IMMUNOLOGY TEXTBOOK - Mercury Podillia 2013

MECHANISMS OF IMMUNE DEFENSE IN BACTERIAL, VIRAL, FUNGAL, AND PROTOZOAN INFECTIONS

Mechanisms of Microbial Immune Evasion

Throughout the evolution of parasitism, many pathogenic microorganisms have developed strategic mechanisms that enable them to overcome the host's defense systems.

Some microorganisms likely attach to and colonize external mucosal surfaces of the body to avoid unwanted contact with phagocytic Cells. Thus, the mucosal epithelium serves as a habitat for human pathogens such as gonococci, Vibrio cholerae, causative agents of pertussis, as well as Protozoa such as Giardia, Trichomonas, and Candida albicans, a pathogenic fungus. Secretory IgA performs a protective function on mucous membranes by preventing the adhesion and proliferation of pathogens through the blockade of surface Antigens. However, certain Bacteria (Haemophilus influenzae, Streptococcus pneumoniae) secrete Enzymes that selectively degrade secretory IgA.

Other pathogens that have established themselves in host Tissues attempt to avoid ingestion by phagocytic cells. For instance, a polysaccharide capsule protects pneumococci from interacting with the receptors of phagocytic cells, thereby hindering adhesion. Sometimes the capsule contains substances that effectively inhibit phagocytosis even if the microbes manage to adhere to phagocytes. Certain bacteria secrete coagulase, which induces The formation of a protective fibrin layer around the bacterium, or toxins that destroy phagocytes.

In such cases, host defense mechanisms rely on the Specificity and diversity of Antibodies. Antibodies circulating in the Blood are able to neutralize bacterial antiphagocytic products and other exotoxins by binding near the Active Site of the toxin and stereochemically blocking its interaction with the substrate. In a complex with antibodies, the toxin loses its ability to diffuse in tissues and can become a target for phagocytosis. By binding to the microbial surface, antibodies not only prevent them from escaping phagocytosis but also facilitate (via opsonization) their uptake by polymorphonuclear leukocytes and macrophages.

Some infectious agents evade the body's immune system by adapting to live and multiply inside phagocytes themselves. In this scenario, microbes not only avoid being captured by these cells, but upon entering the body, they actively migrate toward tissue histiocytes or release chemotactic factors that attract phagocytes. It is also possible that some of them do not wait for phagocytosis, but actively invade macrophage-like cells themselves. Intracellular parasitism of microorganisms can be achieved in various ways. Some rickettsiae and protozoa (Trypanosoma cruzi) avoid destruction by residing directly in the Cytoplasm of the infected Cell rather than in a digestive vacuole (phagosome). This mechanism is based on the fact that Lysosomes cannot release their contents onto a parasite that is not separated from cellular structures by a membrane, as this would lead to the damage and death of the host cell itself.

Certain microbes (mycobacteria, chlamydia, toxoplasma) inhibit the fusion of the phagosomes containing them with lysosomes. Others adapt to the bactericidal substances and Proteolytic Enzymes of lysosomes. Mycobacteria possess a Cell wall resistant to lysosomal enzymes and also produce a series of enzymes that neutralize reactive oxygen radicals of phagocytes. Leishmania secrete proteases that inactivate lysosomal enzymes. Some bacteria produce exotoxins known as leukocidins, which cause the disintegration of lysosomes inside macrophages, leading to the destruction of cellular Organelles and cell death.

Many intracellularly parasitic bacteria, protozoa, and Viruses interfere in various ways with the complex system of intracellular signal Transduction inside macrophages. The resulting disruption of relationships among protein Kinases, phospholipases, and other intracellular secondary messenger molecules leads to the inactivation of macrophages. This diminishes the Processing of engulfed antigens, the expression of MHC Class II Histocompatibility Antigens, antigen presentation, and cytokine production, while also impairing the defensive Functions of macrophages.

In individuals infected with plasmodia, trypanosomes, or mycobacteria, The Emergence of "suppressive" macrophages has been described; these cells secrete a cytokine that inhibits both the secretion of IL-2 and the expression of IL-2 receptors on T lymphocytes. The presence of microbes within macrophage-like cells typically leads to polymorphic diseases, often featuring an acute phase but characterized by a prolonged persistence of the pathogen, with alternating periods of relative well-being and exacerbations. For instance, diseases caused by mycobacteria (tuberculosis, leprosy) are characterized by a very high rate of infection and a low incidence of clinically manifest disease among those infected. While individuals infected with Mycobacterium tuberculosis account for one-third of the global population, the disease develops in only a small fraction of them.

In some individuals, the disease develops immediately after infection, whereas in others it may persist in a subclinical state for many years or even decades before clinical manifestation. However, parasites that are resistant to macrophage microbicidal factors (or those residing in other cell types) are not always resistant to more active phagocytes, such as polynuclear cells (only meningococci and gonococci can survive and multiply for long periods in neutrophils, though even this remains controversial). Polymorphonuclear leukocytes pose no threat to a microbe located inside a living cell, as they do not attack the host cell, which is covered by an intact membrane. However, once the host cell is destroyed, neutrophils accumulate around it and actively phagocytose the pathogen. Intracellular parasites are protected not only from phagocytes but also from the humoral defense factors of the Organism: specific antibodies do not penetrate infected cells. Of particular importance for medical practice is the fact that such microbes are also invulnerable to certain pharmacological agents, notably Antibiotics. Although some of these agents can cross cell membranes, radical therapy for Infections caused by intracellular parasites remains a challenging task.

