BIO 580 - Medical Microbiology - Introduction - The ...
The Dynamic Nature of Infectious DiseaseLecture 1 Objectives:Understand that infectious disease is dynamic; diseases emerge and disappear, and perhaps re-emerge over time. The major diseases of our past may not be the major diseases of today. New diseases will continue to emerge in the future. Understand the major factors that influence why a new disease emerges, especially factors that can be influenced by human activity.Overview of human history with infectious disease:YearEventHomework – ID microbial agent of disease as virus (V), bacterium (B), protozoa (P), Fungi (F)1876Koch proves that a specific microbe (Bacillus anthracis) causes a specific disease (Anthrax)1885Pasteur treats a boy post-exposure, with attenuated rabies1918-19Pandemic of Influenza A H1N1 (Spanish Flu) kills 500,000 Americans, 50 million worldwide1928Penicillium discovered to kill Staphylococcus1944Penicillin introduced into general clinical practice1952Staphylococcal strains demonstrate resistance to penicillin1962Machupo emerges in Bolivia1967Marburg terrorizes Germany1969Emergence of Lassa in Nigeria1975Global vaccination campaign eradicates smallpox 1976Emergence of Ebola in Zaire Emergence of Lyme disease (Borrelia bergdorferi)182 American Legionnaires get sick in Philadelphia, 29 die (Legionella pneumophilia)Emergence of penicillin resistant Neisseria gonorrhoea1977Gonorrhea triple antibiotic resistantJune 1981CDC’s Morbidity and Mortality Weekly Report describes a curious new health problem in American homosexuals19831,000th official AIDS case documented1984Causative agent of AIDS identified - HIV1990Jim Henson is killed by a new stain of Streptococcus1991Drug resistant tuberculosis surfaces in the US19934 children die of E. coli hemorrhagic syndromeSin Nombre emerges in the Four Corners area1996Recognition of BSE and nvCJDVancomycin-resistant S. aureus reported in Japan1997Vancomycin-resistant S. aureus reaches Michigan“Bird flu”(Influenza A H5N1) in Hong Kong 1999West Nile seen in U.S. for first time2002West Nile reaches west coast2003SARS-CoV emerges2009Influenza A (H1N1) – first Influenza pandemic in 40 yrsPreparation for next class meeting:Write the take home message from today in a single sentence in the space below:Read in the text – Introduction and Chapters 1, 2, and 3 (We will discuss the info in order Ch. 1, 3, 2).Terminology – Find definitions for these terms. You may use one of the on-line medical dictionaries on our course web site in Lecture 1Infectious disease - any change from a state of health in which part or all of the host body is not capable of carrying on its normal functions due to the presence of a parasite or its products.Parasite - Attenuated – Pandemic – Eradicate - Unit One - The AdversariesUnit One - Outline of TopicsReview of Microbes (viruses, bacteria, fungi, protozoa, helminths, arthropods, normal microbiota)Host DefensesNonspecific DefensesDefenses against entryPhysicalChemicalBiologicalDefenses of the interiorComplement cascadeAcute phase proteinsInterferonsPhagocytic cellspolymorphonuclear leukocytesmonomorphonuclear leukocytesNonspecific cytolytic cellsSpecific Defenses1.T lymphocytesRecognition of specific antigen (TCR and MHC)Activation against a specific antigen (role of APC and TH)Response to specific antigenT helpersT cytotoxicT regs2.B lymphocytesRecognition of specific antigen (BCR)Activation against a specific antigen (role of APC and TH)Response to a specific antigeni.Plasma cells3. Memory cells (primary vs secondary response)Unit One - Background Terminology/Concepts – will not be covered in lectureObligatory Steps For Infectious Microbes:PhenomenonStepHow1. Entryattach and enter into bodyevade host's natural protective and cleansing mechanisms2. Spreadlocal or general spread in bodyevade natural barriers and immediate local defenses3. Multiplicationmultiplybut many offspring will die in host 4. Evasionevade host defensesevade phagocytic and immune defenses long enough for full cycle in host to be completed5. Transmissionexit from bodyleave body at a site and on a scale that ensures spread to fresh host6. Pathologycause damage in hostnot strictly necessary but often occursPathogen - agent capable of causing diseasePathogenicity – ability to cause diseaseFrank pathogen= obligate pathogen– causes disease in a healthy host by direct interactionOpportunistic pathogen- may cause disease under the right conditionsVirulence – degree or intensity of pathogenicity.Dependent on:Invasiveness – ability of organism to spreadInfectivity – ability of organism to leave point of entryPathogenic potential – degree pathogen causes damageVirulence factors – individual characteristics of a specific strain of microbe that confer virulenceColonization (esp. by bacteria/yeast) – establishment of a site of replication – dependent on attachmentSymbiosis - an association of two different species of mensalism - one species uses the body of another species as a habitat and possibly as a source of nutrition.Mutualism - a reciprocal relationship between two species.Parasitism - one species in a relationship benefits and the other does not.