Infection and immunity

Infection and immunity Prof. Kijeong Kim May 10, 2013

학습목표 1. 바이러스에 대한 면역반응을 설명한다. 2. 세포외 기생세균에 대한 면역반응을 설명한다 3. 세포내 기생세균에 대한 면역 반응을 설명한다 4. 감염 후 면역반응에 의한 합병증을 열거한다.

√Three basic lines of protection against invasion of infectious agents • Natural barriers: restrict entry of the agent (e.g., skin, mucus, ciliated epithelium, gastric acid, bile). • Innate, antigen-nonspecific immune defenses • provide rapid, local responses to challenge by an invader (e.g., lysozyme, lactoferrin, interferon, complement, neutrophils, macrophages, natural killer [NK] cells). • Antigen-specific immune responses: specifically target, attack, and eliminate the invaders that succeed in passing the first two defenses (e.g., antibody, T cells).

Antimicrobial defense mechanisms √ • Bacterial infections: Phagocytic cells, complement (alternative path), antibody • Intracellular bacteria (i.e., mycobacteria): TH1, DTH • Viral infections • Interferon, NK, T cell • Antibody: restricts the spread of virus (viremia) • Fungal infection: TH1-DTH responses are especially important. • Parasitic infections: Activated macrophage, T-cell, eosinophil, IgE-mast cell

√Table 1. Antimicrobial Defenses for Infectious Agents

Immunity to bacteria

Pathogenesis of extracellular and intracellular bacteria • Extracellular bacteria • Two mechanisms • Inflammatory damage of infected tissues by bacterial growth and metabolism, cytolytic enzymes (e.g., pyogenic inflammation by S. aureus infection) • Toxin production (endotoxin, exotoxin) • Endotoxin: LPS, • very strong activator of macrophages • induces macrophages to release cytokines • Exotoxin: causes cytotoxicity • Intracellular bacteria • Intracellular pathogens (e.g., M. tuberculosis) are not easily killed by phagocytic cells. • Bacteria can survive in the cells  antibodies can not access into the cells • Resolution of the disease relies on the cell-mediated immunity

√ Extracellular bacteria • Innate immunity: • Nonspecific humoral defense • Lysozyme (degrades bacteria peptidoglycan layer), lactoferrin (chelates iron) • Neutrophils • Complement • Macrophages • Inflammation

√ Extracellular bacteria • Innate immunity: • Neutrophils • A major antibacterial phagocytic cell • are attracted to the site of infection • phagocytose and kill the internalized bacteria • Complement • Very early and important antibacterial defense • Alternative and Lectin pathways activated by bacterial surfaces and components (LPS, polysaccharides) • Production of chemotactic and anaphylatoxic proteins (C3a, C5a) • Opsonization of bacteria (C3b) • Direct killing of gram-negative bacteria • Activation of B cells (C3d) • Macrophages • Activated by bacterial components teichoic acid, peptidoglycan fragments, LPS

Extracellular bacteria • Innate immunity: • Inflammation • early defense mechanism • contain an infection • prevent its spread from the initial focus • signal subsequent specific immune responses

Extracellular bacteria • Acquired immunity • Major defense: Humoral immunity (Antibody) • Binding to surface structures of bacteria (fimbriae, lipoteichoic acid, capsule) • Blocking of attachment • Opsonization of bacteria for phagocytosis • Promotion of complement action • Promotion of clearance of bacteria • Neutralization of toxins and toxic enzymes • CD4 TH2 T-cell responses are important

√ Intracellular bacteria • Innate immunity; incomplete • Macrophages produce IL-12  NK cell activation • NK cells produce IFN- Macrophage activation • Acquired immunity: cell-mediated immunity • CD4 TH1 T cells (IFN-) activate macrophages killing of intracellular bacteria • CD8 cytotoxic cells kill the infected cells

CD4 TH1 T cells • promote and reinforce inflammatory responses (e.g., IFN- activation of macrophage) • usually occurs first as a local response. • promote growth of T and B cells (IL-2) to expand the immune response • promote B cells to produce complement-binding antibodies(IgM, IgG) • essential for combating intracellular infections (mycobacteria) • IFN- activates macrophage and DTH to kill the infected cell.

CD4 TH2 T-cell responses • often initiated by the B-cell presentation of antigen. • Binding of antigen (to B cell surface Ab.) activates the B cells, promotes uptake, processing of the antigen, and presentation of antigenic peptides on class II MHC molecules to CD4 TH2 cell. • produces IL-4, IL-5, IL-6, and IL-10, which enhance IgG production and, depending on other factors, production of IgE or IgA. • promotes terminal differentiation of B cells to plasma-cell antibody factories or production of memory B cells.

