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5.5C: The Ability to Resist Phagocytic Destruction - Biology

5.5C: The Ability to Resist Phagocytic Destruction - Biology


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Learning Objectives

  1. State at least 4 different ways bacteria might be able to resist phagocytic destruction once engulfed.

We will now look at the ability of bacteria to resist phagocytic destruction and complement serum lysis. Bacteria resist phagocytic destruction by a variety of means.

Preventing fusion of the lysosome with the phagosome

Once Salmonella is engulfed by macrophages and placed in a phagosome, the bacterium uses its type 3 secretion system to inject proteins that prevent the lysosomes from fusing with the phagosomes, thus providing a safe haven for Salmonella replication within the phagosome and protecting the bacteria from antibodies and other defense elements (Figure (PageIndex{1})).

Figure (PageIndex{1}): Salmonella Surviving Inside Macrophages. Once in the phagosome of the macrophage the bacterium uses its type 3 secretion system to inject proteins that prevent the lysosomes from fusing with the phagosomes, thus providing a safe haven for Salmonella replication within the phagosome and protecting the bacteria from antibodies and other defense elements.

Legionella pneumophila, after being ingested by macrophages and placed in a phagosome, uses a type 4 secretion system to inject effector proteins that prevent the lysosomes from fusing with the phagosomes and turning the macrophage into a safe haven for bacterial replication. Neisseria gonorrhoeae produces Por protein (protein I) that prevents phagosomes from fusing with lysosomes enabling the bacteria to survive inside phagocytes.

Cell wall lipids of Mycobacterium tuberculosis, such as lipoarabinomannan, arrest the maturation of phagosomes preventing delivery of the bacteria to lysosomes. Some bacteria, such as species of Salmonella, Mycobacterium tuberculosis, Legionella pneumophila, and Chlamydia trachomatis, block the vesicular transport machinery that enables the lysosome to move to the phagosome for fusion.

Escaping from the Phagosome

Some bacteria, such as Shigella flexneri, Listeria monocytogenes, and the spotted fever Rickettsia, escape from the phagosome into the cytoplasm prior to the phagosome fusing with a lysosome (Figure (PageIndex{2})).

Figure (PageIndex{2}): Bacteria Escaping from a Phagosome. Some bacteria resist phagocytosis by escaping from the phagosome prior to its fusing with a lysosome.

Preventing Acidification of the Phagosome

Some bacteria, such as pathogenic Mycobacterium and Legionella pneumophilia, prevent the acidification of the phagosome that is needed for effective killing of microbes by lysosomal enzymes. (Normally after the phagosome forms, the contents become acidified because the lysosomal enzymes used for killing (acid hydrolases) function much more effectively at an acidic pH.)

Resisting killing by Lysosomal Chemicals

Some bacteria, such as Salmonella, are more resistant to toxic forms of oxygen and to defensins, the toxic peptides that kill bacteria by damaging their cytoplasmic membranes. The carotenoid pigments that give Staphylococcus aureus species its golden color and group B streptococci (GBS) its orange tint shield the bacteria from the toxic oxidants that neutrophils use to kill bacteria.

Resisting phagocytic destruction: killing the phagocyte

Some bacteria are able to kill phagocytes. Bacteria such as Staphylococcus aureus and Streptococcus pyogenes produce the exotoxin leukocidin that damages either the cytoplasmic membrane of the phagocyte or the membranes of the lysosomes, resulting in the phagocyte being killed by its own enzymes. Shigella and Salmonella, induce macrophage apoptosis, a programmed cell death.

Exercise (PageIndex{1}): Think-Pair-Share Questions

  1. Some bacteria, such as pathogenic Mycobacterium and Legionella pneumophilia prevent the acidification of the phagosome within phagocytes. Why might this protect these bacteria from being killed within the phagocyte?
  2. Staphylococcus aureus and Streptococcus pyogenes both produce a toxin called leukocydin. How might this enable these bacteria to resist phagocytosis?

Summary

  1. Some bacteria resist phagocytic destruction by preventing fusion of the lysosome with the phagosome.
  2. Some bacteria resist phagocytic destruction by escaping from the phagosome before the lysosome fuses.
  3. Some bacteria resist phagocytic destruction by preventing acidification of the phagosome.
  4. Some bacteria resist phagocytic destruction by resisting killing by lysosomal chemicals.
  5. Some bacteria resist phagocytic destruction by killing phagocytes.

Study Notes on Microbial Pathogenicity

3. Virulence, a variable factor that may enhance or reduce the capacity of the pathogen to cause overt infection.

Pathogens (Pathogenic microorganisms) cause diseases and they may be:

Opportunistic Pathogens:

Many commensal or non-pathogenic microorganisms may be transmissible from person to person or derived from the environment and are present, in large numbers, on the skin, in the upper respiratory tract, in the intestine and lower urinogenital tract hence they are normal micro flora of the body and sometimes they may act against invading pathogenic microorganisms and are unable to invade the tissues as they cannot overcome the healthy body defences.