------Respiration - use electron transport chain with an external e- acceptor (like O2 or NO3) as the terminal e- acceptorFermentation - no external e- acceptor, one of the substrates involved accepts the e-Facultative fermenter – will respire in the presence of external electron acceptors and ferment in their absence (Ex. Escherichia coli)Obligate aerobe - must have O2 because only O2 can serve as the terminal e- acceptor (Ex. Bacillus spp.)Facultative anaerobe - will use O2 for aerobic respiration if it’s present but will switch to fermentation or anaerobic respiration if no O2 (Ex. E. coli)Aerotolerant anaerobe - can't use O2 as an external e- acceptor, but not killed by it.Strict or obligate anaerobe - killed by exposure to O2 (Ex. Bacteroides fragilis)Microaerophilic - grows optimally in presence of oxygen concentrations that are below atmospheric concentrations (ex. the streptococci)UNIT ONE – THE ADVERSARIESI. The MicrobesObjectives:To Review:important structural features of virusessequence of steps during viral infection consequences of viral infections at a cellular levelimportant structural features of bacteriakey differences between Gram positive and Gram negative cell wallsclinical significance of LPS, capsules, flagella, fimbriae, and piliimportant features of eukaryotic pathogens: fungi, protozoa, helminths, arthropodsdistribution and significance of normal microbiota by way of clinical casesA. VIRUSES - Obligate intracellular parasitesCommon structural featureslefttop1. Genetic material - DNA or RNA, ss or ds2. Outer coat - capsid - composed of subunits called capsomersNucleic acid + capsid = nucleocapsidOnly nucleocapsid = nakedNucleocapsid surrounded by a lipid and protein envelope = enveloped lefttop*Outer surfaces (capsids or envelopes) impt cause they 1st make contact w/ host cells.Viral infection of host proceeds through several steps:1. Entry into body of host - 4 routes1) inhalation of droplets - 2) ingestion - 3) direct transfer - 4) bites of arthropod vectors - 2. Adsorption to target cell(s) in host – specific interaction between virus surface 3021330topmolecules and receptors on target cells ***3. Entry into target cell - 3 mechanisms1) Fusion (enveloped)2) Receptor-mediated endocytosis (RME)(naked & enveloped)Entry step ends with release of viral nucleic acid inside host target cell.4. Multiplication w/in the target cell (obligate intracellular) – complex process1) synthesis of viral mRNADNA viruses may use host RNA polymerase -- viral DNA viral mRNARNA viruses have to use viral RNA polymerasesrighttoptranslation of viral proteins in host cytoplasm using host ribosomes – viral mRNA can displace host mRNA replication of viral nucleic acidassembly of nucleic acid & capsomers into new nucleocapsids (= viral progeny)5. Release from host cell (immediate or delayed) – 2 mechanisms1) lysis - 2) budding (acquisition of envelope) – Pathology - effects of viral infection on the targeted celllysis – persistence –latency ( lytic) – transformation – CONCEPT CHECK - VirusesIn the space below, in your own words, describe in complete detail:1) the significance of surface projection – target cell receptor interactions in viral infections2) the two mechanisms by which an enveloped virus may enter into a target host cell B. BACTERIA - prokaryotesCommon structural features1. Genetic material – ds, circular DNA = “chromosome”2. Ribosomes are only organelle – 70S (30S + 50S)3. Cell membrane – site of many metabolic functions (e.g., respiration)4. Cell wall – shape, rigidity, strength; impt in virulence and immunityCompound responsible for strength of cell wall is peptidoglycan (hexose sugars + amino acids) – unique to bacteriaDifferences in cell wall structure - Gram positive vs. Gram negativeGram positivepeptidoglycan layer is thickhighly polar hydrophilic surfaceLipoteichoic acids = LTAresists activity of biledigested by lysozymesynthesis is disrupted by penicillin and cephalosporin antibiotics (more in Unit 4)Gram negativepeptidoglycan layer is thin, overlaid by outer membrane that contains lipopolysaccharide and lipoproteinouter membrane is polar, but lipids are hydrophilicLipopolysaccharide = LPScarbohydrates antigenicitylipid A is toxic = endotoxin induces fever, increases vascular permeability, may result in shock. etc. (more Units 2 & 3)5. Structures exterior to the cell wall in some bacteria (more common in pathogens)a. Capsule – high molecular weight polysaccharides slimy