Microbiology Chapter 15 Innate Immunity 2018 Pearson Education

Innate Immunity vs. Adaptive Immunity Let’s find Waldo 1. Do we know who Waldo is? ○ He is a person. ○ He wears ……. 2. Can we identify him once we see him? ○ First, we look for patterns (see #1), then we look for specifics! 3. Can we get better at finding him with each puzzle?

Innate Immunity ○ Nonspecific – only detects chemical patterns, often polymers (DNA, peptidoglycan, b-glucan) lipopolysaccharide ○ Quick – rapid detection, rapid response after detection (seconds to minutes) Innate immunity Adaptive Immunity specificity Chemical patterns (seen amino acid or sugar only in pathogens) sequences in polymers speed memory Rapid (sec-min) none Delayed (hrs – days) Successive improvement

An Overview of the Body’s Defenses • Not all microbes are pathogenic • Hosts have resistance to most plant and animal pathogens • Primary resistance is based on species specificity • Most physiological processes in humans are incompatible with those of most pathogens • Host-pathogens interactions are specific due to protein: protein interactions • Correct chemical receptors not present on human cells • Conditions may be incompatible with those needed for pathogen’s survival • Numerous pathogens can cause disease in humans © 2018 Pearson Education, Inc.

The Body’s Three Lines of Defense – SUMMARY SLIDE • First line – external structures • Skin, mucous membranes, eyes, microbiome, fluids of other organ systems • Always on, low-level protection – 99. 9% protection • Second line – cells of innate immune system • Macrophages, neutrophils, innate lymphoid cells • On with pathogen contact; low-level protection • 100% of remaining 0. 1% protection • Third line – cells of the adaptive immune system • Dendritic cells, other lymphoid cells, other granulocytes • On with specific sequence detection; high-level protection – ~ 50% of remaining 0. 1% protection © 2018 Pearson Education, Inc.

The Body’s First Line of Defense KNOW THESE • Innate immune system components found in all animals and plants, and most other unicellulars • Adaptive immunity (oligopeptide-specific or oligosaccharide-specific; next chapter) only found in vertebrate animals • Structures, chemicals, and processes that work to prevent pathogens from entering the body © 2018 Pearson Education, Inc. • • Skin Eyes Microbiome – microbial antagonism Mucous membranes and organ-based fluids • Respiratory • Digestive • Urinary • Reproductive systems

Skin - The Body’s First Line of Defense • Physical defenses • Skin composed of two major layers • Epidermis • Multiple layers of tightly packed dead and alive cells • Few pathogens can penetrate these layers • New dead cells constantly produced from living cells, pushing older cells further away • Shedding of dead skin cells removes microorganisms embedded in skin • Epidermal dendritic cells and macrophages phagocytize pathogens • Dermis • Collagen fibers help skin resist abrasions that could introduce microorganisms • Also contains dendritic cells and macrophages © 2018 Pearson Education, Inc.

Figure 15. 1 A scanning electron micrograph of the surface of human skin. ©

Skin - The Body’s First Line of Defense • (Bio)chemical defenses • Skin has chemicals that defend against pathogens • Perspiration secreted by sweat glands • Salt inhibits growth of pathogens • Antimicrobial peptides act against microorganisms • Lysozyme destroys cell wall of bacteria • Ig. A binds known pathogens before they infect • Sebum secreted by sebaceous (oil) glands • Helps keep skin pliable and less likely to break or tear • Lowers skin p. H to a level inhibitory to many pathogenic bacteria (p. H of 5 -6) © 2018 Pearson Education, Inc.

Mucous Membranes - The Body’s First Line of Defense • Physical defenses • Mucous membranes line all body cavities open to environment • Two distinct layers • Epithelium • Thin outer covering, all living cells • Single layer (columnar) or few layers (cuboidal, pseudostratified) • Tightly packed to prevent entry of many pathogens • Thick fluid layer (mucus) lies on top • Continual shedding of cells carries away microorganisms • Dendritic cells below epithelium phagocytize pathogens • Ciliated cells help remove invaders – fan mucus along • Deeper connective layer that supports the epithelium • Goblet cells produce chemicals that defend against pathogens • Same as skin, but no sebum © 2018 Pearson Education, Inc.

Figure 15. 2 The structure of the respiratory system, which is lined with a

Table 15. 1 The First Line of Defense: A Comparison of the Skin and

The Eyes - The Body’s First Line of Defense • The Role of the Lacrimal Apparatus in Innate Immunity • Lacrimal apparatus • • Resembles skin in terms of secretions - tears Produces and drains tears Blinking spreads tears and washes surface of the eye Lysozyme, salt, antimicrobial peptides, sebum in tears inhibits bacteria • Constitutive tear production helps keep eyes moist and allows eyelids to move without friction • Acute tear production used to flush out acute invaders (dust, spit, gnats, etc. ) © 2018 Pearson Education, Inc.