Sometimes, when the body defence mechanism is lowered and when these commensals leave their natural habitat and reach other parts of the body, e.g., coliform bacilli (Escherichia coli) are mostly harmless commensals in the intestine, but they may cause infection in the urinary tract similarly Clostridium welchii, an intestinal commensal, can cause gangrene in locally damaged tissues Streptococcus viridians is the commensal of the mouth after tooth extraction they may invade the blood stream and settle on previously damaged heart valves as opportunistic pathogens.

True Pathogens:

They are those microorganisms which are able to overcome the normal body defence mechanism and initiate the infection.

Several properties are essential for pathogenicity of microorganisms:

The ability of a pathogen to grow profusely in the body and to be shed in large numbers in body fluids or secretions which are capable of dissemination and reach new host after surviving in the adverse conditions, e.g., desiccation in the dry dust.

Pathogenic microbes are able to initiate the infection by penetrating the healthy body’s first line of defence, that is, skin, mucous membranes to which they readily gain access. To infect a person, only a few of the pathogens can cross the protective barriers in the respiratory and alimentary tracts. The pathogen may initiate a localised lesion at the site of infection, e.g., staphylococcal boil on the skin or streptococcal pharyngitis in the throat.

The capacity of the microbes to initiate the infection is mostly related to the dosage of the pathogen, its phase of growth and its virulence factors. In salmonella family, the infecting dose of Salmonella typhi is very small whereas large number of S. typhimurium (food poisoning salmonellae) must be ingested to produce acute vomiting and diarrhoea.

Microorganisms which are in the logarithmic stage of growth are more likely to overcome host resistance than those in the latent phase: Streptococcus pyogenes is more infective when transferred directly from a person with a sore throat than when it is inhaled after drying in dust particles, because Strepto pyogenes has the capsular M protein (anti-phagocytic component) during the active phase of sore throat infection.

The virulence of a pathogen is the ability to kill susceptible animals (mouse, guinea pig etc.). The tubercle bacillus isolated from Indian patients with tuberculosis are often less virulent to the guinea pigs than strains isolated in Britain. The assessment of virulence for animal is not necessarily applicable to virulence of man.

Shigella dysenteries causes much more severe infection than Sh.sonnei. Similarly, the gravis strain of Corynebacterium diphtheriae causes more deaths than the misstrain. Type 1 poliovirus is more likely to initiate epidemics of paralytic poliomyelitis than is type 2.

Pathogenic bacteria produce diseases by virtue of one or both of the main attributes: Toxigenecity and invasiveness.

Toxigenecity:

Toxins may be (a) exotoxins or (b) endotoxins,

(a) Exotoxins:

German and French workers were first to prove that the products of the diphtheria bacilli, diffused from the local infection or injected as bacteria- free filtrates of cultured diphtheria bacilli, could produce widespread systemic damage in guinea pigs. The toxin produced by diphtheria bacilli in the throat is carried by the blood stream (toxaemia) throughout the body.

When the bacteria grow actively in broth culture, they secrete apparently the poison which is called as “exotoxin” Other bacteria which secrete highly potent toxins are tetanus bacilli and Clostridium botulinum. So 1.0 mg. of tetanus and botulinal toxin can kill more than one million guinea pigs and it is estimated that 3 kg of botulinal toxin can kill the world population.

Exotoxins are mainly produced by gram-positive bacilli (except Shigella bacillus neurotoxin and cholera enterotoxin) and have special affinity for specific tissues for example, tetanus, botulinal and diphtheria toxins all affect different parts of the nervous system: tetanus toxin affects control mechanisms that govern motor cells in the anterior columns of the spinal cord botulinal toxin paralyses cranial nerves by blocking the transmission of effector messages from their endings and diphtheria toxin has affinity for peripheral nerve ending as well as for specialised tissues like heart muscle.

Exotoxins behave like enzymes: alpha toxin of CI. welchii is a phospholipase (lecithinase C) which acts on phospholipids of cell membrane diphtheria toxins depress the formation and/or release of acetylcholine in different parts of the nervous system.

They are complex phospholipid polysaccharide – protein macromolecules. Most of the endotoxins are lipopolysaccharides and additional endotoxin released by few gram-negative pathogenic bacteria (Yersinia pestisand Bordetella pertussis) is protein in nature and is present in the bacterial cytoplasm. They are released only after natural autolysis or artificial disruption of bacterial cells and therefore they are called endotoxins.

Typical endotoxins are particularly associated with gram-negative bacteria (salmonella, shigella, Escherichia, Neisseria) and are distinguishable from exotoxins by the following properties:

1. They are present in the outer layer of the bacterial cell wall

3. They are much less toxic and specific in their cytotoxic effects than exotoxins

4. They cannot be converted into toxoids

5 Homologous antibodies cannot render them non-toxic, if combined.

The complex phospholipid-polysaccharide- protein molecule can be separated by phenol extraction into:

(a) Lipopolysaccharide moiety,

The lipopolysaccharide moiety can be split further into different sugars including those that determine the antigenic specificity of the endotoxin and lipid which is mainly responsible for the toxicity. Pyrogenic effect (fever) is the toxic effect produced by the smallest amount of endotoxin. If 0.002 μ g endotoxin per kg body weight is injected intravenously into rabbit or man, it causes within 15 minutes an elevation of body temperature which lasts for several hours.

It is the other main attribute of pathogenic bacteria. It is its capacity to invade and multiply in the healthy tissues, e.g., pneumococcus produces the disease depending entirely upon the quality of invasiveness just as botulinus bacillus depends entirely on its toxigenicity. Thus, the diphtheria bacillus must be initially invasive in order to establish itself in the tissues of the oropharynx, where it manufactures its toxin the gravis strain of diphtheria bacillus has the greater capacity to invade and multiply in the tissues with a consequent greater production of toxin than mitis strain. Strepto. pyogenes is mainly an invasive pathogen.

It also produces an erythrogenic toxin which is responsible for the rash of the scarlet fever. The invasiveness of Staph, aureus, Strepto. pyogenes and CI. welchii is due to their production of cytolytic and leucocidal toxins which enable them to breach tissue barriers and protect themselves against phagocytosis.

Pathogenic bacteria which are predominantly invasive are:

1. The First Category—:

The pathogenic gram positive cocci initially attract phagocytes by chemotactic mechanisms, resist phagocytosis but ultimately they may be engulfed and destroyed by phagocytes.

2. The Second Category —:

Tubercle bacilli, typhoid, brucella bacilli, though they are readily phagocytosed are more resistant to destruction when within phagocytes and become intracellular parasites which are disseminated by phagocytes throughout the body.

There is fight between phagocytes and anti-phagocytic bacteria when specific antibody acting as opsonins come to the aid of the phagocytes in destroying the anti-phagocytic bacteria, then these bacteria are destroyed by phagocytes and there is a dramatic fall in temperature — the crisis — as observed in pneumococcal pneumonia. In infection with intracellular parasites there is clinical illness that persists for some weeks with low fever.

Capsules and Pathogenicity:

The bacterial capsule plays an important role in conferring the virulence on bacteria by enabling them to resist phagocytosis and bactericidal substances in body fluids, therefore the capsulation is important for the virulence of pneumococci, streptococci of Group A and Group C, the anthrax bacillus, the plague bacillus, Kbesiella pneumonia and Haemophilus influenza.

It has been observed that the non-capsulate bacteria are rapidly phagocytosed and, within a few hours, are mostly destroyed, whereas the capsulate bacteria remain free and soon multiply to large numbers. The mechanism of the anti-phagocytic property of capsulate bacteria is not known, but it may be that the lipid containing cell membrane of the phagocyte’s pseudopodia is inhibited from making contact with the hydrated capsule gel because of the surface charge. However, heavily capsulate harmless saprophytic bacteria and some non-virulent strains of bacillus anthracis and plague bacilli are fairly susceptible to phagocytosis.

Other non-toxic protective or aggressive factors that may contribute to the ability of capsulate and non-capsulate pathogens to invade and multiply in the host tissues are:

1. Hyaluronidase or spreading factor, is an enzyme that dissolves the hyaluronic acid or cement like substances that binds cells together and so allows pathogens (Strepto. pyogenes, Staph, aureus) to permeate through the tissues.

2. Coagulase Prothrombin —:

Like enzyme produced by all pathogenic staphylococci may help to protect the pathogen from phagocytosis into two ways:

(a) by forming fibrin barriers around staphylococci and staphylococcal lesions, and

(b) by inactivating the bactericidal substance present in the normal blood serum.

3. Streptokinase Secreted by Strepto:

Pyogenes may promote the spreading of streptococcal lesions.

4. Collagenase, produced by CI. welchii, may play some part in the pathogenesis of gas gangrene.

5. Neuraminidase produced by some bacteria and viruses acts on mucoproteins of cell surface and may facilitate attacks on the cell.

The affinity of many pathogenic microbes for specific tissues or organs is known as organotropism. Pneumococcus and meningococcus both have the natural habitat in the nasopharynx, but the virulent pneumococcus has a predilection for lung tissues and the meningococcus for the meninges of the brain, whereas gonococcus mainly affects the mucosa of urethra.