and stickyclinically relevant for 2 reasons1) attach to a wide variety of surfaces *2) more resistant to engulfment by host defense cells **b. Flagella 1) allow bacteria to move2) proteins are strongly antigenic/immune stimulatingc. Fimbriae (aka “common pili”, esp. in the Neisseria)1) attachment (fimbriae adhesins to target cell membranes)2) evading engulfment d. Pili (aka “sex pili”)1) exchange of genetic info, incl. antibiotic resistance (more in Unit 4)Bacterial infection of host proceeds through several steps:Entry into body of host – 3 routes1) direct contact2) ingestion3) fomites (inanimate objects)Adhere to, colonize, (and possibly invade) host tissues or cells (infection may be extracellular or intracellular)Evasion of host defenses (more in Unit 2)Multiplication in the host (extracellular or intracellular)Pathology (more in Units 2 and 3)1) toxins2) host immune responseTransmission to new hosts – usually passive in body fluidsEUKARYOTIC PATHOGENSC. FUNGI1. Morphologycell wall contains chitin; plasma membrane contains ergosterolyeastvsmoldhyphae myceliumDimorphic - 2 forms – yeast and mold2. Reproduction moldvsyeastsporesdivisionbudding3 types of fungal infections = mycoses1) superficial – 2) subcutaneous – 3) systemic or deep - Infections are most serious in immunocompromised.D. PROTOZOAInfection may be extracellular or intracellular2. Evasion of host defenses3. Reproductionasexual in humans, sexual absent or in insect vector.4. Transmissionbites of insectsingestionsexually transmittedE. HELMINTHS – multicellular worms1. Exs. tapeworms, flukes, nematodes2. Have complex life cycles3. Transmissionfecal-oralingestion of larvae in tissuesactive penetration by larvaebites of insectsF. ARTHROPODSExs. mosquitoes, biting flies, fleas, ticks, liceincreases potential for infection with viruses and protozoaNORMAL MICROBIOTA = Indigenous microbiota (= Normal flora)1012 eukaryotic cells in adult human - 1013 prokaryoticClinical significance1. common contaminants of clinical specimens Fig 8.1 and Fig 8.22. opportunistic pathogensIn class mini clinical casesObjectives:understand the multiple lines of defenses against microbial infectionrecognize the signs of acute inflammation when presented in a clinical context and describe how each sign of acute inflammation is generated at a cellular/tissue levelknow why/how the alternate complement cascade is activated, what the important molecules formed are, what their function is, and what the consequences of complement activation areunderstand how complement and phagocytosis are integrated processescompare and contrast PMNs and macrophagesunderstand the importance of direct cell-cell contact in phagocytosis and the relationships between capsules, opsonins, and phagocytosisTerminology:Inflammation - the body’s response to injury or infection, which may be acute or chronic.Acute inflammation - the immediate defensive reactions to any injury. It involves swelling, redness, heat, and pain.Edema - excessive accumulation of fluid in the tissues.Erythema - abnormal flushing of the skin caused by dilation of the blood capillaries.Opsonin - a molecule that attaches to cells, provides a bridge to receptors on phagocytic cells, and enhances the rate of phagocytosiCells of the Immune System(White Blood Cells = WBC = leukocytes)MonocytesMononuclear Macrophages (differentiated monocytes, found in tissues)leukocytes(agranulocytes)PhagocytesNeutrophilsEosinophilsPolymorphonuclearBasophilsleukocytesMast cells (differentiated basophils, found in tissues)(granulocytes)Natural Killer (NK) cellsLarge Granular Lymphocytes (LGL)Killer (K) cellsCytotoxic T cell (TC)LymphocytesHelper T cell (TH)T lymphocytes (T cells)Regulatory T cell (Tregs)Effector B cells/ Plasma cellsB lymphocytes (B cells)Origins of Cells of the Immune System14859000II. HOST DEFENSES The immune system is composed of 2 armsinnate = nonspecific – already in place, response is rapid, not as efficientadaptive = specific – must be induced, response is slower, highly efficient, enhances nonspecific. Has “memory”A. Nonspecific Defenses1. Defenses against entry into the host (1st line defenses)Physical defenses (examples)1. epithelial cells2. turbulence3. shedding, scraping, flushing (saliva, urine)4. muco-ciliary clearance (1-3 cm/hr) Chemical defenses (exs)1. acids (e.g. gastric, fatty acids)2. enzymes (e.g. lysozyme in saliva, tears, perspiration, urine)3. other microbicidal chemicals (e.g. zinc, dermicidin)Biological defenses (exs)1. normal microbiota – physical, competition, inhibitory substances2. immune defense cells and molecules2. Defenses of the interior of the host (2nd line defenses)Inflammation a. phagocytic cells b. cytolytic cells c. acute phase proteinsCRPinterferoncomplementInflammation - a process that coordinates and regulates all aspects of