Resisting infection Chapter 16: • Innate defenses (ch. 16) Innate host defenses • Physical & chemical barriers; cellular defenses; Phagocytosis inflammation, fever; molecular defenses Lymph Inflammation • Adaptive defenses (ch. 17) Complement • Sometimes called “specific” defenses • Mediated by lymphocytes Bio 139 • Exposure to specific antigens creates an improved ability to battle the same infection a second time Dr. Amy Rogers (immunity) 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: • Blood protein that binds free iron Cilia (hairlike structures on the • Many bacteria require iron as an enzymatic cofactor respiratory epithelium) “wave” – Some get iron from erythrocytes (RBC) using hemolysins together to drag microbes & other • Transferrin minimizes the amount of iron accessible particles in a sea of mucus up & to bacteria out of the lungs Cellular Defenses: Leukocytes Leukocytes: Myeloid cells • All cells of the blood are derived from • Most are “granulocytes”, a reference to pluripotent stem cells in the bone marrow their microscopic appearance • “pluripotent”: has the potential to differentiate into • Cytoplasm has spots, or granules many cell types • Granules are storage compartments • Leukocytes (white blood cells) • Critical for both innate & adaptive host defenses Basophils • Two major lineages (categories): Mast Cells Myeloid (granulocytes) Eosinophils Lymphoid (agranulocytes) Neutrophils • Number of leukocytes (white blood count) is Monocytes / Macrophages elevated during infection 1 Leukocytes: Myeloid cells Leukocytes: Myeloid cells Neutrophils Basophils & Mast cells • Phagocytes • 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 allergies 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 phagocyte’s phagocytes cell membrane • 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 (chemotaxis). • Opsonization: •Signals on the microbes (e.g., peptidoglycan, • Bacteria can be coated with antibodies, or molecules of the lipopolysaccharide) complement system, 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 • Phagosome fuses with Lysosomes, organelles full of destructive enzymes that surround the microbe, • Within this “phagolysosome”, the microbe’s cell fuse, membrane is breached, all cell components broken down and create a membrane-bound cytoplasmic vacuole • In macrophages, toxic reactive oxygen phagosome compounds are also used to kill ingested microbes hydrogen peroxide H O , nitric oxide NO, with the microbe trapped inside. 2 2 superoxide O2-, hypochlorite OCl- (bleach) 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 viruses, host defenses must destroy for neutrophils & macrophages to engulf infected cells • Intracellular killing by phagocytosis is not possible • Natural killer (NK) cells recognize virus- • Eosinophils attack worms (helminth infected cells infections) by excreting enzymes toxic to worms • NK cells trigger death of the infected cell, • “Major basic protein” often by apoptosis (suicide, or programmed cell death) 3 Lymphatic system 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 lymph node 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 • Vasodilation, 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: Pus 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 – Streptococcus pyogenes: produces leukocidins Interleukin-1 (IL-1) which kill phagocytes, enhance pus formation – IL-1 acts on the hypothalamus (brain) to reset body temperature Pyogen = pus-inducing Pyrogen = fever-inducing Fever Molecular Defenses: Interferons Elevated temperature can be GOOD. • So named because these proteins “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? Activation of the Classical Pathway: Step One: Antibodies bound to antigens Activate the system (for example, on the surface of bacteria) Two ways: