Microbiology Chapter 14

Steps of phagocytosis

1) Chemotaxis 2) Recognition and attachment 3) Engulfment 4) Phagosome maturation and phagollysosome formation 5) Destruction and digestion 6) Exocytosis

How do cytokine receptors help cytokines?

A cytokine produced by one cell diffuses to another and binds to this appropriate receptor of that cell. Binding of a cytokine to its receptor induces a change in the cell such as growth, differentiation, movement, or cell death.

Ligands

A molecule that can bind to a given receptor is called this for that receptor. When it binds to its surface receptor, the internal portion of the receptor becomes modified in some manner. This change then triggers some type of response by the cell, such as chemotaxis

Complement system

A series of proteins always present in the blood and tissue fluids; these proteins are collectively called this because they can "complement" (act in combination with) the adaptive immune defenses. It becomes activated in response to certain stimuli, setting off a chain of events that results in removal and destruction of invading microbes

Hematopoietic stem cell

All blood cells, including those important in the body's defenses, originate from this same cell type, found in the bone marrow. They are capable of long-term self-renewal, meaning they can divide repeatedly. They are induced to develop into the various types of blood cells by a group of proteins called colony-stimulating factors

Three pathways that can activate complement system

Alternative pathway, lectin pathway, and classical pathway

Antibodies

An important action of the adaptive immune response is the production of these Y-shaped proteins. These bind specifically to antigens, thereby targeting them for destruction or removal by other host defenses.

Lactoferrin

An iron-binding protein in saliva, mucus, and milk; it is also found in some types of phagocytes

Natural killer cells

Another type of lymphocyte; unlike B cells and T cells, however, they lack specificity in their mechanism of antigen recognition

Pattern recognition receptors

Certain cells serve as lookouts or guards and have these receptors on their surface and within their endosomes or phagosomes. These recognize groups of compounds unique to microbes, allowing the lookouts to detect invaders. When invasion is detected, the cells send chemical signals to alert other components of the host defenses, triggering a protective response

Membrane attack complexes

Complexes of complement system proteins (C5b, C6, C7, C8, and multiple C9 molecules) spontaneously assemble in cell membranes, forming these doughnut-shaped structures. This creates pores in the membrane, disrupting the integrity of the cell

What do chemokines do?

Cytokines important in chemotaxis of immune cells. Certain types of cells have receptors for chemokines, allowing the cells to sense the location where they are needed, such as an area of inflammation.

Neutrophils

Efficiently engulf and destroy bacteria and other material. Their granules, which stain poorly, contain many enzymes and antimicrobial substances that help destroy the engulfed materials. They are the most numerous and important granulocytes of the innate responses. They are also called polymorphonuclear neutrophillic leukocytes, polys, or PMNs, names that reflect the appearance of multiple lobes of their single nucleus. Normally account for over half of the circulating white blood cells, and their numbers increase during most bacterial infections. Few are generally found in tissues, except during inflammation.

What is the surface of the body lined with?

Epithelial cells. They are tightly packed together and rest on a thin layer of fibrous material, the basement membrane. Skin is composed of dermis (tightly woven fibrous connective tissue, making it extremely tough and durable), and epidermis (composed of many layers of epithelial cells, outermost sheets made of dead cells filled with a water-repelling protein called keratin)

How is alternative pathway triggered?

It is triggered when C3b binds to foreign cell surfaces. The binding of C3b allows other complement proteins to then attach, eventually forming the C3 convertase. Some C3b is always present to trigger the alternative pathway when needed

How does a phagosome attain antimicrobial capabilities?

It matures to develop antimicrobial capabilities. As part of this process, it fuses with various endosomes, allowing it to gain properties that characterize those endosomes. For example, the pH becomes progressively more acidic. The phagosome maturation stages are highly regulated, and appear to depend on the type of material ingested. For instance, a phagosome that contains host cell material has a different fate than one that carries microbial components

How is classical pathway triggered?

It requires antibodies, a component of adaptive immunity. When antibodies bind to an antigen (forming an antigen-antibody complex, also called an immune complex), they interact with the same complement system component involved with the lectin pathway to form a C3 convertase

What does tumor necrosis factor do?

It was discovered because of its role in killing tumor cells, a characteristic reflected by the name, but it has multiple roles. It helps initiate the inflammatory response and triggers the process of "cell suicide"

Activated macrophages

Macrophages can increase their otherwise limited killing power to become these. One mechanism for this requires the assistance of certain T cells, an example of the cooperation between the innate and adaptive defenses. The compounds produced by these also damage tissues when released, so it would be potentially harmful for macrophages to routinely be in an activated state.

