into macrophages and dendritic cells in response to inflammation. They are stored in spleen, move through blood vessels to infected tissues. Neutrophils are first responders at the site of infection or trauma, these abundant phagocytic cell representing 50-60% of all leukocytes. Release toxins that kill or inhibit bacteria and fungi and recruit other immune cells to the site of infection. They migrate from blood vessels into tissues. Basophils are responsible for defense against parasites. They release histamines that cause inflammation and may be responsible for allergic reactions. They circulate in blood and migrate to tissues. Eosinophils release toxins that kill bacteria and parasites but also causes tissue damage. They circulate in blood and migrate to tissues.

The characteristics and location of cells involved in the innate immune system are described. (credit: modification of work by NIH)

Micrograph shows a blood smear. Red blood cells are disk-shaped, and pinched together in the center. Monocytes, lymphocytes and neutrophils are all ball-shaped and fuzzy. Platelets are small, flat disks.

Cells of the blood include (1) monocytes, (2) lymphocytes, (3) neutrophils, (4) red blood cells, and (5) platelets. Note the very similar morphologies of the leukocytes (1, 2, 3). (credit: modification of work by Bruce Wetzel, Harry Schaefer, NCI; scale-bar data from Matt Russell)

Cytokine Release Effect

The binding of PRRs with PAMPs triggers the release of cytokines, which signal that a pathogen is present and needs to be destroyed along with any infected cells. A cytokine is a chemical messenger that regulates cell differentiation (form and function), proliferation (production), and gene expression to affect immune responses. At least 40 types of cytokines exist in humans that differ in terms of the cell type that produces them, the cell type that responds to them, and the changes they produce. One type cytokine, interferon, is illustrated in the figure below.

One subclass of cytokines is the interleukin (IL), so named because they mediate interactions between leukocytes (white blood cells). Interleukins are involved in bridging the innate and adaptive immune responses. In addition to being released from cells after PAMP recognition, cytokines are released by the infected cells which bind to nearby uninfected cells and induce those cells to release cytokines, which results in a cytokine burst.

A second class of early-acting cytokines is interferons, which are released by infected cells as a warning to nearby uninfected cells. One of the functions of an interferon is to inhibit viral replication. They also have other important functions, such as tumor surveillance. Interferons work by signaling neighboring uninfected cells to destroy RNA and reduce protein synthesis, signaling neighboring infected cells to undergo apoptosis (programmed cell death), and activating immune cells.

In response to interferons, uninfected cells alter their gene expression, which increases the cells’ resistance to infection. One effect of interferon-induced gene expression is a sharply reduced cellular protein synthesis. Virally infected cells produce more viruses by synthesizing large quantities of viral proteins. Thus, by reducing protein synthesis, a cell becomes resistant to viral infection.

Illustration shows a virus-infected cell secreting interferon, which binds to receptors of neighboring cells. Interferon signals neighboring uninfected cells to destroy RNA and reduce protein synthesis, thus making it more difficult for virus to infect the cell. It signals neighboring infected cells to undergo apoptosis. It also activates nearby immune cells.

Interferons are cytokines that are released by a cell infected with a virus. Response of neighboring cells to interferon helps stem the infection.

Phagocytosis and Inflammation

The first cytokines to be produced are pro-inflammatory; that is, they encourage inflammation, the localized redness, swelling, heat, and pain that result from the movement of leukocytes and fluid through increasingly permeable capillaries to a site of infection. The population of leukocytes that arrives at an infection site depends on the nature of the infecting pathogen. Both macrophages and dendritic cells engulf pathogens and cellular debris through phagocytosis.

A neutrophil is also a phagocytic leukocyte that engulfs and digests pathogens. Neutrophils, shown in the figure below, are the most abundant leukocytes of the immune system. Neutrophils have a nucleus with two to five lobes, and they contain organelles, called lysosomes, that digest engulfed pathogens. An eosinophil is a leukocyte that works with other eosinophils to surround a parasite; it is involved in the allergic response and in protection against helminthes (parasitic worms).

Neutrophils and eosinophils are particularly important leukocytes that engulf large pathogens, such as bacteria and fungi. A mast cell is a leukocyte that produces inflammatory molecules, such as histamine, in response to large pathogens. A basophil is a leukocyte that, like a neutrophil, releases chemicals to stimulate the inflammatory response as illustrated in the figure below. Basophils are also involved in allergy and hypersensitivity responses and induce specific types of inflammatory responses. Eosinophils and basophils produce additional inflammatory mediators to recruit more leukocytes. A hypersensitive immune response to harmless antigens, such as in pollen, often involves the release of histamine by basophils and mast cells.

 Illustration shows a capillary near the surface of skin that has a cut in it. Bacteria have penetrated the skin around the cut. In response, mass cells in the lower part of the skin tissue release histamines, and dendritic cells release cytokines. The histamines cause the capillary to become permeable. Neutrophils and monocytes exit the capillary into the damaged skin. Both the neutrophil and macrophage release cytokines and consumes bacteria by phagocytosis.

In response to a cut, mast cells secrete histamines that cause nearby capillaries to dilate. Neutrophils and monocytes leave the capillaries. Monocytes mature into macrophages. Neutrophils, dendritic cells and macrophages release chemicals to stimulate the inflammatory response. Neutrophils and macrophages also consume invading bacteria by phagocytosis.

Cytokines also send feedback to cells of the nervous system to bring about the overall symptoms of feeling sick, which include lethargy, muscle pain, and nausea. These effects may have evolved because the symptoms encourage the individual to rest and prevent them from spreading the infection to others. Cytokines also increase the core body temperature, causing a fever, which causes the liver to withhold iron from the blood. Without iron, certain pathogens, such as some bacteria, are unable to replicate; this is called nutritional immunity.

Resource:

Watch this 23-second stop-motion clip showing a neutrophil that searches for and engulfs fungus spores during an elapsed time of about 79 minutes.

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