FIGURE 15. 3 THE LACRIMAL APPARATUS-OVERVIEW Why do you sniffle when you cry? )

Resident flora - The Body’s First Line of Defense • Microbial antagonism • Microbiome (resident microbiota) competes with everyone else, including potential pathogens • Members of the microbiome make it hard for pathogens to establish themselves • Consumption of nutrients • Create an environment unfavorable to other microorganisms • Prevent pathogens from attaching to host cells • Their continual “detection” by the immune system helps stimulate the body’s second line of defense • Generate antimicrobial compounds - antibiotics • Some promote overall health by providing vitamins to host © 2018 Pearson Education, Inc.

Secretions and Activities of Other Organ Systems That Contribute to the First Line of

The Body’s Second Line of Defense – SUMMARY SLIDE • If pathogens get past the physical and chemical barriers, the 2 nd line of the innate immune system comes into play • Operates when pathogens penetrate the skin or mucous membranes • Composed of cells, antimicrobial chemicals, and cellular processes • Many of these components are contained in or originate in the blood © 2018 Pearson Education, Inc.

The Body’s Second Line of Defense blood plasma formed elements (blood cells) clotting factors serum • Defense Components of Blood • Plasma • Mostly water with electrolytes, dissolved gases, nutrients, and proteins (clotting factors, others) • Serum is the fluid remaining when clotting factors are removed • Contains iron-binding compounds (ferritin most common) • Iron needed for metabolism • Some microbes produce proteins that bind iron • Complement proteins and antibodies are also found in plasma © 2018 Pearson Education, Inc.

Blood cells - The Body’s Second Line of Defense – SUMMARY SLIDE • Defensive blood cells: Leukocytes • Cells and cell fragments in plasma called formed elements • Three types of formed elements • Erythrocytes – red blood cells • Carry oxygen and carbon dioxide in the blood • Platelets • Fragments of a megakaryocyte • Involved in blood clotting • Analogous to stuff caught in strainers • the strainer ~ clotting factors • Leukocytes • Involved in defending the body against invaders • Divided into granulocytes and agranulocytes © 2018 Pearson Education, Inc.

Hematopoiesis – how the body forms its blood cells (via megakaryocyte) “managers” immune “effector”

Granulocytes - The Body’s Second Line of Defense • Granulocytes • Contain large granules that stain different colors • Granules contains inflammatory chemicals and toxic enzymes – “carpet bombing” and “flares” • Phagocytic cells – engulf pathogens (especially when “tagged” by immune system) and release granule contents • Capable of diapedesis • squeeze through capillary walls to enter tissues • “leave the highway and enter any neighborhood” • Eosinophils—attack large pathogens (helminths, organ transplants) • Neutrophils—attack any foreign pathogen • Non-phagocytic cells – only release granule contents • Basophils— attack blood-borne pathogens © 2018 Pearson Education, Inc.

Figure 15. 5 a Leukocytes as seen in stained blood smears. stain blue with basic dye methylene blue Fairly rare – only stays in blood stain red/orange with acidic dye eosin Reasonable frequency stain lilac with mix of acidic and basic dyes VERY common, short-lived – “kamikaze” © 2018 Pearson Education, Inc.

Agranulocytes - The Body’s Second Line of Defense • Agranulocytes • Cytoplasm appears uniform under a light microscope • Two types • Lymphocytes • Adaptive lymphocytes – to be discussed in Chapter 16 • T cells, B cells, NKT cells • Innate lymphoid cells recognize non-self or “compromised-self” cells • • Natural killer cells have cytocidal activities Monocytes • Circulate in the blood, looking for inflammatory signals • Leave the blood (by what process? ) and mature into phagocytes • phagocytes - devour foreign objects – “Pac-man” • Macrophages – engulf and destroy engulfed pathogens • Dendritic cells – macrophages interfacing with adaptive immune cells © 2018 Pearson Education, Inc.

Figure 15. 5 b Leukocytes as seen in stained blood smears. common – lots

Measuring The Body’s Second Line of Defense • Lab analysis of leukocytes • Differential white blood cell count (in blood) can signal disease • Increased eosinophils indicate allergies or parasitic worm infection • Eosinophils looking for antigens that seem to be everywhere or on a really large object • Bacterial diseases often show increase in leukocytes and neutrophils • Looking for pathogens to carpetbomb or swallow • Viral infections show increase in lymphocytes • Extracellular pathogens too small, pathogens appear in cells © 2018 Pearson Education, Inc.