What makes up a granuloma and what does it do?

Macrophages, giant cells, and T cells form these concentrated groups that wall off and retain organisms or other material that cannot be destroyed. They are part of the disease process in tuberculosis and several other illnesses, and prevent the microbes from escaping to infect other cells.

Phagosome

Membrane-bound vacuole that contains the material engulfed by a phagocyte

What control mechanisms do host cells have in regards to the complement system?

Molecules in host cell membranes bind regulatory proteins that quickly inactivate C3b. This prevents host cell surfaces from triggering the alternative pathway of complement regulation. It also prevents host cells from being opsonized.

Monocytes

Mononuclear phagocytes that circulate in the blood

What lines the digestive tract?

Mucous membranes. It is constantly bathed with mucous or other secretions that help wash microbes from the surface

What are NETs and what do they do?

Neutrophils release the contents of their granules along with DNA to form neutrophil extracellular traps. The DNA strands in the NET ensnare microbes, allowing the granule contents (enzymes and peptides) that accumulate within the NET to destroy them

How does a phagolysosome destroy and engulf invaders?

O2 consumption increases dramatically-called respiratory burst-allowing an enzyme to produce reactive oxygen species (ROS), which are toxic. Another enzyme makes nitric oxide, which reacts with ROs to produce additional toxic compounds. Special pumps move protons into the phagolysosome, lowering the pH. The various enzymes contributed by the lysosomes degrade peptidoglycan and other components. Defensins damage membranes of the invader, and lactoferrin ties up iron.

What does normal microbiota do for you?

One protective effect is the competitive exclusion of pathogens; for example, it prevents pathogens from adhering to host cells by covering binding sites that might otherwise be used for attachment. It also consumes available nutrients that could otherwise support the growth of less desirable organisms. Some members of this population also produce compounds toxic to other bacteria. Disruption of the normal microbiota, which occurs when antibiotics are used, can predispose a person to various infections

What are the three outcomes of the activation of the complement system?

Opsonization, an inflammatory response, and lysis of foreign cells

What happens during chemotaxis?

Pagocytic cells are recruited to the site of infection or tissue damage by chemicals that act as chemoattractants. These include products of microorganisms, phospholipids released by injured host cells, chemokines, and the complement system component C5a.

Columnar epithelium

Passages of respiratory system, various tubes of the reproductive systems.

Pathogen-associated molecular patterns

Pattern recognition receptors (PRRs) detect these generic microbe-associated patterns. These substances are common on all microbes, not just pathogens so they are sometimes referred to as microbe-associated molecular patterns (MAMPS). Some of these are various cell wall components (lipopolysaccharide, peptidoglycan, lipoteichoic acid, and lipoproteins), flagellin subunits, and RNA molecules that characterize viruses

Erythrocytes

Red blood cells; they carry O2 in the blood. Platelets, which are actually fragments arising from large cells called megakaryocytes, and are important for blood clotting

Defensins

Short antimicrobial peptides produced by neutrophils and epithelial cells. They insert into bacterial membranes, forming pores that damage cells

Transferrin

Similar to lactoferrin; it is in the blood and tissue fluids. Iron is one of the major elements, so withholding it prevents microbial growth

Stratified epithelium

Skin (the outer cell layers are embedded with keratin), lining of mouth, vagina, urethra, and anus.

Danger-associated molecular patterns

Some PRRs recognize these patterns, which are molecules that indicate host cell damage

Interferon beta

Source: Fibroblasts; Effect: Antiviral

Interferon alpha

Source: Leukocytes; Effect: Antiviral

IL-1

Source: Macrophages, epithelial cells; Effect: T-cell activation; macrophage activation; induces fever

Interferon gamma

Source: T cells, NK cells; Effect: Macrophage activation; promotes certain adaptive immune responses

IL-4

Source: T cells, mast cells; Effect: Promotes antibody responses

IL-2

Source: T cells; Effect: T-cell proliferation

IL-6

Source: T lymphocytes, macrophages; Effect: T- and B-cell growth; inflammatory response; fever

What do colony-stimulating factors do?

They are important in the multiplication and differentiation of leukocytes. When more leukocytes are needed during an immune response, a variety of different colony-stimulating factors direct immature cells into the appropriate maturation pathways.