From an immunological standpoint, viral infections differ from other (protozoan, bacterial) infections in that the Genetic information of the virus is closely integrated with The Genome of the invaded cell. Viruses lack their own machinery for Protein Synthesis AND Replication, and instead co-opt the corresponding host cell mechanisms for this purpose. Therefore, from the perspective of viral species survival, prolonged persistence within the host organism is advantageous. Many viruses are protected from immunological mechanisms when they replicate in tissues inaccessible to lymphocytes. Such viruses may not induce an Immune Response at all. These are the so-called slow viruses that develop in the Brain and cause infections with very long incubation periods. In infections caused by these viruses (such as scrapie), Immunity does not develop at all: neither antibodies nor cell-mediated immunity are detected. These viruses are also insensitive to interferon. Viruses that replicate in the keratinized epidermis likewise evade the pressure of immune defense mechanisms, as lymphocytes and antibodies cannot penetrate these areas.

"Latent" viruses are capable of persisting in the organism for long periods (years and decades) while remaining inside cells without entering the extracellular space (e.g., Herpes simplex, Epstein-Barr virus). In such infections, much like intracellular bacterial parasitism, decades of latency without overt manifestations alternate with recurrent inflammations that cause clinical symptoms. Very frequently, viruses directly interfere with the execution of immune defense mechanisms. For instance, the adenovirus genome encodes a protein that impedes the METABOLISM/31.html">Transcription and Translation of MHC class I molecules, which play a crucial role in the antiviral immune response. Another adenovirus Gene product can bind directly to MHC I molecules within cells and prevent their expression on cell membranes. This results in a decreased surface expression of MHC I molecules, protecting infected cells from attack by cytotoxic T lymphocytes. Herpesviruses are also capable of downregulating the expression of MHC class I and II antigens, as well as adhesion molecules ICAM-1 and LFA-3, which are involved in the initial anchoring of immunocompetent cells to other cells (antigen-presenting cells, infected cells). Rhinoviruses bind to ICAM-1 on epithelial cells, utilizing these adhesion molecules as their own receptors.

Furthermore, human cytomegalovirus stimulates macrophages to produce cytokines, which in turn promote The production of hemagglutinin—allowing the virus to attach to The Cell—and neuraminidase, which releases newly formed Viral Particles from the surface sialic acids of the infected cell. Gradual Changes in the antigenic properties of hemagglutinin occur As a result of point Mutations in the viral genome (antigenic drift), whereas major changes arise from the EXCHANGE OF GENETIC material with viruses from other hosts (antigenic shift). When the antigenic specificity of hemagglutinin shifts to such an extent that immunity acquired during a previous epidemic becomes ineffective, a new Influenza epidemic begins. During antigenic variation, some viruses generate a set of quasispecies with mutant Proteins that are either unrecognized by cytotoxic lymphocytes or fail to be transported from the Cytosol to the extracellular space at all.

Parasites such as protozoa and helminths have also evolved highly sophisticated mechanisms to evade the numerous Components of the immune system. Among these, alterations in the antigenic COMPOSITION OF THE parasite during ontogenesis are widespread. Eggs, larvae, and adult forms of various helminths exhibit significant antigenic differences, which benefits the parasite because upon transitioning to a new developmental stage, the host's existing specific defense mechanism fails for a time, requiring restructuring and supplementation. For example, the outer surface layer of adult parasites eventually lacks antigens recognized by antibodies specific to earlier Stages of the parasite's development.

Trypanosoma brucei and certain Plasmodium species utilize antigenic variation to evade the deleterious effects of antibodies. Molecular mimicry—coating the parasite's surface with host antigens—plays a significant role. For instance, adult schistosomes possess receptors for the Fc fragment of host IMMUNOGLOBULINS. Even specific IgE is harmless to such a parasite because the Fc region, through which eosinophils attach to it, remains occupied. Moreover, schistosomes can rapidly induce the Cleavage of Fab fragments from Fc fragments, with the detached Fab fragments exerting a strong suppressive effect—in particular, inhibiting IgE-dependent macrophage cytotoxicity against schistosomes in vitro. The Fc fragment remains attached to the parasite, continuing to promote mimicry. In addition to immunoglobulins, parasites can adsorb other host antigens onto their membranes, such as erythrocyte Glycolipids and Glycoproteins and MHC molecules, which further AIDS in parasite masking and impairs the effective action of immune mechanisms.

Intracellular parasitic protozoa, much like bacteria, block the normal Mechanisms of microbial destruction by macrophages. Toxoplasma gondii, for example, inhibits the fusion of phagosomes with lysosomes by somehow "positioning" host cell Mitochondria along the phagosomal membrane. Trypanosoma cruzi escapes from the phagosome into the cytoplasm, whereas Leishmania are surrounded by electron-dense material that presumably protects them from the "respiratory burst." Nevertheless, macrophages can destroy these parasites if they are activated by lymphokines (IFNs) produced by T lymphocytes. Most parasitic infections (as well as many others) are accompanied by immunosuppression. Some helminths are capable of the polyclonal activation of IgE-producing B lymphocytes, which gives an advantage to the parasite and correspondingly weakens host immunity: high concentrations of nonspecific IgE can bind to mast cells, displacing parasite-specific IgE molecules and thereby reducing the likelihood of mast cell activation by the specific antigen. Other helminths secrete factors that shift the balance of T helper subsets ($T_H1/T_H2$) in a direction favorable for pathogen survival. An extreme case of parasite Interference with The Immune System is the utilization of host immunoregulatory proteins—cytokines—as their own growth factors by certain pathogens (primarily trypanosomatids).

The strategies chosen by parasitic organisms to counteract the host immune system are no less numerous, complex, and ingenious than the defense mechanisms designed to combat them. It is precisely these strategies that allow infectious agents not only to survive but sometimes even to thrive within the host organism.