Lecture 29: Immunity to Infection - PDF

Chapter 13: Immunity to infection.  Lecture outline Immunity to Infection Overview Host Pathogen Encounters Extracellular Bacteria Intracellular Bacteria  Immunity to infection : Overview Infectious diseases cause about 14 million human deaths annually whi...

Chapter 13: Immunity to infection.  Lecture outline Immunity to Infection Overview Host Pathogen Encounters Extracellular Bacteria Intracellular Bacteria  Immunity to infection : Overview Infectious diseases cause about 14 million human deaths annually which are caused by six types of pathogens. – Extracellular bacteria – Intracellular bacteria – Viruses – Parasite – Fungi – prions Infection occurs when an organism successfully avoids innate defense and colonizes a niche in the body. There is a biological ‘horse race’ or ‘war’ between pathogen & immune system where the pathogen tries to replicate and expand, while immune system tries to eliminate pathogen.  Immunity to infection : Overview Only if pathogen replication results in detectable clinical damage then host experience ‘disease’. Bacterial toxins can cause disease even in the absence of colonization. Immunopathic damage can occur if host tissues are unintentionally injured by the immune response. Innate and adaptive effector mechanisms best suited to countering a particular pathogen are determined by the invader’s lifestyle and mode of replication.  General features of host-pathogen encounters Most of the mechanisms of innate defense help the host to combat any type of pathogen. The first obstacles encountered by an invader are the intact skin & mucosae. However, a breach of skin or mucosae may allow pathogen access to sub epithelial tissues. When immune system is compromised either by disease or therapeutic immunosuppression, the opportunistic pathogens may even cause disease. In contrast, invasive pathogens can enter the body even when surface defenses are intact. Invasive pathogens usually gain access to mucosae via the M cells of EAE or by binding to host cell surface molecules that initiates receptor-mediated internalization.  General features of host-pathogen encounters A pathogen that penetrates skin or mucosae triggers the influx of site with acute phase proteins, pro-inflammatory cytokines (IL-1, TNF & IL-6), & complement components. Coating of pathogen by C3b or mannose binding lectin (MBL) facilitates its removal by alternate or lectin complement cascades, respectively. At a cellular level, general innate defense is mediated by the PRRs of resident DCs, neutrophils & other granulocytes, macrophages, NK cells, gd T cells and NKT cells. These PRRs include TLRs, NLRs, RLRs, CLRs, scavenger receptors and cell-bound collectins as well as the antigen recognition receptors of NK, NKT and gd T cells.  General features of host-pathogen encounters Soluble collectins in the extracellular matrix that have bound to pathogens or their products may activate complement or stimulate phagocytosis. Leukocytes activated by PRR engagement eliminate the pathogen or infected cells by endocytosis or phagocytosis, secretion of cytotoxic cytokines or perforin/granzyme- mediated cytotoxicity. They also produce toxic NO & ROIs. In inflammatory response, chemokines draw neutrophils and other leukocytes into the area of infection.  General features of host-pathogen encounters In blood infections, neutrophils & monocytes provide innate defenses while the organisms that reach the liver or spleen are confronted by the resident macrophages. As innate response proceeds, local DCs after maturation due to exposure to pathogen components present pMHCs to naïve T cells & trigger adaptive immune response. Both T & B cell activation takes place in inductive sites in MALT/SALT & effector cells migrate to effector sites. A systemic immune response is generated if mature DCs move to draining lymph node or spleen.  Immunity to extracellular bacteria Disease mechanisms: Extracellular bacteria tend to accumulate in the interstitial regions in connective tissues; in lumens of the respiratory, urogenital and gastrointestinal tracts and in the blood. These organisms often secrete proteins that penetrate or enzymatically cleave components of the mucosal epithelium, allowing access to underlying tissues. A wide variety of extracellular bacteria enter the M cells whereas other exploit surface receptors on other host cells.  Immunity to extracellular bacteria Disease mechanisms: Cont’d Many disease symptoms caused by extracellular bacteria can be attributed to their toxins. Exotoxins are toxic proteins actively secreted by either Gram +ve or Gram –ve bacteria. Endotoxins are the lipid portions of the LPS molecules embedded in the walls of Gram –ve bacteria. Endotoxins (LPS) are not secreted but rather are released only when the cell walls of Gram-ve bacteria are damaged. A given Gram –ve bacterial species may supply both exotoxins and endotoxins.  Immunity to extracellular bacteria Disease mechanisms: Cont’d Different exotoxins and endotoxins cause disease by different means and in different locations. For example, infection with Vibrio cholerae results in local release of an exotoxin that binds to gut epithelial cells and induces severe diarrhea. Clostridium botulinum produces a neuro-exotoxin that blocks the transmission of nerve impulses to muscles, resulting in paralysis. In contrast, damage to a host caused by an endotoxin is always immunopathic (endotoxic/septic shock).  Fig 13.1: Major mechanisms of immune defense against extracellular bacteria Read details from textbook. Read details on the table from textbook.  Immunity to intracellular bacteria Disease mechanisms: Most intracellular bacteria access the host via breaches in mucosae & skin, but some are introduced into bloodstream by the bites of vectors such as ticks, mosquitoes & mites. Once inside host, intracellular bacteria avoid phagocytes, complement & Abs by moving right inside the host cells. Epithelial & endothelial cells, hepatocytes & macrophages are popular targets. As macrophages are mobile, bacteria that infect these cells are disseminated all over the body.  Immunity to intracellular bacteria Disease mechanisms: Cont’d Intracellular bacteria generally enter host cells by clathrin- mediated endocytosis & are first confined to a clathrin- coated vesicle. Some species remain in the vesicle while others escape & take up residence in the cytoplasm. Intracellular bacteria usually not very toxic to host cells and do not produce tissue-damaging bacterial toxins. Intracellular bacteria are hard to eradicate completely & cause chronic diseases. Fig 13.2: Major mechanisms Read details from textbook. of immune defense against intracellular bacteria Fig 13.2: Major mechanisms Read details from textbook. of immune defense against intracellular bacteria  Granuloma formation When an intracellular pathogen like Mycobacterium tuberculosis is able to resist killing by CTLs and hyperactive macrophages, body walls off the pathogen in a structure called ‘granuloma’ that forms around infected macrophages. Inner layer of granuloma contains macrophages & CD4+ T cells, whereas exterior layer contains CD8+ T cells. Eventually granuloma becomes calcified & fibrotic & the cells in the center undergo necrosis. In some cases, all the pathogens trapped in the Plate 13.2: Granuloma cross section- A dying cells are killed & central zone of necrosis is surrounded by infection is resolved. activated macrophages.  Granuloma formation In other cases, a few pathogens remain viable but dormant within the granuloma causing it to persist. Granuloma persistence is an overt sign that the disease is becoming chronic. If the granuloma breaks down, the trapped pathogens are released back into the body to resume replication. If the host is immunosuppressed and unable to marshal the T cells & macrophages necessary to fight the fresh assault, the pathogen may reach the blood.  Granuloma formation As the bacteria travel in the circulation, they can infect organs throughout the body and even precipitate death. Cytokines IL-17, IL-12 and IFN-g (produced by Th1 cells) play important roles in granuloma formation. While IL-4 & IL-10 produced by Th2 cells control granuloma formation by damping it down as the bacterial threat is contained. Read details on the table from textbook.  Next Lecture Chapter 13: Immunity to infection.