Bordetella Pertussis Infections☆

Definition

Bordetella organisms, all of which are nonfermentative and catalase positive, are small, aerobic, gram-negative coccobacilli. Currently, there are eight species, four of which (B. pertussis, B. parapertussis, Bordetella bronchiseptica and Bordetella holmesii) cause human disease ( Cherry and Heininger, 2014 Winn et al., 2006 ). Whooping cough, or pertussis, is the most common human infection caused by the genus Bordetella. It is an acute respiratory infection, affecting primarily non- or under-immunized individuals, especially infants and children. Pertussis is highly communicable, typically by airborne droplets.


Immunity to Parasites

Author(s): Nuria Tormo, Maria del Remedio Guna, Maria Teresa Fraile, Maria Dolores Ocete, Africa Garcia, David Navalpotro, Mercedes Chanza, Jose Luis Ramos, Concepcion Gimeno Servicio de Microbiologia, Pabellon A-3, Consorio Hospital General Universitario, Avda. Tres Cruces, 2, 46014, Valencia, Spain., Spain

Affiliation:

Journal Name: Current Immunology Reviews (Discontinued)

Volume 7 , Issue 1 , 2011

Abstract:

Parasites such as protozoa or helminths currently account for greater morbidity and mortality than any other class of infectious organisms, particularly in developing countries. The structural and antigenic diversity of pathogenic parasites is reflected in the heterogeneity of the adaptive immune responses that they elicit. Protozoa that live within host cells are destroyed by cell-mediated immunity, whereas helminths are eliminated by IgE antibody and eosinophil mediated killing as well as by other leukocytes. The principal innate immune response to protozoa is phagocytosis, but many of these parasites are resistant to phagocytic killing and may even replicate within macrophages. Phagocytes also attack helminthic parasites and secrete microbicidal substances to kill organisms that are too large to be phagocytosed. Some helminths may also activate the alternative pathway of complement. The principal defense mechanism against protozoa that survive within macrophages (e.g. Leishmania spp., Toxoplasma gondii) is cell-mediated immunity, particularly macrophage activation by TH1 cell-derived cytokines. Protozoa that replicate inside various host cells and lyse these cells stimulate specific antibody and cytotoxic T lymphocytes (CTL) responses (e.g. Plasmodium spp.). Defense against many helminthic infections is mediated by the activation of TH2 cells, which results in production of IgE antibodies and activation of eosinophils and mast cells. The combined actions of mast cells and eosinophils lead to expulsion and destruction of the parasites. Most parasitic infections are chronic because of weak innate immunity and the ability of parasites to evade or resist elimination by adaptive immune responses Parasites evade the immune system by varying their antigens during residence in vertebrate hosts, by acquiring resistance to immune effector mechanisms, and by masking and shedding their surface antigens.

Current Immunology Reviews (Discontinued)

Title: Immunity to Parasites

VOLUME: 7 ISSUE: 1

Author(s):Nuria Tormo, Maria del Remedio Guna, Maria Teresa Fraile, Maria Dolores Ocete, Africa Garcia, David Navalpotro, Mercedes Chanza, Jose Luis Ramos and Concepcion Gimeno

Affiliation:Servicio de Microbiologia, Pabellon A-3, Consorio Hospital General Universitario, Avda. Tres Cruces, 2, 46014, Valencia, Spain.


Soluble Mediators of the Innate Immune Response

The previous discussions have alluded to chemical signals that can induce cells to change various physiological characteristics, such as the expression of a particular receptor. These soluble factors are secreted during innate or early induced responses, and later during adaptive immune responses.

Cytokines and Chemokines

A cytokine is signaling molecule that allows cells to communicate with each other over short distances. Cytokines are secreted into the intercellular space, and the action of the cytokine induces the receiving cell to change its physiology. A chemokine is a soluble chemical mediator similar to cytokines except that its function is to attract cells (chemotaxis) from longer distances.

Practice Question

Visit this website to learn about phagocyte chemotaxis. Phagocyte chemotaxis is the movement of phagocytes according to the secretion of chemical messengers in the form of interleukins and other chemokines. By what means does a phagocyte destroy a bacterium that it has ingested?

Early Induced Proteins

Early induced proteins are those that are not constitutively present in the body, but are made as they are needed early during the innate immune response. Interferons are an example of early induced proteins. Cells infected with viruses secrete interferons that travel to adjacent cells and induce them to make antiviral proteins. Thus, even though the initial cell is sacrificed, the surrounding cells are protected. Other early induced proteins specific for bacterial cell wall components are mannose-binding protein and C-reactive protein, made in the liver, which bind specifically to polysaccharide components of the bacterial cell wall. Phagocytes such as macrophages have receptors for these proteins, and they are thus able to recognize them as they are bound to the bacteria. This brings the phagocyte and bacterium into close proximity and enhances the phagocytosis of the bacterium by the process known as opsonization. Opsonization is the tagging of a pathogen for phagocytosis by the binding of an antibody or an antimicrobial protein.