Basophils

They are involved in allergic reactions and inflammation. Their granules, which stain dark purplish-blue with methylene blue, contain histamine and other chemicals that increase capillary permeability during inflammation

Adhesion molecules

They are on the surface of cells that allow those cells to "grab" other cells.

What do interleukins do?

They are produced by leukocytes and have diverse, often overlapping, functions. As a group, they are important in both innate and adaptive immunity.

What protects the skin and mucous membrane?

They are protected by a variety of antimicrobial substances that inhibit or kill microorganisms. For example, the salty residue that accumulates on skin as perspiration evaporates inhibits all but salt-tolerant microbes

Lymphocytes

They are responsible for adaptive immunity. Cells of the two major groups of lymphocytes, B cells and T cells, are remarkably specific in their recognition of antigen

Opsonins

They are secreted proteins that tag particles for phagocytosis and include the complement component C3b and certain classes of antibody molecules. Phagocytes have specific receptors for opsonins, making it easier for the cells to attach to and subsequently engulf the material.

Mast cells

They are similar in appearance and function to basophils but are not found in tissues rather than blood. They do not come from the same precursor cells as basophils. These are important in the inflammatory response and are responsible for many allergic reactions

Eosinophils

They are thought to be primarily important in riding the body of parasitic worms. They are involved in allergic reactions, causing some of the symptoms associated with allergies, but reducing others. The granules, which stain red with the acidic dye eosin, contain antimicrobial substances wand also histaminase, an enzyme that breaks down histamine

Surface receptors

They can be viewed as the "eyes" and "ears" of a cell. They are proteins that generally span the plasma membrane, connecting the outside of the cell with the inside, allowing the inner workings of the cell to sense and respond to external signals. Each receptor is specific with respect to the compound or compounds it will bind. Cells can alter the types and numbers of surface molecules they make, allowing them to respond to signals relevant to their immediate situation.

Cytokines

They can be viewed as the "voices" of a cell. They act at extremely low concentrations, having local, regional, or systemic effects. They often act together or in sequence, in a complex fashion.

Macrophages

They can be viewed as the scavengers and sentries-routinely phagocytizing dead cells and debris, but ready to destroy invaders and call in reinforcements when needed. They are always present in tissues, where they either slowly wander or remain stationary. Plan an essential role in every major tissue in the body. Maintain killing power by continually regenerating their lysosomes. Various TLRs on their surfaces and in phagosomes help them sense microbial invaders. When receptors are triggered, the macrophage responds by producing cytokines that alert and stimulate various other cells of the immune system.

Granulocytes

They contain granules filled with biologically active chemicals. There are three types: neutrophils, basophils, and eosinophils; their names reflect the staining properties of their granules

Where can you find B cells and T cells

They generally reside in lymph nodes and other lymphatic tissues

What effect do MACs have on gram-positive and gram-negative bacteria?

They have little effect on gram-positive bacteria because the peptidoglycan layer of these cells prevents the complement system components from reaching their cytoplasmic membranes. The outer membranes of gram-negative bacteria, however, make them susceptible

Mononuclear phagocytes

They make up the mononuclear phagocyte system (MPS). This grouping includes monocytes and cell types that develop from them as they leave the blood stream and migrate into tissues

How do neutrophils help the body?

They play a critical role during the early stages of inflammation, being the first cell type recruited to the site of damage from the bloodstream. They have more killing power than macrophages. Have short lifespan - 1-2 days.

How can the complement system be activated?

They routinely circulate in an inactive form, but in response to certain signals indicating the presence of microbial invaders, a cascade of reactions occurs. This results in the rapid activation of the system. The activated forms of the system have specialized functions that cooperated with other host defenses to quickly remove and destroy the invader. Can be activated by three different pathways that converge when a complex called C3 convertase is formed. C3 convertase then splits C3, leading to additional steps of the activation cascade

How do phagocytic cells bind invading microbes?

They use various receptors either directly or indirectly. For example, direct binding occurs when a phagocyte's receptors bind mannose, a sugar found on some bacteria and yeasts. Indirect binding happens when a particle has first been opsonized.

Antigens

This is the substance that causes an immune response

When do NOD-like receptors form inflammasomes?

