Microbiology Chapter 16

Complement Proteins

- C1-C9, inactive until they are split into fragments, which are labeled a and b - C3b causes opsonization - C3a + C5a cause inflammation - C5b + C6 + C7 +C8 + C9 cause cell lysis

Microbial evasion of phagocytosis

- Inhibit adherence: M protein, capsules, found on Streptococcus pyogenes and S. pneumoniae - Kill phagocytes: Leukocidins, found on Staphylococcus aureus - Lyse phagocytes: Membrane attack complex, found on Listeria monocytogenes - Escape phagosome: Shigella and Rickettsia - Prevent phagosome-lysosome fusion: HIV, Mycobacterium tuberculosis - Survive in phagolysosome: Coxilla burnettii

The Complement System

- a defensive system consisting of over 30 proteins produced by the liver and found circulating in blood serum and within tissues throughout the body - not adaptable and does not change over the course of a person's lifetime - part of innate immune system, but can be recruited and brought into action by the adaptive immune system - proteins destroy microbes by cytolysis, inflammation, and phagocytosis, and prevent excessive damage to host tissues - proteins act in a cascade, so more product is formed with each succeeding reaction so that the effect is amplified many times as the reaction continue

inflammation

- a local defensive response triggered by damage to the body's tissues - activation of acute-phase proteins (complement, cytokine, and kinins) - component of the second line of defense - characterized by 4 signs: redness, pain, heat, and swelling

second line of defense

- a microbe's penetration of the first line of defense encourages production of phagocytes, inflammation, fever, and antimicrobial substances - phagocytes - natural killer (NK) cells - inflammation - fever - complement system - interferons - iron-binding proteins - antimicrobial peptides (AMPs)

fever

- abnormally high body temperature - 3rd component of second line of defense - most frequent cause is infection from bacteria (and their toxins) or viruses - hypothalamus controls body temp, normally set at 37°, induces fever

adaptive immunity

- based on a specific response to a specific microbe once a microbe has breached the innate immunity defenses - adapts or adjusts to handle a particular microbe - slower to respond than innate immunity - has a memory component

monocytes

- become phagocytic when they mature into macrophages - fixed macrophages are found in lungs, liver, and bronchi - wandering macrophages roam tissues

Bacterial Evasion of Complement

- capsules prevent C activation - surface lipid-carbohydrate complexes prevent formation of membrane attack complex (MAC) - enzymatic digestion of C5a

kinins

- cause vasodilation and increased permeability of blood vessels - present in blood plasma - once activated, play a role in chemotaxis by attracting phagocytic granulocytes, chiefly neutrophils, to the injured area

antimicrobial peptides (AMPs)

- component of innate immunity - short peptides that consist of a cain of about 12 to 50 amino acids synthesized on ribosomes - have a broad spectrum of antimicrobial activity against bacteria, viruses, fungi, and eukaryotic parasities - synthesis is triggered by protein and sugar molecules on the surface of microbes - cells produce AMPs when chemicals in microbes attach to Toll-like receptors - have shown synergy with other antimicrobial agents, so thtat the effect of them working together is greater than either of them working separately - microbes don't appear to develop resistance even though the microbes are exposed to them for long periods of time

dendritic cells

- derived from monocytes - involved in phagocytosis and initiation of adaptive immune responses

AMPs produced by humans

- dermcidin: produced by sweat glands - defensins and cathelicidins: produced by neutrophils, macrophages, and epithelium - thrombocidin: produced by platelets

vasodilation

- dilation of blood vessels, increases blood flow to the damaged area - responsible for the redness and heat associated with inflammation

antiviral proteins (AVP)

- enzymes that disrupt various stages of viral multiplication - oligoadenylate synthetase: degrades viral mRNA - protein kinase: inhibits protein synthesis

chemical factors in immunity

- fungistatic fatty acid in sebum - low pH (3-5) of skin - lysozyme in perspiration, tears, saliva, and urine - low pH (1.2-3.0) of gastric juice - low pH (3-5) of vaginal secretions

chemicals released by damaged cells

- histamine - kinins - prostaglandins - leukotrienes

concept of immunity

- host toll-like receptors (TLRs) attach to pathogen-associated molecular patterns (PAMPs) - TLR induce cytokines that regulate the intensity and duration of immune responses

advantages of fever

- increases transferrins - increases IL-1 activity - produces interferon

phagocytosis

- ingestion of microbes or particles by a cell - performed by neutrophils, fixed macrophages, wandering macrophages

modes of action of AMPs

- inhibiting cell wall synthesis - forming pores in the plasma membrane, resulting in lysis - destroying DNA and RNA - can sequester the LPS (endotoxin) shed from gram-negative bacteria - attract dendritic cells, which destroy microbes by phagocytosis and initiate an adaptive immune response - have been shown to recruit mast cells, bringing about inflammation, which destroys microbes, limits the extent of damage, and initiates tissue repair

lymphocytes

- natural killer (NK) cells - destroy target cells by cytolysis and apoptosis - involved in specific immunity

White Cell (Leukocytes)

- neutrophils - basophils - eosinophils - dendritic cells - monocytes - lymphocytes

commensal microbiota

- one organism (microbe) benefits, and the other (host) is unharmed - may be opportunistic pathogens

Interferons

- one way infected host uses to fight viral infections - a class of similar antiviral proteins produced after viral stimulation - interfere with viral multiplications - host cell-specific but not virus-specific - active against a number of different viruses - produced by fibroblasts in connective tissue and by lymphocytes and other leukocytes - quite stable at low pH and fairly resistant to heat

Effects of Complement Activation

- opsonization, or immune adherence: enhanced phagocytosis - membrane attack complex: cytolysis - attract phagocytes

gamma interferon

- produced by lymphocytes - induces neutrophils and macrophages to kill bacteria - causes macrophages to produce nitric oxide that appears to kill bacteria as well as tumor cells by inhibiting ATP production - increases the expression of class I and class II molecules and increases antigen presentation

alpha and beta interferon

- produced by virus-infected host cells only in very small quantities - diffuse to uninfected neighboring cells - react with plasma or nuclear membrane receptors, inducing the uninfected cells to manufacture mRNA for the synthesis of antiviral proteins

eosinophils

- produces toxic proteins against certain parasite - performs some phagocytosis

siderophores

- proteins secreted by pathogenic bacteria to obtain iron - compete to take away iron from iron-binding proteins by binding it more tightly - once iron-siderophore complex is formed, it's taken up by siderophore receptors on the bacterial surface and brought into the bacterium - iron is them split from siderophore and utilized by bacteria

iron-binding proteins

- proteins that transport and store iron - by transporting and storing free iron, they also deprive most pathogens of the available iron - transferrin: found in blood and tissue fluids - lactoferrin: found in milk, saliva, and mucus - ferritin: located in the liver, spleen, and red bone marrow - hemoglobin: located within RBCs

Function of lacrimal apparatus in 1st line of defense

- provides tears that wash away microbes - tears contain lysozyme, which destroys cell walls, especially of gram-positive bacteria

innate immunity

- refers to defenses that are present at birth - always present and available to provide rapid responses to protect us against disease - does not involve specific recognition of a microbe - does not have a memory response

histamine

- released in direct response to the injury of cells that contain it - released in response to stimulation by certain components of the complement system - can also be released by phagocytic granulocytes attracted to the site of injury - cause vasodilation and increased permeability of blood vessels

physical factors in immunity

- skin - mucous membranes - mucus - cilia - lacrimal apparatus - saliva - urine - vaginal secretions - peristalsis, defecation, vomiting, and diarrhea

leukotrienes

- substances produced by mast cells and basophils - cause increased permeability of blood vessels and help attach phagocytes to pathogens

prostaglandins

- substances released by damaged cells - intensify the effects of histamine and kinins - help phagocytes move through capillary walls

adherence

- the attachment of the phagocyte's plasma membrane to the surface of the microorganism or other foreign material - facilitated by the attachment of pathogen-associated molecular patterns (PAMPs) of microbes to receptors on the surface of phagocytes - binding also induces the phagocyte to release specific cytokines that recruit additional phagocytes

Classical Pathway of Complement Activation

1. C1 is activated by binding to antigen-antibody complexes. 2. Activated C1 splits C2 into C2a and C2b, and C4 into C4a and C4b. 3. C2a and C4b combine and activate C3, splitting it into C3a and C3b. 4. The splitting of C3 into C3a and C3b starts a cascade that results in cytolysis, inflammation, and opsonization.

Alternative Pathway of Complement Activation

1. C3 combines with factors B, D, and P on the surface of a microbe 2. This causes C3 to split into fragments C3a and C3b. 3. Once C3a and C3b are formed, they participate in cytolysis, inflammation, and opsonization per the classical pathway.

Inflammation stimulated by complement

1. C3a and C5a bound to mast cells, basophils, and platelets trigger the release of histamine, which increases blood vessel permeability. 2. C5a functions as a chemotactic factor that attracts phagocytes to the site of complement activation.

The Phases of Phagocytosis

1. Chemotaxis and adherence of phagocyte to microbe 2. Ingestion of microbe by phagocyte 3. Formation of phagosome (phagocytic vesicle) 4. Fusion of phagosome with a lysosome to form a phagolysosome 5. Digestion of ingested microbes by enzymes in the phagolysosome 6. Formation of the residual body containing indigestible material 7. Discharge of waste material

Outcomes of Complement Activation

1. Inactivated C3 splits into activated C3a and C3b. 2. C3b binds to microbe, resulting in opsonization. 3. C3b also splits C5 into C5a and C5b. 4. C5b, C6, C7, and C8 bind together sequentially and insert into the microbial plasma membrane, where they function as a receptor to attract a C9 fragment; additional C9 fragments are added to form a channel. Together, C5b through C8 and the multiple C9 fragments form the membrane attack complex, resulting in cytolysis. 5. C3a and C5a cause mast cells to release histamine, resulting in inflammation; C5a also attracts phagocytes.