Complement System

The complement system is a series of proteins constitutively found in the blood plasma. As such, these proteins are not considered part of the early induced immune response, even though they share features with some of the antibacterial proteins of this class. Made in the liver, they have a variety of functions in the innate immune response, using what is known as the “alternate pathway” of complement activation. Additionally, complement functions in the adaptive immune response as well, in what is called the classical pathway. The complement system consists of several proteins that enzymatically alter and fragment later proteins in a series, which is why it is termed cascade. Once activated, the series of reactions is irreversible, and releases fragments that have the following actions:

  • Bind to the cell membrane of the pathogen that activates it, labeling it for phagocytosis (opsonization)
  • Diffuse away from the pathogen and act as chemotactic agents to attract phagocytic cells to the site of inflammation
  • Form damaging pores in the plasma membrane of the pathogen

Figure 2 shows the classical pathway, which requires antibodies of the adaptive immune response. The alternate pathway does not require an antibody to become activated.

Figure 2. The classical pathway, used during adaptive immune responses, occurs when C1 reacts with antibodies that have bound an antigen.

The splitting of the C3 protein is the common step to both pathways. In the alternate pathway, C3 is activated spontaneously and, after reacting with the molecules factor P, factor B, and factor D, splits apart. The larger fragment, C3b, binds to the surface of the pathogen and C3a, the smaller fragment, diffuses outward from the site of activation and attracts phagocytes to the site of infection. Surface-bound C3b then activates the rest of the cascade, with the last five proteins, C5–C9, forming the membrane-attack complex (MAC). The MAC can kill certain pathogens by disrupting their osmotic balance. The MAC is especially effective against a broad range of bacteria. The classical pathway is similar, except the early stages of activation require the presence of antibody bound to antigen, and thus is dependent on the adaptive immune response. The earlier fragments of the cascade also have important functions. Phagocytic cells such as macrophages and neutrophils are attracted to an infection site by chemotactic attraction to smaller complement fragments. Additionally, once they arrive, their receptors for surface-bound C3b opsonize the pathogen for phagocytosis and destruction.


5.5C: The Ability to Resist Phagocytic Destruction - Biology

The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism.

Learning Objectives

Illustrate the key points of the complement system

Key Takeaways

Key Points

  • Three biochemical pathways activate the complement system–the classical complement pathway, the alternative complement pathway, and the lectin pathway.
  • The following are the basic functions of the complement: Opsonization (enhancing phagocytosis of antigens ) chemotaxis (attracting macrophages and neutrophils) cell lysis (rupturing membranes of foreign cells) and clumping (antigen-bearing agents).
  • The complement system consists of a number of small proteins found in the blood, generally synthesized by the liver, and normally circulating as inactive precursors (pro-proteins).

Key Terms

  • antibodies: An antibody (Ab), also known as an immunoglobulin (Ig), is a large Y-shaped protein produced by B-cells that is used by the immune system to identify and neutralize foreign objects, such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, called an “antigen. “
  • phagocytic: Phagocytosis, meaning “cell,” and -osis, meaning “process,” is the cellular process of engulfing solid particles by the cell membrane to form an internal phagosome by phagocytes and protists.
  • pathogens: A pathogen or infectious agent (colloquially known as a germ) is a microorganism (in the widest sense, such as a virus, bacterium, prion, or fungus) that causes disease in its host. The host may be an animal (including humans), a plant, or even another microorganism.
  • classical pathway: a group of blood proteins that mediate the specific antibody response

The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the ” innate immune system ” that is not adaptable and does not change over the course of an individual’s lifetime. However, it can be recruited and brought into action by the adaptive immune system.

The complement system consists of a number of small proteins found in the blood, generally synthesized by the liver, and normally circulating as inactive precursors (pro-proteins). When stimulated by one of several triggers, proteases in the system cleave specific proteins to release cytokines and initiate an amplifying cascade of further cleavages. The end result of this activation cascade is massive amplification of the response and activation of the cell-killing membrane attack complex. Over 25 proteins and protein fragments make up the complement system, including serum proteins, serosal proteins, and cell membrane receptors. They account for about 5% of the globulin fraction of blood serum.

Three biochemical pathways activate the complement system: the classical complement pathway, the alternative complement pathway, and the lectin pathway. The following are the basic functions of the complement: opsonization (enhancing phagocytosis of antigens) chemotaxis (attracting macrophages and neutrophils) cell lysis (rupturing membranes of foreign cells) and clumping (antigen-bearing agents).

The proteins and glycoproteins that constitute the complement system are synthesized by the liver hepatocytes. But significant amounts are also produced by tissue macrophages, blood monocytes, and epithelial cells of the genitourinal tract and gastrointestinal tract. The three pathways of activation all generate homologous variants of the protease C3-convertase. The classical complement pathway typically requires antigen, antibody complexes for activation (specific immune response), whereas the alternative and mannose-binding lectin pathways can be activated by C3 hydrolysis or antigens without the presence of antibodies (non-specific immune response). In all three pathways, C3-convertase cleaves and activates component C3, creating C3a and C3b, and causing a cascade of further cleavage and activation events. C3b binds to the surface of pathogens, leading to greater internalization by phagocytic cells by opsonization. C5a is an important chemotactic protein, helping recruit inflammatory cells.

C3a is the precursor of an important cytokine (adipokine) named ASP and is usually rapidly cleaved by carboxypeptidase B. Both C3a and C5a have anaphylatoxin activity, directly triggering degranulation of mast cells, as well as increasing vascular permeability and smooth muscle contraction. C5b initiates the membrane attack pathway, which results in the membrane attack complex (MAC), consisting of C5b, C6, C7, C8, and polymeric C9. MAC is the cytolytic endproduct of the complement cascade it forms a transmembrane channel, which causes osmotic lysis of the target cell. Kupffer cells and other macrophage cell types help clear complement-coated pathogens. As part of the innate immune system, elements of the complement cascade can be found in species earlier than vertebrates, most recently in the protostome horseshoe crab species, putting the origins of the system back further than was previously thought.

n the classical pathway, C1 binds with its C1q subunits to Fc fragments (made of CH2 region) of IgG or IgM, which forms a complex with antigens. C4b and C3b are also able to bind to antigen-associated IgG or IgM, to its Fc portion.

Such immunoglobulin-mediated binding of the complement may be interpreted, as that the complement uses the ability of the immunoglobulin to detect and bind to non-self antigens as its guiding stick. The complement itself is able to bind non-self pathogens after detecting their pathogen-associated molecular patterns (PAMPs) however, utilizing specificity of antibody, complements are able to detect non-self enemies much more specifically. There must be mechanisms that complements bind to Ig but would not focus its function to Ig but to the antigen.

shows the classical and the alternative pathways with the late steps of complement activation schematically. Some components have a variety of binding sites. In the classical pathway, C4 binds to Ig-associated C1q and C1r2s2 enzyme cleaves C4 to C4b and 4a. C4b binds to C1q, antigen-associated Ig (specifically to its Fc portion), and even to the microbe surface. C3b binds to antigen-associated Ig and to the microbe surface. The ability of C3b to bind to antigen-associated Ig would work effectively against antigen-antibody immune complexes to make them soluble. In the figure, C2b refers to the larger of the C2 fragments.

Complement Pathways: The classical and the alternative pathways with the late steps of complement activation.


Phagocytosis

Phagocytosis is the ingestion of large particles such as bacteria, foreign bodies, and remnants of dead cells (Fig. 22-2). Cells use the actin cytoskeleton to push a protrusion of the plasma membrane to surround these particles.

(Courtesy of John Heuser, Washington University, St. Louis, Missouri.)

Some cells, including macrophages, dendritic cells, and neutrophils, are specialized for phagocytosis. The presence of bacteria or protozoa in tissues attracts professional phagocytes from the blood (see Fig. 30-13), where they ingest the microorganisms and initiate inflammatory and immune responses. Other cell types use phagocytosis to remove dead neighboring cells, while amoeba use phagocytosis for feeding.

Phagocytosis proceeds through four steps: attachment, engulfment, fusion with lysosomes, and degradation (Fig. 22-3). These steps are highly regulated by cell surface receptors, phospholipids, and signaling cascades mediated by Rho-family GTPases.


Via interferons

Virally infected cells produce and release small proteins called interferons, which play a role in immune protection against viruses. Interferons prevent replication of viruses, by directly interfering with their ability to replicate within an infected cell. They also act as signalling molecules that allow infected cells to warn nearby cells of a viral presence – this signal makes neighbouring cells increase the numbers of MHC class I molecules upon their surfaces, so that T cells surveying the area can identify and eliminate the viral infection as described above.


Plasma Protein Mediators

Many nonspecific innate immune factors are found in plasma, the fluid portion of blood. Plasma contains electrolytes, sugars, lipids, and proteins, each of which helps to maintain homeostasis (i.e., stable internal body functioning), and contains the proteins involved in the clotting of blood. Additional proteins found in blood plasma, such as acute-phase proteins, complement proteins, and cytokines, are involved in the nonspecific innate immune response.

Plasma versus Serum

There are two terms for the fluid portion of blood: plasma and serum. How do they differ if they are both fluid and lack cells? The fluid portion of blood left over after coagulation (blood cell clotting) has taken place is serum. Although molecules such as many vitamins, electrolytes, certain sugars, complement proteins, and antibodies are still present in serum, clotting factors are largely depleted. Plasma, conversely, still contains all the clotting elements. To obtain plasma from blood, an anticoagulant must be used to prevent clotting. Examples of anticoagulants include heparin and ethylene diamine tetraacetic acid (EDTA). Because clotting is inhibited, once obtained, the sample must be gently spun down in a centrifuge. The heavier, denser blood cells form a pellet at the bottom of a centrifuge tube, while the fluid plasma portion, which is lighter and less dense, remains above the cell pellet.

Acute-Phase Proteins

The acute-phase proteins are another class of antimicrobial mediators. Acute-phase proteins are primarily produced in the liver and secreted into the blood in response to inflammatory molecules from the immune system. Examples of acute-phase proteins include C-reactive protein, serum amyloid A, ferritin, transferrin, fibrinogen, and mannose-binding lectin. Each of these proteins has a different chemical structure and inhibits or destroys microbes in some way (Table 2).

Table 2. Some Acute-Phase Proteins and Their Functions
C-reactive protein Coats bacteria (opsonization), preparing them for ingestion by phagocytes
Serum amyloid A
Ferritin Bind and sequester iron, thereby inhibiting the growth of pathogens
Transferrin
Fibrinogen Involved in formation of blood clots that trap bacterial pathogens
Mannose-binding lectin Activates complement cascade

The Complement System

The complement system is a group of plasma protein mediators that can act as an innate nonspecific defense while also serving to connect innate and adaptive immunity (discussed in the next chapter). The complement system is composed of more than 30 proteins (including C1 through C9) that normally circulate as precursor proteins in blood. These precursor proteins become activated when stimulated or triggered by a variety of factors, including the presence of microorganisms. Complement proteins are considered part of innate nonspecific immunity because they are always present in the blood and tissue fluids, allowing them to be activated quickly. Also, when activated through the alternative pathway (described later in this section), complement proteins target pathogens in a nonspecific manner.

The process by which circulating complement precursors become functional is called complement activation. This process is a cascade that can be triggered by one of three different mechanisms, known as the alternative, classical, and lectin pathways.

The alternative pathway is initiated by the spontaneous activation of the complement protein C3. The hydrolysis of C3 produces two products, C3a and C3b. When no invader microbes are present, C3b is very quickly degraded in a hydrolysis reaction using the water in the blood. However, if invading microbes are present, C3b attaches to the surface of these microbes. Once attached, C3b will recruit other complement proteins in a cascade (Figure 2).

The classical pathway provides a more efficient mechanism of activating the complement cascade, but it depends upon the production of antibodies by the specific adaptive immune defenses. To initiate the classical pathway, a specific antibody must first bind to the pathogen to form an antibody-antigen complex. This activates the first protein in the complement cascade, the C1 complex. The C1 complex is a multipart protein complex, and each component participates in the full activation of the overall complex. Following recruitment and activation of the C1 complex, the remaining classical pathway complement proteins are recruited and activated in a cascading sequence (Figure 2).

The lectin activation pathway is similar to the classical pathway, but it is triggered by the binding of mannose-binding lectin, an acute-phase protein, to carbohydrates on the microbial surface. Like other acute-phase proteins, lectins are produced by liver cells and are commonly upregulated in response to inflammatory signals received by the body during an infection (Figure 2).

Figure 2. The three complement activation pathways have different triggers, as shown here, but all three result in the activation of the complement protein C3, which produces C3a and C3b. The latter binds to the surface of the target cell and then works with other complement proteins to cleave C5 into C5a and C5b. C5b also binds to the cell surface and then recruits C6 through C9 these molecules form a ring structure called the membrane attack complex (MAC), which punches through the cell membrane of the invading pathogen, causing it to swell and burst.

Although each complement activation pathway is initiated in a different way, they all provide the same protective outcomes: opsonization, inflammation, chemotaxis, and cytolysis. The term opsonization refers to the coating of a pathogen by a chemical substance (called an opsonin) that allows phagocytic cells to recognize, engulf, and destroy it more easily. Opsonins from the complement cascade include C1q, C3b, and C4b. Additional important opsonins include mannose-binding proteins and antibodies. The complement fragments C3a and C5a are well-characterized anaphylatoxins with potent proinflammatory functions. Anaphylatoxins activate mast cells, causing degranulation and the release of inflammatory chemical signals, including mediators that cause vasodilation and increased vascular permeability. C5a is also one of the most potent chemoattractants for neutrophils and other white blood cells, cellular defenses that will be discussed in the next section.

