Resisting

Chapter 16: • Innate defenses (ch. 16) Innate host defenses • Physical & chemical barriers; cellular defenses; , fever; molecular defenses Lymph Inflammation • Adaptive defenses (ch. 17) Complement • Sometimes called “specific” defenses • Mediated by Bio 139 • Exposure to specific creates an improved ability to battle the same infection a second time Dr. Amy Rogers ()

Physical & Chemical Barriers Physical & Chemical Barriers

1. Skin • Sweat: 2. Mucous membranes • High salt content, acid pH

• Cover surfaces exposed to the outside world • Stomach: • Extremely acid pH • Difficult to penetrate – (major defense against intestinal pathogens) – Microbes can be flushed out by coughing & • Lysozyme in tears sneezing, vomiting & diarrhea, tears & saliva, urination • Transferrin: • that binds free iron Cilia (hairlike structures on the • Many require iron as an enzymatic cofactor respiratory ) “wave” – Some get iron from erythrocytes (RBC) using together to drag microbes & other • Transferrin minimizes the amount of iron accessible particles in a sea of mucus up & to bacteria out of the

Cellular Defenses: Leukocytes Leukocytes: Myeloid cells • All cells of the blood are derived from • Most are “”, a reference to pluripotent stem cells in the their microscopic appearance • “pluripotent”: has the potential to differentiate into • has spots, or granules many types • Granules are storage compartments • Leukocytes (white blood cells) • Critical for both innate & adaptive host defenses • Two major lineages (categories): Mast Cells Myeloid (granulocytes) Lymphoid () • Number of leukocytes (white blood count) is / elevated during infection

1 Leukocytes: Myeloid cells Leukocytes: Myeloid cells Neutrophils Basophils & Mast cells • • release histamine • Circulate in blood, and migrate into tissues • First defenders at initial sites of infection • Mast cells reside in tissue, not blood • Best at inactivating bacteria & small particles • Associated with Monocytes/Macrophages • Phagocytes Eosinophils • In blood: monocytes • Prominent during allergic reactions • Monocytes mature into macrophages, which • Major fighters against worm infestations reside in the tissues • Can destroy larger particles/debris

Leukocytes: Lymphoid cells

• B lymphocytes • T lymphocytes • NK (natural killer) cells

Crucial to adaptive host immunity (Much more on this later)

Phagocytosis Phagocytosis

• Neutrophils & monocytes/macrophages are • First, microbe must adhere to the ’s phagocytes • Antigens, or substances the body recognizes as foreign, tend • Their job is to engulf and destroy: to adhere well to phagocytes 1. Dead cells, cellular debris • Capsules on bacteria make adherence 2. Microbes difficult, protecting the bacteria from A complex range of chemical signals attract phagocytosis phagocytes to invading microbes (). • Opsonization: •Signals on the microbes (e.g., peptidoglycan, • Bacteria can be coated with , or molecules of the ) , that mark them for easy phagocytosis •Signals released by damaged host cells • “Opsonization” is the process of marking antigens/bacterial •Signals released by other leukocytes in the area cells to make them more appetizing to phagocytes

2 Phagocytosis Phagocytosis Ingested bacteria are destroyed. Phagocyte membrane forms extensions pseudopodia • fuses with , organelles full of destructive enzymes that surround the microbe, • Within this “”, the microbe’s cell fuse, membrane is breached, all cell components broken down and create a membrane-bound cytoplasmic • In macrophages, toxic reactive oxygen phagosome compounds are also used to kill ingested microbes H O , NO, with the microbe trapped inside. 2 2 O2-, OCl- ()

Phagocytosis

• Doesn’t always work: some microbes survive phagocytosis

• Acid-fast mycobacteria such as M. tuberculosis (TB) actually live inside macrophages • This gives them a stable, well-protected “home” hidden from other host defenses

Phagocytosis

Other killing Other killing

• Large parasites (like worms) are too large • To kill , host defenses must destroy for neutrophils & macrophages to engulf infected cells • Intracellular killing by phagocytosis is not possible • Natural killer (NK) cells recognize - • Eosinophils attack worms (helminth infected cells ) by excreting enzymes toxic to worms • NK cells trigger death of the infected cell, • “Major basic protein” often by (suicide, or )

3 Lymphatic System • Lymph nodes are full of • A kind of parallel cardiovascular system lymphocytes, macrophages, • Body fluid lymph circulates through lymphatic & other immunologically important cells vessels, pumped by contraction of surrounding muscles • Lymph nodes act as filters • Lymphatic system drains extracellular fluids from – During infection, some all over the body, delivers to venous system bacteria not destroyed at the • Lymphatic vessels are interrupted by lymph infection site are transported nodes to the draining