non-specific interior defense.Acute inflammation is characterized by:1. increased blood supply to the area2. increased capillary permeability3. accumulation of neutrophilsSigns of acute inflammation – 4 signs1.2.3.4.Triggers of acute inflammation – 2 triggers1. cell/tissue damage/injury chemical “alarms”2. cell wall components of bacteria (peptidoglycan, LTA, LPS)How Signs of Acute Inflammation are Produced release of Inflammatory Mediators (=IM; see table 9.3)2. vaso-dilation & blood flow 2. endothelial cells of vessels contract 3. plasma leaks out of vessels & into tissues = exudation 4. swelling pressure on nerve endings bradykinin ***Increased blood flow & capillary permeability - a mechanism for white blood cells and critical soluble factors to enter the tissues to combat microbial invaders.The Critical White Blood Cells (WBC = leukocytes)a. Phagocytes – professional engulfing cells2 main roles for phagocytes1. engulf and destroy foreign matter2. secrete chemicals (esp. cytokines)Cytokines: (see table 11.2)small secreted proteins that mediate and regulate inflammation, immunity, and hematopoiesisact over short distances, short duration, and low conc.receptor binding induces signal transduction and transcription and translation2 main kinds of professional phagocytic cells1. polymorphonuclear leukocytes (= PMN = polymorph = neutrophils) – are granulocytes - 2. mononuclear leukocytes - monocytes & macrophages – are agranulocytes -1. polymorphonuclear leukocytedominant cell type in early stages acute inflammatory responsemade in the bone marrow - 80 mil/mindominant WBC, ~5,000/ul of blood - ↑15,000-20,000/ul live for 2-3 days - function in anaerobic environmentsabundant cytoplasmic granules contain loads of antimicrobial enzymes and chemicals, esp. lysozymebest with extracellular pathogens, esp. bacteria2. mononuclear leukocytemajors players later in inflammatory processmade in bone marrowin the blood - monocytes (~600/ul); in tissues - macrophages (~60,000)conc. in lung, liver, lymph nodes, spleenlive for months-yearsfewer granules (acid hydrolases, peroxidase)one of the antigen presenting cellssecrete lots of different proteins (incl. lysozyme, nitric oxide, cytokines, complement factors)best with intracellular pathogensProcess of Phagocytosis – 6 stepsActivation – phagocytes are circulating with the bloodstream, need to move to the site of inflammation.marginationpavementingdiapedesisMigration via chemotaxis – phagocytes have receptors for chemoattractant molecules, will track a concentration gradient of these molecules to the site where they are being produced.3-6. – illustrated in diagramAttachment – phagocytosis cannot happen until the phagocyte makes direct contact with the surface of the microbe. That direct contact is mediated by receptors on the surface of the phagocyte.Pathogen-Associated Molecular PatternsMicrobe - PAMP – PRR – phagocyte Pattern Recognition ReceptorsPAMP incl. LTA & LPS (table 9.2)After PAMP-PRR interaction, macrophages secrete pro-inflammatory cytokines (TNF, IL-1) enhance antigen-presentation leads to activation of Th1. We’ll talk about this later.EngulfmentPhagosome-lysosome fusion and intracellular killingExpulsion of debrisPhagocytosis - DiagramRole of Opsonins in Process of Phagocytosis - Diagram(review definition of opsonin)OpsoninInteractionRate of PhagocytosisMicrobe+phagocytenonepresentPhagocyte Intracellular Killing Mechanisms1. Oxygen-dependent killing (see box 9.2, p. 83) – PMN and macrophages“oxidative burst”Reductionsuperoxide anionO2-O2hydrogen peroxideH2O2 Reactive OxygenNADPHNADPsinglet oxygen1O2 Intermediates (ROI)hydroxyl radicalsOHphagosome membraneOther reactive intermediatesreactive nitrogen (nitric oxide = NO) (macrophages)reactive chlorine (OCl) + myeloperoxidase (PMN)2. Oxygen-independent killing compounds contained in cytoplasmic granules (see Table 14.2, p. 153)acid hydrolases (PMN)cathepsin G (PMN)cationic proteins (PMN, eosinophils)defensins (PMN)lactoferrin (PMN) - lysozyme (PMN, macrophage) – peroxidase (eosinophils)b. Cytolytic Cells1. natural killer cells (NK)(LGL)target - intracellular pathogens, primarily virusesattach – by way of receptors to glycoproteins on infected cellsrelease - perforins (membrane channels) granzyme (apoptosis)also secrete TNFalso – secrete ?