Bacterial immunopathogenesis (Complication) • Extracellular bacterial infection • Inflammation (tissue damage) • Septic shock (life threatening) • Activation of macrophages in the liver and spleen by endotoxin can promote release of TNF-into the blood, causing many of the symptoms of sepsis, including circulatory collapse, disseminated intravascular coagulation (DIC) and death. • Complications of humoral immunity • √ After recovery of Streptococcus pyogenes infection • Rheumatic fever: Antibodies produced against bacterial antigens that share determinants with cardiac muscle proteins can initiate tissue destruction (myositis)  Rheumatic fever • Post-streptococcal glomerulonephritis: caused by immune complex deposition of bacterial antigens and antibody

Bacterial immunopathogenesis (Complication) • Intracellular bacterial infection • Persistent survival of bacteria in the macrophages  chronic antigenic stimulation  formation of granulomastissue necrosis and fibrosis, dysfunction • Results from protective immunity and immunopathologic hypersensitive reaction • E.g., mycobacteria infection, Hansen disease

Bacteria • Cellular organisms • Mostly capable of fully independent life • Bacterial infection has been controlled by chemotherapy. • Because of the recent rise in antibiotic-resistant strains of bacteria, there is renewed interest in developing new or improved vaccines against : • Tuberculosis • Meningitis • Food-poisoning

Usual destiny of unsuccessful bacteria is death by phagocytosis • Bacterial survival entails avoidance of this fate • The main ways avoiding phagocytosis • Capsule …………(affects attachment) • Cell wall ………..(affects digestion) • Exotoxins ………(damage phagocytic and other cells) • Most cell wall components and toxins are strongly antigenic • antibody overcomes many of their effects • the basis of the majority of antibacterial vaccines

Capsule • A virulence factor • Protects bacteria from contact with phagocytes • Most are large branched polysaccharide molecules • Some are protein • Many of capsular polysaccharides are T-independent antigens • Examples of capsulated bacteria: • Pneumococcus, meningococcus, Haemophilus • Exotoxins • The proteins secreted often by gram-positive bacteria • Destructive effects on phagocytes, local tissues, CNS, etc. • Frequent cause of death • Aggressins; proteins collectively known • Help the bacteria to spread by dissolving host tissue

Sepsis • Uncontrolled systemic responses to bacterial infection • Can lead to rapid life-threatening disease • An important cause of death after major surgery • Overproduction of TNF-, especially by macrophages, plays a major role in these reactions

Immunity to viruses

Virus characteristics • Much smaller than all other infectious organisms • Lack cell walls • Lack independent metabolic activity • Are unable to replicate outside the cells of their host • Key process in virus infection is intracellular replication • May or may not lead to cell death

Protection from viral infection • √ Prevention of infection • Interferon(,) • Provides the rapid protection • Induces “antiviral state” in neighboring normal cells • Blocks local viral replication by inhibition of protein synthesis • Plays the same ‘natural antibiotic’ role as lysozyme in bacterial infection • Activates NK cells • Increases expression of MHC antigens II and I • Promotes APC’s antigen presentation to T cells • Makes infected cells a better target for cytotoxic T cells • Antibody • Prevents entry and blood-borne spread of viruses (extracellular) • Blocks viral attachment proteins (Neutralization) • Opsonizes virus for phagocytosis (Opsonization) • Dose not prevent cell to cell viral spread

Protection from viral infection • √Control of infection • Natural Killer (NK) Cells • Are activated by interferon-, IL-12 • Kill virus-infected cells • Can destroy some virus-infected cells but are not MHC restricted • Come into action more rapidly than TC cells. • Activate macophages (interferon-) • T cells • Cytotoxic T cell (TC cell) system • Recognizes altered ‘self’ MHC class I antigens by viral peptides • CD4 TH1 cells activate TC cells (CD8) • Prevention of virus cell to cell spread by: • Cytotoxic T cell (TC cell) system • NK cells

Macrophages • Filter viral particles from blood • Phagocytose (opsonized) virus particles • Tissue damage result from: • Virus itself • Host immune response to the virus • Receptors • All viruses need to interact with specific receptors on the cell surface • E.g. • Epstein-Barr virus (EBV) – CR2 on cells • Rabies – acetylcholine receptor on neurones • Measles – CD46 on cells

Interferon • A group of proteins produced in response to virus infection (and also bacterial LPS, etc.) • Stimulates cells to make proteins that block viral transcription and protects from infection. • Tc, NK, CMI • Tccells ‘learn’ to recognize class IMHC antigens, and then respond to these in association with virus antigens on the cell surface • NK cells can destroy some virus-infected cells but are not MHCrestricted • The role of DTH in viral infection, via macrophage activation, remains controversial • Antibody • Specific antibody can bind to virus and thus block its ability to bind to its specific receptor and hence infect cells = Neutralization • Neutralizing antibody is probably an important part of protection against many viruses (e.g. influenza)

Infection and immunity