Effector functions - The Body’s Second Line of Defense – SUMMARY SLIDE • How do immune cells eliminate pathogens? • Phagocytic killing • Swallow and digest them – phagocytosis • Can be swallowed alive or swallowed when destroyed • Non-phagocytic killing • Carpet bomb them - degranulation • Cell-to-cell killing – cytotoxic activity • Suicide bombing – neutrophil’s final surge © 2018 Pearson Education, Inc.

Phagocytes - The Body’s Second Line of Defense • Phagocytosis – swallowing of pathogens • Cells capable of phagocytosis are called phagocytes • Phagocytosis is not completely understood • Can be divided into six stages • Chemotaxis – detect inflammatory signals; diapedesis; move toward pathogen • Adhesion – attach to pathogen (who may tagged for clearance) • using pathogen receptors (if untagged or to confirm foreign status) • using “immune system tags” to make identification easier • • • Ingestion – swallow pathogen Maturation – fuse “swallowed” pathogen with lysosome Killing – let the lysosome do its work Elimination – release pieces of pathogen that cannot be used Antigen Presentation – digested pieces of microbe (antigens) presented to adaptive immune system © 2018 Pearson Education, Inc.

Figure 15. 6 The events in phagocytosis. © 2018 Pearson Education, Inc.

The Body’s Second Line of Defense • Nonphagocytic Killing • Killing by eosinophils • Attack parasitic helminths by adhering to their surface • Secrete toxins that weaken or kill the helminth • Eosinophilia is often indicative of a helminth infestation or allergies • Eosinophil mitochondrial DNA and proteins form structure that kills some bacteria as the eosinophil dies (called eosinophil extracellular trap or EET) – “suicide bombing” https: //www. youtube. com/watc h? v=t. Rgq 3 v 1 W 61 w © 2018 Pearson Education, Inc.

The Body’s Second Line of Defense • Nonphagocytic Killing • Killing by natural killer lymphocytes (NK cells) • “glues” itself onto surface of virally infected cells and tumors (membrane pores and proteases) • Secrete toxins onto surface of cell • No release of toxic components into interstitial fluid; no inflammation • They can differentiate normal body cells from compromised cells because healthy cells have membrane proteins that tell the NK cells to “shut down” https: //www. youtube. com/watch? v=c 3 zhm. TFu. DTE https: //www. youtube. com/watch? v=O 7 kyu 9 r. Gq. TY © 2018 Pearson Education, Inc.

The Body’s Second Line of Defense • Nonphagocytic Killing • Killing by neutrophils • • Often phagocytoses microbes, but… Can destroy microbes without phagocytosis Produce chemicals that kill or slow down nearby invaders Short lived – only live hours after germination at bone marrow • As the neutro dies, it generates extracellular fibers called neutrophil extracellular traps (NETs) composed of neutrophil’s self-shredded genomic DNA that bind to and trap bacteria like a spiderweb. https: //www. youtube. com/watch? v=Z_m. XDv. ZQ 6 d. U © 2018 Pearson Education, Inc.

How does the immune system knows it contacted a pathogen? ? ? Toll-like receptors (TLRs) ○ Integral membrane proteins produced by phagocytic cells ○ TLRs are found at: cell surface (touch extracellular pathogen) in endosomes (touch often-tagged swallowed pathogen) ○ Bind pathogen-associated molecular patterns (PAMPs) present in bacteria (capsules, cell walls, lipids, DNA) ○ Initiate defensive responses Apoptosis (if it detects pathogens on or in cells) Secretion of inflammatory mediators Production of stimulants of adaptive immune response

The Body’s Second Line of Defense • Why should immune system slow down viral infections? • 400 particles can be created out of 1 in 20 minutes • Need to slow down viral infections to save the host and let immune system catch up • Need to warn tissues to get ready for and resist a viral infection © 2018 Pearson Education, Inc.

Interferons - The Body’s Second Line of Defense • Interferons • Protein molecules released by host cells (especially lymphocytes) to nonspecifically inhibit the spread of viral infections • Cause many symptoms associated with viral infections – nausea, muscle soreness, weakness • Warns nearby cells to initiate virus-resistance programming • Three types • Type I (alpha and beta) – rapidly induced; highly active; initial viral clearance at tissues • Type II (gamma) – shift immune response to anti-viral response • Type III (lambda) – less active than Type I, final viral clearance from tissues? ? © 2018 Pearson Education, Inc.

