Section 20.4: Pathogen Recognition

Learning Objectives

• Explain how leukocytes migrate from peripheral blood into infected tissues
• Explain the mechanisms by which leukocytes recognize pathogens
• Explain the process of phagocytosis and the mechanisms by which phagocytes destroy and degrade pathogens

Several of the cell types discussed in the previous section can be described as phagocytes—cells whose main function is to seek, ingest, and kill pathogens. This process, called phagocytosis, was first observed in starfish in the 1880s by Nobel Prize-winning zoologist Ilya Metchnikoff (1845–1916), who made the connection to white blood cells (WBCs) in humans and other animals. At the time, Pasteur and other scientists believed that WBCs were spreading pathogens rather than killing them (which is true for some diseases, such as tuberculosis). But in most cases, phagocytes provide a strong, swift, and effective defense against a broad range of microbes, making them a critical component of innate nonspecific immunity. This section will focus on the mechanisms by which phagocytes are able to seek, recognize, and destroy pathogens.

Extravasation (Diapedesis) of Leukocytes

Some phagocytes are leukocytes (WBCs) that normally circulate in the bloodstream. To reach pathogens located in infected tissue, leukocytes must pass through the walls of small capillary blood vessels within tissues. This process, called extravasation, or diapedesis, is initiated by complement factor C5a, as well as cytokines released into the immediate vicinity by resident macrophages and tissue cells responding to the presence of the infectious agent (Figure \(\PageIndex{1}\)). Similar to C5a, many of these cytokines are proinflammatory and chemotactic, and they bind to cells of small capillary blood vessels, initiating a response in the endothelial cells lining the inside of the blood vessel walls. This response involves the upregulation and expression of various cellular adhesion molecules and receptors. Leukocytes passing through will stick slightly to the adhesion molecules, slowing down and rolling along the blood vessel walls near the infected area. When they reach a cellular junction, they will bind to even more of these adhesion molecules, flattening out and squeezing through the cellular junction in a process known as transendothelial migration. This mechanism of “rolling adhesion” allows leukocytes to exit the bloodstream and enter the infected areas, where they can begin phagocytosing the invading pathogens.

Note that extravasation does not occur in arteries or veins. These blood vessels are surrounded by thicker, multilayer protective walls, in contrast to the thin single-cell-layer walls of capillaries. Furthermore, the blood flow in arteries is too turbulent to allow for rolling adhesion. Also, some leukocytes tend to respond to an infection more quickly than others. The first to arrive typically are neutrophils, often within hours of a bacterial infection. By contract, monocytes may take several days to leave the bloodstream and differentiate into macrophages.

Figure \(\PageIndex{1}\): Damaged cells and macrophages that have ingested pathogens release cytokines that are proinflammatory and chemotactic for leukocytes. In addition, activation of complement at the site of infection results in production of the chemotactic and proinflammatory C5a. Leukocytes exit the blood vessel and follow the chemoattractant signal of cytokines and C5a to the site of infection. Granulocytes such as neutrophils release chemicals that destroy pathogens. They are also capable of phagocytosis and intracellular killing of bacterial pathogens.

Link to Learning

Watch the following videos on leukocyte extravasation and leukocyte rolling to learn more.

Exercise \(\PageIndex{1}\)

Explain the role of adhesion molecules in the process of extravasation.

Pathogen Recognition

As described in the previous section, opsonization of pathogens by antibody; complement factors C1q, C3b, and C4b; and lectins can assist phagocytic cells in recognition of pathogens and attachment to initiate phagocytosis. However, not all pathogen recognition is opsonin dependent. Phagocytes can also recognize molecular structures that are common to many groups of pathogenic microbes. Such structures are called pathogen-associated molecular patterns (PAMPs). Common PAMPs include the following:

• peptidoglycan, found in bacterial cell walls;
• flagellin, a protein found in bacterial flagella;
• lipopolysaccharide (LPS) from the outer membrane of gram-negative bacteria;
• lipopeptides, molecules expressed by most bacteria; and
• nucleic acids such as viral DNA or RNA.

Like numerous other PAMPs, these substances are integral to the structure of broad classes of microbes.

The structures that allow phagocytic cells to detect PAMPs are called pattern recognition receptors (PRRs). One group of PRRs is the toll-like receptors (TLRs), which bind to various PAMPs and communicate with the nucleus of the phagocyte to elicit a response. Many TLRs (and other PRRs) are located on the surface of a phagocyte, but some can also be found embedded in the membranes of interior compartments and organelles (Figure \(\PageIndex{2}\)). These interior PRRs can be useful for the binding and recognition of intracellular pathogens that may have gained access to the inside of the cell before phagocytosis could take place. Viral nucleic acids, for example, might encounter an interior PRR, triggering production of the antiviral cytokine interferon.

In addition to providing the first step of pathogen recognition, the interaction between PAMPs and PRRs on macrophages provides an intracellular signal that activates the phagocyte, causing it to transition from a dormant state of readiness and slow proliferation to a state of hyperactivity, proliferation, production/secretion of cytokines, and enhanced intracellular killing. PRRs on macrophages also respond to chemical distress signals from damaged or stressed cells. This allows macrophages to extend their responses beyond protection from infectious diseases to a broader role in the inflammatory response initiated from injuries or other diseases.

Figure \(\PageIndex{2}\): Phagocytic cells contain pattern recognition receptors (PRRs) capable of recognizing various pathogen-associated molecular patterns (PAMPs). These PRRs can be found on the plasma membrane or in internal phagosomes. When a PRR recognizes a PAMP, it sends a signal to the nucleus that activates genes involved in phagocytosis, cellular proliferation, production and secretion of antiviral interferons and proinflammatory cytokines, and enhanced intracellular killing.

Exercise \(\PageIndex{2}\)

1. Name four pathogen-associated molecular patterns (PAMPs).
2. Describe the process of phagocyte activation.

Key Concepts and Summary

• Phagocytes are cells that recognize pathogens and destroy them through phagocytosis.
• Recognition often takes place by the use of phagocyte receptors that bind molecules commonly found on pathogens, known as pathogen-associated molecular patterns (PAMPs).
• The receptors that bind PAMPs are called pattern recognition receptors, or PRRs. Toll-like receptors (TLRs) are one type of PRR found on phagocytes.
• Extravasation of white blood cells from the bloodstream into infected tissue occurs through the process of transendothelial migration.
• Phagocytes degrade pathogens through phagocytosis, which involves engulfing the pathogen, killing and digesting it within a phagolysosome, and then excreting undigested matter.

Footnotes

1. 1 World Health Organization. “Leishmaniasis.” 2016. http://www.who.int/mediacentre/factsheets/fs375/en/.