-IFN, impt early source, can activate macrophages13779501035052. basophils and mast cellstarget – parasitescan be triggered to discharge cytoplasmic granulesrelease histamine, heparin, anaphylactic factors3. eosinophils target - large parasites (e.g. helminthes)can be triggered to discharge cytoplasmic granulesrelease basic proteins, perforins, ROI chemical burnsc. The Critical Soluble FactorsAcute Phase ProteinsPlasma proteins – proteins that increase in concentration 2-100X during the acute phase of an infection, in response to cytokines (IL-1, TNF).i.. C-reactive protein (CRP) – produced by liver - uses pattern recognition to bind to bacteriaacts as an opsoninactivates complement cascadeoften used to monitor inflammationii. InterferonsInterferons – first recognized because they interfere w/ viral replication3 classes of Interferons:1. ? - produced by leukocytes (WBC) – anti-viral - prod w/in 24h2. ? - produced by fibroblasts and other cells – anti-viral - prod w/in 24 h3. ? - produced by NK and esp. T lymphocytes – anti-viral and involved in cell-cell communication.iii. Complement - activation of the alternate cascade (= properdin pathway) - A group of 20 serum proteins – form an enzymatic cascadeC3 (most abundant, prod. by liver cells)C3aC3bFactor BC3bBFactor DC3bBb = C3 convertase---------------------------------------------------------------------------------------------------------------------C3C3C3aC3b C3aC3bC5 (prod by macrophages)C5aC5bC5b678 multiple C9cell lysisOpsoninInteractionRate of PhagocytosisMicrobe+phagocytenoneC3bCRPIntegration of Nonspecific DefensesStimuluscell/tissue injuryinflammatory mediators releasedmicrobial surface polysaccharidesWithin seconds to minutesacute inflammation beginsvaso-dilation of capillaries increases blood flow to/volume at the siteincreased vascular permeability exudation of plasma, cells, and proteinsacute phase proteins increase in concentrationalternate complement cascade is activatedC3a and C5a mast cell degranulation maintains vaso-dilation/vascular permeabilityC5a attracts phagocytes from vasculatureC3b and C5b bind to cell surfacesC3b opsoninMinutes to hoursPMNs arrive in huge number and encounter cells opsonized by C3b and CRP phagocytosis is enhanced.Hours to daysInterferons are producedNK arriveMacrophages arriveSUMMARIZE – Nonspecific DefensesList the Nonspecific Interior Defenses important against Bacteria List the Nonspecific Interior Defenses important against VirusesCONCEPT CHECK – Nonspecific defensesBubble MapCharacteristics unique to PMNShared characteristicsCharacteristics unique to macrophagesMacrophagePMNCONCEPT CHECK – Nonspecific defensesDraw a concept map that illustrates the integration of complement and phagocytosisCONCEPT CHECK - Nonspecific Host DefensesSteve, a college student, was backpacking in a remote wilderness region with some friends. While pitching a tent, he tripped and fell. In an attempt to break his fall, he extended his arms and sustained a puncture wound to his right palm. Although the wound was painful and bled for a short time, it didn’t appear to be serious, and Steve fell asleep that night unconcerned.By the next morning, however, Steve noticed that the tissues immediately surrounding his wound were red, swollen, and warm. A round area about 1 inch in diameter really looked abnormal compared to the rest of his hand. The affected area was also painful, especially when he touched it or bumped it. After hiking all day, the sore hand was even more painful, and a thick yellow discharge oozed from the open wound. Steve felt unusually tired, his body ached, and a brief chill made him aware that he was getting a fever. His friends helped him elevate his arm and applied warm compresses to his palm, hoping that he would feel better in the morning.1. List the nonspecific defenses against entry that are relevant to skin.??2. How were Steve’s skins defenses against entry overcome? ??3. List the nonspecific interior defenses that would become activated in this case of bacterial invasion.??4. What are the signs in the case history that Steve is experiencing an inflammatory process? List them.??5. Describe the mechanisms at the cellular/tissue level that cause each of the signs of inflammation listed in 4 above? Supplemental information FYIBlood (modified from Wikipedia)Blood accounts for 8% of the human body weight. The average adult has a blood volume of roughly 5 liters (1.3 gal), composed of plasma and several kinds of cells; these formed elements of the blood are erythrocytes (red blood cells; RBC), leukoytes (white blood cells; WBC), and thrombocytes (platelets). By volume, the red blood cells constitute about 45% of whole blood, the plasma about 54.3%, and white cells about 0.7%.Cells:One microliter of blood contains:4.7 to 6.1 million (male), 4.2 to 5.4 million (female) erythrocytes. The proportion of blood occupied by red blood cells is referred to as the hematocrit, and is normally about 45%.4,000–11,000 leukocytes. White blood cells are part of the immune system; they destroy and remove old or aberrant cells and cellular debris, as well as attack infectious agents and foreign substances. 