Lymphatic System Inflammation

• Bacteria entering a lymph node: • Inflammation is a set of nonspecific responses to injury or infection that – May be phagocytosed minimize damage or infection, and – Can activate the adaptive (specific) immune promote healing response – Stimulate proliferation of leukocytes and • Cardinal signs of inflammation: migration to the site Calor: heat Rubor: redness – May actually infect the node Tumor: swelling Lymphadenopathy, or swelling of the lymph nodes, is Dolor: pain a common symptom of various kinds of infections

Inflammation Inflammation

• There are a huge number of chemical • , increased vascular mediators of inflammation permeability (leakiness) – most have multiple effects, causing the – Causes redness & heat from increased blood flow cardinal signs of inflammation; – Leaking fluids can cause swelling – or act as chemotactic factors to attract leukocytes to the site – Increased blood flow brings clotting factors & phagocytes to the site • They exist the blood vessel by passing between endothelial cells: diapedesis

4 Inflammation: Fever

• Phagocytes reach infected area and • Unlike the localized heat mentioned, fever is a engulf microbes systemic response that often accompanies inflammation • Pus may form • Many things, including infections, can cause – An accumulation of live & dead phagocytes, fever other cells & cell debris, remains of ingested • Exogenous pyrogens from microbes promote microbes, etc. release of the endogenous pyrogen – : produces Interleukin-1 (IL-1) which kill phagocytes, enhance pus formation – IL-1 acts on the hypothalamus () to reset body temperature Pyogen = pus-inducing Pyrogen = fever-inducing

Fever Molecular Defenses: Interferons Elevated temperature can be GOOD. • So named because these “interfere” with multiplication of viruses 1. Slows growth of pathogens who prefer 37oC • 3 categories: 2. Some microbial enzymes & toxins may be inactivated α (alpha) 3. By making you feel lousy, it encourages rest (!) β (beta) γ (gamma)

Alpha & beta interferons INF-α and INF-β (INF-α & INF-β) Antiviral proteins target viral RNAs • Released by a virus-infected cell • Other signals of infection, such as endotoxin, can • All RNA-genome viruses go through at also trigger INF release least one phase with dsRNA

• INF binds to receptors on neighboring, dsRNA viruses: the genome itself uninfected cells -- and + sense RNA viruses: • This activates expression of various Replication of RNA genome depends on antiviral proteins RNA-dependent RNA synthesis. Small bits of dsRNA exist during this process.

5 INF-α and INF-β

dsRNA structures are NOT normal in healthy cells; they are good targets for selectively toxic antiviral activity

Ultimately: Interferon-induced antiviral proteins help block viral replication in the uninfected cell

INF-γ Interferons

• Gamma interferon is produced by lymphoid cells: lymphocytes & NK cells • Various INFs can be manufactured using – They do NOT need to be infected by a virus recombinant DNA techniques and are used therapeutically (as drugs) •INF-γ has MANY effects that enhance both the specific and innate immune responses • Limited applications at this time – “Activates” lymphocytes, NK cells, • Certain unusual cancers macrophages • Hepatitis C – Has some anti-tumor activity too – LOTS of bad side effects

The Complement System The Complement System

What is it? What does it do? A set of >20 proteins found in plasma (blood). 1. Enhance phagocytosis (by opsonization) The proteins function in a cascade 2. Directly lyse microbes with membranes A B C D E 3. Regulate inflammation & immune where A acts on B, B acts on C, etc.; NOT a metabolic pathway where A is converted into B, etc. responses

Amplification with each step (analagous to the clotting cascade) Nonspecific & Fast (doesn’t matter which microbe has entered the body; mobilizes long before adaptive immune defenses)

6 The Complement System The Complement System

How does it work? of the Classical Pathway:

Step One: Antibodies bound to antigens Activate the system (for example, on the surface of bacteria) Two ways: 1. Classical Pathway activate complement proteins 2. Alternative Pathway C1-C4-C2

The Complement System The Complement System

Activation of the Alternative Pathway: Both classical & alternative pathways of complement activation Polysaccharide markers on the surface of activate the central molecule of the cascade, pathogens

(for example, on the surface of bacteria) C3 activate complement proteins Factor B//Factor P which splits into and

The Complement System

1. Opsonization: – C3b binds to the surface of -marked microbes – C3b is acts as an • phagocytes have C3b receptors • recognition of C3b stimulates phagocytosis 2. Inflammation: – C3a (and other complement proteins) can initiate & enhance inflammation • Chemotaxis promotes diapedesis of neutrophils out of blood vessels

7 The Complement System

3. Direct lysis of microbes (complement- mediated lysis): The Membrane Attack Complex Complement molecules downstream of C3 catalyze formation of pores in membranes. Pores are made of C9 molecules

These pores, or holes, in cell membranes or viral The Membrane Attack Complex (MAC) envelopes, kill the organism.

Innate host defenses summary

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