The complement proteins C6, C7, C8, and C9 assemble into a membrane attack complex (MAC), which allows C9 to polymerize into pores in the membranes of gram-negative bacteria. These pores allow water, ions, and other molecules to move freely in and out of the targeted cells, eventually leading to cell lysis and death of the pathogen (Figure 2). However, the MAC is only effective against gram-negative bacteria it cannot penetrate the thick layer of peptidoglycan associated with cell walls of gram-positive bacteria. Since the MAC does not pose a lethal threat to gram-positive bacterial pathogens, complement-mediated opsonization is more important for their clearance.

Cytokines

Cytokines are soluble proteins that act as communication signals between cells. In a nonspecific innate immune response, various cytokines may be released to stimulate production of chemical mediators or other cell functions, such as cell proliferation, cell differentiation, inhibition of cell division, apoptosis, and chemotaxis.

When a cytokine binds to its target receptor, the effect can vary widely depending on the type of cytokine and the type of cell or receptor to which it has bound. The function of a particular cytokine can be described as autocrine, paracrine, or endocrine (Figure 3). In autocrine function, the same cell that releases the cytokine is the recipient of the signal in other words, autocrine function is a form of self-stimulation by a cell. In contrast, paracrine function involves the release of cytokines from one cell to other nearby cells, stimulating some response from the recipient cells. Last, endocrine function occurs when cells release cytokines into the bloodstream to be carried to target cells much farther away.

Figure 3. Autocrine, paracrine, and endocrine actions describe which cells are targeted by cytokines and how far the cytokines must travel to bind to their intended target cells’ receptors.

Three important classes of cytokines are the interleukins, chemokines, and interferons. The interleukins were originally thought to be produced only by leukocytes (white blood cells) and to only stimulate leukocytes, thus the reasons for their name. Although interleukins are involved in modulating almost every function of the immune system, their role in the body is not restricted to immunity. Interleukins are also produced by and stimulate a variety of cells unrelated to immune defenses.

Figure 4. Click for a larger image. Interferons are cytokines released by a cell infected with a virus. Interferon-α and interferon-β signal uninfected neighboring cells to inhibit mRNA synthesis, destroy RNA, and reduce protein synthesis (top arrow). Interferon-α and interferon-β also promote apoptosis in cells infected with the virus (middle arrow). Interferon-γ alerts neighboring immune cells to an attack (bottom arrow). Although interferons do not cure the cell releasing them or other infected cells, which will soon die, their release may prevent additional cells from becoming infected, thus stemming the infection.

The chemokines are chemotactic factors that recruit leukocytes to sites of infection, tissue damage, and inflammation. In contrast to more general chemotactic factors, like complement factor C5a, chemokines are very specific in the subsets of leukocytes they recruit.

Interferons are a diverse group of immune signaling molecules and are especially important in our defense against viruses. Type I interferons (interferon-α and interferon-β) are produced and released by cells infected with virus. These interferons stimulate nearby cells to stop production of mRNA, destroy RNA already produced, and reduce protein synthesis. These cellular changes inhibit viral replication and production of mature virus, slowing the spread of the virus. Type I interferons also stimulate various immune cells involved in viral clearance to more aggressively attack virus-infected cells. Type II interferon (interferon-γ) is an important activator of immune cells (Figure 4).


CONCLUSION

ROS production in phagocytes serves multiple purposes, from cell signaling to microbial killing. Numerous reactive species over a wide range of concentrations are involved. Timing and location of ROS production, diffusion, and scavenging are critical for the outcome. To illustrate this complexity, we referred the reader to reviews that deal with fundamental aspects of phagocyte ROS production wherever possible, and we apologize to those whose work is not mentioned explicitly. The phagocyte community needs new probes for high-level (phagosomal) ROS detection, as well as low-level (signaling) detection. The recent interest in redox biology has pushed the development of new detection methods with improved specificity, better sensitivity, and new ways to localize the detector with cells. The harsh conditions of the phagosome (pH, proteases, level, and diversity of ROS) are particularly challenging to any detection method, and the specificity of any new dye should be tested under these conditions. Subcellular targeting of FPs and the SNAP-tag technology for organic dyes are good candidates to improve the spatial resolution of ROS detection. The end of ROS production may be addressed with nanoparticles. The spatiotemporal correlation of ROS production with signaling events will be addressed by combining dyes of different color that become available now. We are convinced that new organic compounds, as well as FPs, will increase our choice to explore in more detail the why, when, and where of phagocyte ROS production.



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