200,000–500,000 thrombocytes: Platelets are responsible for blood clotting (coagulation). They change fibrinogen into fibrin. This fibrin creates a mesh onto which red blood cells collect and clot, which then stops more blood from leaving the body and also helps to prevent bacteria from entering the body.Plasma:About 55% of whole blood is blood plasma, a fluid that is the blood's liquid medium, which by itself is straw-yellow in color. The blood plasma volume totals of 2.7–3.0 liters (2.8–3.2 quarts) in an average human. It is an aqueous solution containing 92% water, 8% blood plasma proteins, and trace amounts of other materials. Plasma circulates dissolved nutrients, such as glucose, amino acids, and fatty acids (dissolved in the blood or bound to plasma proteins), and removes waste products, such as carbon dioxide, urea, and lactic acid.Other important components include:Serum albuminBlood-clotting factors (to facilitate coagulation)Immunoglobulins (antibodies)lipoprotein particlesVarious other proteinsVarious electrolytes (mainly sodium and chloride)The term serum refers to plasma from which the clotting proteins have been removed. Most of the proteins remaining are albumin and immunoglobulins.Constitution of normal bloodParameterValuehematocrit45 ± 7 (38–52%) for males42 ± 5 (37–47%) for femalespH7.35–7.45base excess?3 to +3PO210–13 kPa (80–100 mm Hg)PCO24.8–5.8 kPa (35–45 mm Hg)HCO321–27 mMoxygen saturationOxygenated: 98–99%Deoxygenated: 75%Saliva (modified from Wikipedia) - Produced in salivary glands, human saliva is 98% water, but it contains many important substances, including electrolytes, mucus, antibacterial compounds and various enzymes It is a fluid containing:WaterElectrolytes: (sodium, potassium, calcium, magnesium, chloride, bicarbonate, phosphate, iodine)Mucus. Mucus in saliva mainly consists of mucopolysaccharides and glycoproteins;Antibacterial compounds (HYPERLINK "" \o "Thiocyanate"thiocyanate, hydrogen peroxide, and secretory IgA)Epidermal growth factor or EGFVarious enzymes. There are three major enzymes found in saliva. α-amylase - starts the digestion of starch and lipase fat. lingual lipaseAntimicrobials that kill bacteria: **LysozymeSalivary lactoperoxidaseLactoferrinProline-rich proteins (function in enamel formation, Ca2+-binding, microbe killing and lubrication) Minor enzymes Cells: Possibly as much as 8 million human and 500 million bacterial cells per mL. The presence of bacterial products (small organic acids, amines, and thiols) causes saliva to sometimes exhibit HYPERLINK "" \o "Halitosis"foul odor.Opiorphin, a newly researched pain-killing substance found in human saliva.Lysozyme, also known as muramidase or N-acetylmuramide glycanhydrolase, are a family of enzymes that damage bacterial cell walls by catalyzing hydrolysis of 1,4-beta-linkages between N-acetylmuramic acid and N-acetyl-D-glucosamine residues in a peptidoglycan and between N-acetyl-D-glucosamine residues in chitodextrins. Lysozyme is abundant in a number of HYPERLINK "" \o "Secretion"secretions, such as tears, saliva, human milk, and mucus. It is also present in cytoplasmic granules of the polymorphonuclear neutrophils (PMN).lefttopUrine is approximately 95% water. The other components of normal urine are the solutes that are dissolved in the water component of the urine. These solutes can be divided into two categories according to their chemical structure (e.g. size and electrical charge).Organic molecules These include:Urea – Makes up 2% of urine. Urea is an organic compound derived from ammonia and produced by the deamination of amino acids. The amount of urea in urine is related to quantity of dietary protein. Creatinine - Creatinine is a normal constituent of blood. It is produced mainly as a result of the breakdown of creatine phosphate in muscle tissue. It is usually produced by the body at a fairly constant rate (which depends on the muscle mass of the body). Uric acid - Due to its insolubility, uric acid has a tendency to crystallize, and is a common part of kidney stones. Other substances/molecules - Example of other substances that may be found in small amounts in normal urine include carbohydrates, enzymes, fatty acids, HYPERLINK ""hormones, pigments, and mucins (a group of large, heavily glycosylated proteins found in the body). Ions These include: Sodium Potassium Chloride Magnesium Calcium AmmoniumSulfatesPhosphates Objectives:1. understand how the appropriate lymphocytes are selected and activated and amplified2. understand how immune cells “talk” with each other via cytokines3. compare and contrast activation and response of T and B lymphocytes 4. compare and contrast the activation and response of Th1, Th2, and TC5. understand the interactions between nonspecific and specific host defenses6. understand how the specific immune response focuses the nonspecific response7. understand the power of the secondary (anamnestic) immune responseB. Specific Defenses = adaptive = acquired3rd line of defense – only one with antigenic memorybased on lymphocytesfeedback into the nonspecific defenses – enhance the effectiveness of the non-specific defensesSpecific immune system has to:recognizeactivaterespond1. Overviewa. Recognition of antigenA specific interaction between an antigen and a receptorAnti genAntigens incl:***proteins (incl. proteins + carbos or lipids) (T and B)***complex polysaccharides (B only)***nucleic acids (B only)Full activation of the specific defenses involves several different types of immune cells working in concert:non-specific cells (antigen-presenting cells)specific cells (lymphocytes)Antigen-Presenting Cell (APC)Specialized cells that present microbial peptides (antigenic determinants) in a way that can be recognized by lymphocyte receptors.Most significant: dendritic cells (tissues) > macrophages > B cellsAntigenic determinant (= epitope) – a certain stretch of peptides from a larger microbial antigenlinear or conformationalsmall in size2 main types of LymphocytesT lymphocytes (T cells)B lymphocytes (B cellsLymphocyte receptors (R)constant region – transmembrane variable region – interacts with microbial peptideGeneral Overview of Antigen Presentation - DiagramPresentation of antigenic determinant by an APC to a lymphocyte occurs in draining lymph nodes (surfaces, tissues) or spleen (blood)Initiates a chain of events that transforms a small, resting, na?ve lymphocyte into a highly active, functional lymphocyte (more later)4352925-314325b. Activation – from all the antigen na?ve lymphocytes, selection of lymphocytes with complementary receptor that matchesspecific microbial antigenic determinant1. receive and secrete cytokines2. undergo proliferation = clonal expansion1104 – 105 - occurs in lymphoid organsResults in an expanded population of immature effector lymphocytes3. differentiate into functional sub-typeseffectors – fight this timememory – reserves, to be deployed in the futurec. Response – of activated effector sub-typesactivated (= primed) effector T lymphocytes either:1. kill infected cells2. coordinate and regulate immune responseactivated effector B lymphocytes (called plasma cells)secrete antibodies2. Add in specificsT Lymphocytes2 categories of T cells by surface marker called Cluster Determinant1. CD4 - 2 functional types1) T helper cells = TH - regulate the immune system by increasing the response ( by activating other immune cells).a) Subset Th1b) Subset Th22) T regulatory cells (=Tregs) - regulate the immune system by the response2. CD8 =T cytotoxic cells =TC = CTL- kill cells infected w/ intracellular pathogensa. Antigen Recognition by Antigen-Na?ve, Resting T lymphocytes*T cell receptor interacts with microbial (foreign) antigenic determinant complexed with a self antigenSelf antigens – Major Histocompatibility Complex (MHC) proteins – protein molecules on the surface of cells that mark them as “cells”.2 classes of MHC Class I - on the surface of all nucleated host cellsClass II – on the surface of APCTHR - recog. antigenic determinant complexed w/ Class II MHC + co-stimulatory interactions (depend on who the APC is)TCR - recog. antigenic determinant complexed w/ Class I MHC + co-stimulatory interactionsb. Activation of T lymphocytes – 3 steps415290074930Receive cytokines from APC ex. IL-1 from macrophage↑ # of IL-2R and secrete/receive IL-2 proliferationResults in an expanded set of immature effector lymphocytes, all with same receptor for antigenic determinant complexed to MHC II (will all recognize the same microbial threat)Differentiation into effector and memory T cellsTc, and NKc. Response of Effector T LymphocytesEach category of effector T cell has a unique response:regulating the immune response = immunoregulationenhance response - THsubset Th1 – secretes IL-2 – stimulates Tc proliferation & maturation. Secretes ?-IFN – activates effector TC , activates macrophages and NK to kill their intracellular pathogens; (down regulates Th2)subset Th2 – secretes IL-4 – stimulates B cell proliferation & differentiation into plasma cells; (down regulates Th1)suppress response - TregsORdirect cell killing = cytotoxicity – TCsecrete perforin transmembrane channelssecrete granzyme apoptosisalso secrete TNFalso secrete ?