When NLRs detect PAMPs or DAMPs, they unleash a series of events that lead to outcomes that protect the host, sometimes at the expense of the cell itself. In macrophages, some NRLs can join with other proteins in the cytoplasm to form this. This complex then activates a potent pro-inflammatory cytokine, thereby initiating an inflammatory response

How do microbes trigger the inflammatory process?

When TLRs on sentinel cells such as macrophages detect PAMPs, the cells produce inflammatory mediators. One of these, TNF, induces the liver to synthesize acute-phase proteins, a group of proteins that facilitate phagocytosis and complement activation. When NLRs within cells detect PAMPs, additional inflammatory mediators are released. Meanwhile, microbial surfaces trigger complement activation, also leading to an inflammatory response

What do toll-like receptors do?

When a TLR detects a compound, a signal is transmitted to the cell's nucleus, causing certain genes to be expressed. The actual response is dictated by the cell type and the array of TLRs triggered, so it can be tailored to the situation and category of pathogen. For example, when macrophages "see" bacterial products, they begin producing pro-inflammatory cytokines, leading to an inflammatory response. If a TLR detects viral nucleic acid, the cell synthesizes products that promote and antiviral response

When do cells secrete interferons? What do interferons do?

When a cell's RLRs detect viral RNA, the cell responds by synthesizing and secreting interferons. These proteins then attach to specific receptors on both the infected cell and neighboring cells, causing the cells to express what can be viewed as inactive "suicide enzymes" (protein kinase R, RNase L, and others). Thus, when cells bind interferon, only the infected ones are sacrificed. Their uninfected counterparts remain functional but are prepared to undergo apoptosis should they become infected.

Inflammatory response

When invading microorganisms or tissue damage is detected, this response occurs, involving many components of the innate defenses. During this response, cells that line local blood vessels undergo changes that allow complement system components and other proteins to leak out into tissues. Phagocytes also leave the bloodstream and accumulate in the tissues

What do adhesion molecules do?

When phagocytic cells in the blood are needed in tissues, the endothelial cells that line the blood vessels synthesize adhesion molecules that bind to passing phagocytic cells. This slows the rapidly moving phagocytes, allowing them to then leave the bloodstream. Other types are used by cells to form connections so that one cell can deliver cytokines or other molecules directly to another cell.

Inflammation

When tissues have been damaged, such as when an object penetrates the skin or microbes are introduced, this occurs. The purpose of this is to contain a site of damage, localize the response, eliminate the invader, ad restore tissue function. Four cardinal signs are swelling, redness, heat and pain; loss of function is sometimes present

Leukocytes

White blood cells. They are important in all host defenses. They can be divided into four broad groups: granulocytes, mononuclear phagocytes, dendritic cells, and lymphocytes

Inflammatory mediators

A collective term for various pro-inflammatory cytokines and chemicals such as histamine and bradykinin

How does the cell rid itself of remains after digestion?

Following digestion, the vesicle fuses with the plasma membrane, expelling the remains. In the case of macrophages, some of the ingested material is also put on the cell's surface as a way of displaying bits of invaders to certain cells of the adaptive immune system

C3 convertase

Forms when three different pathways of complement system converge

Giant cells

If activated macrophages fail to destroy microbes, the phagocytes can fuse together to become these cells

Innate immunity

If microbes get past skin and mucous membrane barriers, sensor systems in the tissues detect them and then direct and assist other defenses that destroy the invaders. This immunity is the routine protection provided by these mechanisms

Phagocytosis

It involves a series of steps. These are particularly important mechanically, because most pathogens have evolved the ability to evade one or more of them.

How is the lectin pathway triggered?

It involves pattern recognition molecules called mannose-binding lectins (MBLs). These bind to certain arrangements of multiple mannose molecules that characterize microbial cells. Once an MBL attaches to a surface, it can interact with other complement system components to form a C3 convertase

Adaptive immunity

It is a more specialized defense system. This develops throughout the life and substantially increases the host's ability to defend itself. Each time the body is exposed to a microbe, or certain other types of foreign material, the adaptive defense system first "learns" and then "remembers" the most effective response to that specific material; it then reacts accordingly if the material is encountered again.

What is the complement system?

It is a series of proteins that circulate in the blood and fluid that bathes the tissues. Their name is derived from the observation that they "complement" the function of antibodies.

Normal microbiota

It is the population of microorganisms that routinely grow on the body surfaces of healthy humans. Although they are not technically part of the immune system, they provide considerable protection.

What happens when C3b molecules bind to bacterial cells or foreign particles?