Figure 15. 7 The actions of alpha and beta interferons. © 2018 Pearson Education,

Table 15. 4 The Characteristics of Human Interferons Affects infections at tissues “effector interferons”

The Body’s Second Line of Defense • Complement • Set of serum proteins designated numerically according to their order of discovery • Complement activation results in lysis of the foreign or compromised cell by forming the membrane attack complex on the cell membrane of the pathogen • Bacteria (especially gram-neg), protozoa, helminth, enveloped virus • Pathogen-infected cell – loses its defenses • Pathogens or pathogen-infected cells covered in complement are “labeled” and are highly able to be bound and ingested by phagocytes or killed by cytotoxic lymphocytes • Indirectly trigger inflammation and fever • Activated by three ways: • Alternative – always on, but healthy cells keep it off • Lectin – pathogen polysaccharide labeling (innate) • Classical – antibody labeling (adaptive) © 2018 Pearson Education, Inc.

Figure 15. 8 Pathways by which complement is activated. antibody: antigen initiated constitutively initiated Host-inhibited pathogen sugar: lectin initiated Host components that bind mannose © 2018 Pearson Education, Inc.

Membrane Attack Complex (MAC) results in a hole being punched in the membrane of the pathogen or compromised cell START DOWN HERE

MEMBRANE ATTACK Membrane attack complex COMPLEXES

Inflammation – SUMMARY SLIDE • How does our body let the immune system know there is an infection? • How does our body help the immune system fight an infection? • Inflammation • Redness, heat, swelling, pain • Two types • Acute – the body successfully clears the infection (days to a few weeks) • Chronic – the body cannot clear the infection, no matter how long and hard it tries (weeks/months/years) • The effects of chronic immune activation, and poorquality tissue repair begin to permanently damage tissues © 2018 Pearson Education, Inc.

The Body’s Second Line of Defense • So what is inflammation? • Nonspecific response to tissue damage from various causes (infection, burn, physical trauma) • Characterized by redness, heat, swelling, and pain • Redness is increased blood flow to get the immune system to the site of infection • Heat inhibits pathogens • Swelling (localized edema) • makes room for immune cells at site of damage • Restricted drainage into lymphatic system • Better tissue clearing of infections • More careful monitoring of interstitial fluid by downstream lymph nodes • Pain alerts body to damage to protect from further insult © 2018 Pearson Education, Inc.

The Body’s Second Line of Defense • Inflammation • Acute inflammation • Develops quickly and is short lived • Is typically beneficial • Is important in the second line of defense • Dilation and increased permeability of the blood vessels • Migration of phagocytes • Tissue repair • Chronic inflammation • Long-lasting (pathogen may be present, or not!) • Damage to tissues can cause secondary disease called sequelae (e. g. , arthritis or neurologia after Lyme’s Disease, liver failure after hepatitis, paralysis after polio) © 2018 Pearson Education, Inc.

The Body’s Second Line of Defense • Inflammation - redness • Dilation and increased permeability of blood vessels • Vasodilation produces redness and localized heat associated with inflammation • Many chemicals trigger and promote dilation • Allows greater fluid flow from blood (cells, clotting factors) © 2018 Pearson Education, Inc.

Figure 15. 13 Increased vascular permeability during inflammation. • Inflammation - redness • Dilation and increased permeability of blood vessels • • Vasodilation also makes vessels more “leaky” Cells more easily pass into inflamed tissues – diapedesis Fluid more easily enters tissues – edema Chemokines enter blood vessels and attract immune cells © 2018 Pearson Education, Inc.

The Body’s Second Line of Defense • Inflammation – Redness and edema • Migration of phagocytes • Neutrophils and monocytes delivered to site of infection • Recruited by chemotactic factors • Attach to receptors on blood vessels • Squeeze between cells of vessel wall and enter site of infection - diapedesis • Tissue repair (after pathogens cleared) • Immune system gives the “green light” • Delivery of nutrients and oxygen to site facilitates repair • Some tissues cannot be repaired (biological limitations) • Fibrinogen deposition to make tissue more resistant to subsequent attack – scar tissue • Scar tissue often inhibits tissue function – degenerative disease © 2018 Pearson Education, Inc.

Figure 15. 14 An overview of the events in inflammation following a cut and

The Body’s Second Line of Defense • Fever • Systemic temperature increase • A body temperature over 37°C (or the body’s natural set point) • Results when pyrogens trigger the hypothalamus to increase the body's core temperature • Various types of pyrogens • Endogenous pyrogens (IL-1) released by phagocytes that have phagocytized: • Bacterial toxins • Cytoplasmic contents of bacteria released by lysis • Antibody-antigen complexes © 2018 Pearson Education, Inc.

Figure 15. 15 One theoretical explanation for the production of fever in response to

The Body’s Second Line of Defense • Fever • Continues as long as pyrogens are present • Outcomes of fever • Enhances effects of interferons • Inhibits growth of some microbes • May enhance the activities of phagocytes, cells of specific immunity, and the process of tissue repair © 2018 Pearson Education, Inc.