-IFN (activates NK and macrophages)Integration via Lymphocyte Recognition, Activation, and Response - DiagramB Lymphocytesa. Antigen Recognition by B LymphocytesReceptor interacts with microbial (foreign) antigen alone – receptor does not interact with MHC.Can present antigen to Th2b. Activation of B LymphocytesIL-2 from subset Th2 clonal expansion (= proliferation)IL-4 from subset Th2 differentiation into effector (= plasma) and memory B cellsc. Response of Effector B lymphocytes (=Plasma Cells)Secrete Antibody (Ab) at the rate of 1,000 molecules/min.Antibody Structure - DiagramActions of Antibody Molecules – focus the non-specific1. bind to microbial antigen – interfere with receptor interaction for any microbe that uses specific attachment sites = neutralizing***2linking a bacterium to a phagocyte = opsonization (followed by phagocytosis)OpsoninRate of PhagocytosisMicrobe+phagocytenone-/+C3b+CRP+AbC3b + Ab3. linking many small antigens together = agglutination (followed by phagocytosis)4. complement activation - classical pathway (followed by either opsonization and phagocytosis or lysis) (notes p.45)5. ADCC - antibody dependent cellular cytotoxicity (notes p. 47)2612390118745Activation of Classical Complement Cascade - DiagramC1C2C4C2bC2aC4bC4aC2a4bC3C3C3aC3b C3aC3bC5 C5aC5bC5b678 multiple C9 (MAC)Fill in:Triggers –Important molecules – Consequences - Timing – Complement activation enhances phagocytosis and inflammation and leads to cell lysis.Classes of Antibody MoleculesAntibody = Immunoglobulin (Ig) – proteins found in fluids in the body5 Classes:ClassStructure%LocationRolesIgGmonomer75-80serum, extra vascular spaces, crosses placentafix complementopsoninIgAmonomerdimer15-21serum, tears, saliva, mucus, colostrumneutralizingIgMpentamer6-7serum, 1st made by virgin B cells, 1st made by fetusfix complementagglutinatingIgDmonomer<1low levels in serumB cell surface? regulate clonal expansion?IgEmonomer0.01skinRT fluidbind to mast cells & basophilsFeedback into the non-specific defenses; esp. complement, phagocytosisFunction of Memory Lymphocytes – the reserves - stronger response on secondary exposure to antigenare more memory cells then there were naive cells at the beginning of the primary responsewere primed to antigen during primary response so are able to bind more strongly to APCantigen-primed memory B cells differentiate into plasma cells more quicklymemory is usually long-lasting, yearsPrimary versus Secondary (= anamnestic) ResponseMisc.Killer (K) cellsRely on antigen specific antibodies BUT interact with antibody in a nonspecific way, by way of the Fc. Participate in the non-specific interior defenses:K cells include:NKmacrophageeosinophilAll K cells have receptors for Fc of antibody moleculesK cells bring about lysis of the antibody-coated cell in a process called antibody-dependent cellular cytotoxicity (ADCC); for pathogens that are too big to phagocytize.SUMMARIZE – Specific DefensesFill in tableCytokine or pro-inflammatory mediatorSecreted by:Acts on:Functions to:IL-1IL-2IL-4IFN ?IFN ?IFN ?TNFComplete:TH301828232131function – recognition – activation – response – Th1 - -- Th2 – TCfunction – recognition - activation – response – Tregfunction – recognition - activation – response – B Lymphocyterecognition – activation – response –SUMMARIZE – Specific DefensesList the Specific Interior Defenses important against Bacteria List the Specific Interior Defenses important against VirusesCONCEPT CHECK – Specific defensesConcept MapDraw a concept map that illustrates the connections between the specific and nonspecific immune responsesCONCEPT CHECK – Specific DefensesContinuation of the Case of SteveWhen Steve. awoke on the second morning, his condition was clearly deteriorating. The first thing he noticed was that the small area of redness and swelling had extended to include his entire hand, with the margin of redness now visible just above his wrist. Faint red streaks had appeared along the inner part of his arm and tender lumps were noticeable below his elbow and under his arm. His fever seemed higher than the night before, and he felt too weak to walk.Steve was too sick to travel, and his friends figured that it would take several days to return with medical help. They decided to stay in camp and let Steve rest. Over the next couple of days Steve and his friends were relieved to find him gradually improving. The red area did not advance past his forearm. Although the hand remained painful and swollen, he felt less tired and the fever was gone. Four days after the first presentation of inflammation, when he was a little better, they headed back and took Steve to the nearest emergency room.The doctor diagnosed a presumed bacterial infection and prescribed a broad-spectrum antibiotic that was likely to be effective against the unknown infecting bacterium. The medication was taken orally, and Steve was sent home. The redness and swelling of the hand subsided gradually over the next two weeks.1. What were the tender swellings that Steve noticed behind his elbow and under his arm and why were they swollen? 2. Steve began to improve within 4-5 days of initial infection. How could antibody have played a role in resolving Steve’s symptoms within this time frame?3. What functions did these antibodies play in the immune response to Steve’s bacterial infection? ................
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