The C3b concentration increases substantially when complement system is activated, and these molecules bind to bacterial cells or other foreign particles. This has two effects: 1) continued complement activation via the alternative pathway, 2) opsonization. Material that has been opsonized (meaning "prepared for eating") it is easier for phagocytes to bind to and engulf because phagocytes have receptors that attach specifically to the opsonins (in this case, C3b)

Host cells or "self" cells

The adaptive immune response can also destroy the body's own cells-referred to as these cells-if they harbor a virus or other invador

First line defenses

The barriers that separate and shield the interior of the body from the surrounding environment; they are the initial obstacles microbes must overcome to invade the tissues. The anatomical barriers, skin and mucous membranes, not only provide physical separation but are often bathed in secretions that have antimicrobial properties.

What happens in the inflammatory response?

The complement component C5a is a potent chemoattractant, drawing phagocytes to the area where the complement system has been activated. In addition, C3a and C5a induce changes in the endothelial cells that line the blood vessels, contributing to the vascular permeability associated with inflammation. They also cause mast cells to release various pro-inflammatory cytokines

Pattern recognition

The components of innate immunity detect molecules associated with invading microbes or tissue damage. The molecules recognized include parts of bacterial cell walls and other compounds unique to microbes, as well as substances associated with damaged host cells

Peristalsis

The contractions of the intestinal tract-it propels food and liquid and also helps remove microbes

Lysozymes

The enzyme that degrades peptidoglycan; it is in tears, saliva, and mucus. It is also found within the body, in phagocytic cells, blood, and the fluid that bathes the tissues

Hematopoiesis

The formation and development of blood cells

What do NOD-like receptors do?

They are cytoplasmic proteins that detect bacterial components, allowing the cell to recognize when its own borders have been breached; some also detect signs of cell damage. At least 23 NLRs have been described, but details about their roles are still being uncovered. Mutations in the genes encoding NLRs seem to be a predisposing factor in certain inflammatory diseases such as Crohn's disease

RIG-like receptors

They are cytoplasmic proteins that detect viral RNA. As with pattern recognition by NLRs, this provides a mechanism for an infected cell to detect the invader. RLRs can distinguish viral RNA from normal cellular RNA because at least two characteristics differ. First, viral RNA often has three phosphates at the 5' end (cellular RNA has phosphates removed at 5' end); second, viral RNA is often double stranded. Cellular RNA is typically not double-stranded because only one DNA strand in a gene is used as a template for mRNA synthesis

Phagolysosome

The phagosome fused with enzyme-filled lysosomes

Mucociliary escalator

The respiratory tract is lined with ciliated cells; the hair-like cilia constantly beat in an upward motion, moving materials away from the lungs to the throat where they can be swallowed

What are the bodies borders?

These borders separate the interior of the body from the surrounding environment; they are the initial obstacles microorganisms must overcome to invade tissues. They include: mouth, eye, skin, anus, respiratory tract, digestive tract, urogenital tract

What do pro-inflammatory cytokines do?

These certain cytokines (TNF, IL-1, IL-6, and others) contribute to inflammation

Perioxidase enzymes

These enzymes break down hydrogen peroxide to produce reactive oxygen species; they are in saliva and milk; they are also found within body tissues and inside phagocytes. Catalase-negative organisms are more readily killed by peroxidase because it can't break down the hydrogen peroxide before it is reached by peroxidase

Dendritic cells

They also develop from monocytes. They are sentinel cells that function as "scouts." They engulf material in the tissues and then bring it to the cells of the adaptive immune system for "inspection." Most develop from monocytes, but some descend from other cell types.

Where are toll-like receptors found?

They are anchored in membranes of sentinel cells such as macrophages, dendritic cells, and cells that line sterile body sites. At least TLRs have been described in humans and each recognizes a distinct compound or group of compounds associated with microbes. Some are anchored in plasma membranes, allowing cells to "see" PAMPs in the extracellular environment. Others are phagosomal or endosomal membranes, facing the lumen of the organelle. These let macrophages and dendritic cells characterize the material they ingested.

Phagocytes

They are cells that specialize in engulfing and digesting microbes and cell debris. Some of these play a dual role, destroying invaders while communicating with cells of the adaptive immune system, enlisting their far more powerful effects

What do interferons do?

They are important in the control of viral infections. In addition to being antiviral, IFN-gamma helps regulate the function of cells involved in the inflammatory response and adjusts certain actions of adaptive immunity