Lectin Pathway of Complement Activation

1. Lectin binds to an invading cell. 2. Bound lectin splits C2 into C2b and C2a and C4 into C4a and C4b. 3. C2a and C4a combine and activate C3. When mannose-binding lectin (MBL) binds to mannose on the surface of microbes, MBL functions as an opsonin that enhances phagocytosis and activates complement.

functions of inflammation

1. To destroy the injurious agent, if possible, and to remove it and its by-products from the body 2. If destruction is not possible, to limit the effects on the body by confining or walling off the injuries agent and its by-products 3. To repair or replace tissue damaged by the injurious agent or its by-products

antiviral action of alpha and beta interferons (IFNs)

1. Viral RNA from an infecting virus enters the cell 2. The infecting virus replicates into new viruses 3. The infecting virus also induces the host cell to produce interferon mRNA (IFN-mRNA), which is translated into alpha and beta interferons 4. Interferons released by the virus-infected host cell bind to plasma membrane or nuclear membrane receptors on uninfected neighboring host cells, inducing them to synthesize AVPs. 5. New viruses released by the virus-infected host cell infect neighboring host cells 6. AVPs degrade viral mRNA and inhibit protein synthesis- and thus interfere with viral replication.

how fever is induced

1. When phagocytes ingest gem-negative bacteria, endotoxins are released, causing the phagocytes to release the cytokines interleukin-1 and TNF-alpha. 2. Cytokines cause the hypothalamus to release prostaglandins that reset the hypothalamic thermostat at a higher temperature 3. The body responds by constricting blood vessels, increasing the rate of metabolism, and shiver, all of which raise body temperature. 4. When body temperature reaches the setting of the thermostat, the chill disappears. The body will continue to maintain its temperature at 39°C until the cytokines are eliminated. 5. The thermostat is then reset at 37°C and heat-losing mechanisms such as vasodilation and sweating go into operation.

3 principal interferons

1. alpha interferon 2. beta interferon 3. gamma interferon

immunity

ability to ward off disease

Chemical factors of saliva in 1st line of defense

contains lysosome, urea, and uric acid, which inhibit microbes has immunoglobin A, which prevents attachement of microbes to mucous membranes - slightly acidity discourages microbial growth

Chemical factors of urine in 1st line of defense

contains lysozyme slight acidity discourages microbial growth

Function of saliva in 1st line of defense

dilutes and washes microbes from mouth

Function of peristalsis, defecation, vomiting, and diarrhea in 1st line of defense

expel microbes from body

Chemical factors of earwax in 1st line of defense

fatty acids in earwax inhibit the growth of bacteria and fungi

Function of hairs in 1st line of defense

filter and trap microbes and dust in nose

Chemical factors of perspiration in 1st line of defense

flushes microbes from skin and contains lysozymes

Chemical factors of sebum in 1st line of defense

forms a protective acidic film over the skin surface that inhibits microbial growth

Chemical factors of vaginal secretions in 1st line of defense

glycogen breakdown into lactic acid provides slight acidity, which discourages bacterial and fungal growth

Chemical factors of gastric juice in 1st line of defense

high acidity destroys bacteria and most toxins in stomach

Function of mucous membranes in 1st line of defense

inhibit the entrance of many microbes, but not as effectively as intact skin

Function of epidermis of skin in 1st line of defense

intact skin forms a physical barrier to the entrance of microbes shedding helps remove microbes

susceptibility

lack of resistance to a disease

Function of vaginal secretions in 1st line of defense

move microbes out of body

microbial antagonism/competitive exclusion

normal microbiota compete with pathogens or alter the environment

differential white cell count

percentage of each type of white cell in a sample of 100 WBCs

neutrophils

performs phagocytosis

Function of earwax in 1st line of defense

prevents microbes from entering ear

Function of epiglottis in 1st line of defense

prevents microbes from entering lower respiratory tract

basophils

produces histamine

chemotaxis

the chemical attraction of phagocytes to microorganism

Function of cilia in 1st line of defense

together with mucus form a ciliary escalator, which traps and removes microbes from upper respiratory tract

Function of mucus in 1st line of defense

traps microbes in respiratory and gastrointestinal tracts

Function of urine in 1st line of defense

washes microbes from urethra to prevent colonization in genitourinary tract

crisis

when body temperature falls after a fever as a result of vasodilation and sweating