Chapter 3- Innate Immunity- Induced Response to Infection Flashcards
Paneth cells
The immune cells of the intestine. Paneth cells are the main source of defensins in the intestine- the α-defensins HD5 and HD6, also known as cryptidins are made only by Paneth cells
Constitutive regulation
Constitutive genes are always expressed at a basal level
Pentraxins
Pentraxins are a family of cyclic multimeric proteins found in blood and lymph. They are effector molecules of innate immunity that have a similar role to the antibodies of adaptive immunity in binding to microbial surfaces and facilitating the phagocytosis of pathogens. Two subfamilies- short and long pentraxins
Short vs long pentraxins
Long or short refers to how many amino acids make up the pentraxin
Pentraxin structure
Contain a 200-residue pentraxin domain at the C-terminal end of the polypeptide
Serum amyloid P component
A short pentraxin produced by liver hepatocytes. Its ligands are bacteria, viruses, fungi, and parasites
PTX3
A long pentraxin produced by monocytes, macrophages, dendritic cells, endothelial cells, and epithelial cells. Its ligands are bacteria, viruses, and fungi
Pentraxin mechanism
Function as bridging molecules that bind pathogens on one binding site and cell surface receptors of phagocytes to another.
Effector cells of the innate immune system (4)
- Neutrophils
- Macrophages
- Dendritic cells
- NK cells
Innate immunity cell receptors function
The cellular receptors of innate immunity distinguish between “non-self” (microbes themselves) and “self” or “altered-self” (infected or cancerous cells) and “self” by recognizing structural features on microbes that are not present on mammalian cells. This includes differences in the macromolecules produced by pathogens. Some features are expressed by entire families of pathogens, allowing a wide range of pathogens to be detected by a much smaller number of receptors. The receptors are expressed by neutrophils, macrophages, NK cells, and other innate immune cells. There are more than 100 different innate immune receptors, and each type of innate cell only expresses a subset of them
Macrophage recognition of bacterial carbohydrates
One example of innate cells recognizing “self” vs “non-self”. Macrophages can capture a bacteria using receptors that bind to carbohydrates on the bacterial cell surface but do not bind to the carbohydrates on human cells. In this context the bacterial carbohydrates are perceived as non-self, whereas the human carbohydrates are seen as self. On capturing the bacterium with these receptors, the macrophage is signaled to internalize the bacterium by phagocytosis and then break it down in a phagosome
NK cell recognition of viral proteins
One example of innate cells recognizing “self” vs “non-self”. In a virus-infected human cell, the viral genome is transcribed and translated, leading to the presence of viral glycoproteins on the epithelial cell surface. NK cells are another innate immune cell that have surface receptors which bind to the viral glycoproteins. Binding to these receptors instructs the NK cell to kill the infected cell. In this context, the virus-infected cell is perceived as altered-self, whereas the neighboring uninfected cells are seen as self.
Tissue macrophages
During embryonic development, macrophage precursors are seeded into every tissue of the human body. All tissues contain resident macrophages which are ready to phagocytose invading pathogens. Tissue macrophages carry a battery of phagocytic and signaling receptors. The receptors work together to bind the pathogens and trigger their phagocytosis by the macrophage. Ligands recognized by phagocytic receptors are mostly bacterial carbohydrates, lipids, proteins, and DNA. Signaling receptors distinguish ‘self’ from ‘non-self’ and induce changes in gene expression and macrophage function
Langerhans cells
Resident tissue macrophages of the skin
Alveolar macrophages
Resident macrophages of the lung
Kupffer cells
Resident macrophages of the liver
Microglia
Resident macrophages of the CNS
Red pulp macrophages
Resident macrophages of the spleen
Osteoblasts
Resident macrophages of the bone
Macrophage phagocytic receptors (there are 5)
- Mannose receptor
- Dectin-1
- Scavenger receptors
- MARCO
- Complement receptors CR3 and CR4
Mannose receptor and dectin-1
Part of the SR-E class of scavenger receptors. Macrophage phagocytic cell-surface receptors and plasma proteins that recognize carbohydrates are called lectins- there are C-type and B-type lectins. Lectins differ on the surface of microbes, identifying them as “non-self”
C-type lectins
Calcium ion coordinates the interaction of carbohydrate ligand with the receptor
B-type lectins
Bind sulfated galactosamine residues
Scavenger receptors
Macrophage phagocytic receptors. Scavenge damaged molecules of low-density lipoprotein from blood as well as negatively charged microbial products. In the absence of infection, macrophages use their scavenger receptors to remove dead and dying cells and unwanted macromolecules. They also remove cells that have died by apoptosis. SR-A: Gram negative LPS, Gram positive teichoic acid, CpG DNA. SR-B: lipopeptides
Macrophage Receptor with Collagenous Structure (MARCO)
Phagocytic scavenger receptor on the surface of macrophages that binds a wide range of bacteria as well as apoptotic cells. It recognizes bacterial LPS, which is the most abundant component of the outer membrane
Complement Receptors CR3 and CR4
Macrophage phagocytic receptors that are members of the integrin family of proteins. They bind to complement fragment iC3b and recognize microbial PAMPs. This includes the LPS of Gram-negative bacteria
Phagocytic and signaling receptors
The mannose receptor has 10 extracellular domains of 4 types. The receptors work in a cooperative fashion to securely capture the pathogen. Then, macrophages carry out receptor-mediated endocytosis and internalize the pathogen into the phagosome
Pathogen-associated Molecular Patterns (PAMPs)
Part of how recognition of pathogens is achieved by WBCs. PAMPS are any structural feature on a microbe that is recognized by Pattern Recognition Receptors (PRRs) expressed on the surface and in subcellaular compartments within leukocytes.
The ideal PAMPs should be (3)
- Conserved (i.e., unlikely to mutate)
- Shared by a large group of pathogens (i.e., bacteria, fungi, viruses)
- Clearly distinguishable from self molecules
Major families of pattern recognition receptors (PRRs-)
- Toll-like receptors (TLRs)
- C-type lectin receptors (CLRs)
- Nucleotide-binding oligomerization
domain (NOD)- Leucin Rich Repeats
(LRR)-containing receptors (NLR) - Retinoic acid-inducible gene 1
(RIG-1)-like receptors (RLR; aka
RIG-1-like helicases—RLH)
Pattern recognition receptors (PRRs)
PRRs recognize PAMPs, allowing for pathogen recognition. Engagement of PRRs on the innate immune cells activate microbicidal and pro-inflammatory responses required to eliminate (or at least to contain) infectious agents. One major result is the secretion of small biologically active proteins (cytokines) that induce inflammation in order to recruit other immune cells to the infected tissue
Toll-like receptors
One type of transmembrane PRR located on the cell membrane or within endosomes. They are a family of 10 genes which encode TLRI-10. They have an extracellular domain for recognizing pathogens and a cytoplasmic domain that signals this information to the inside of the cell. TLRs are important in innate cell activation. When pathogens are degraded by macrophages, their nucleic acids are delivered to endosomes for recognition by TLRs
Extracellular vs intracellular TLRs
Extracellular TLRs recognize extracellular microbial ligands, while intracellular TLRs recognize intracellular microbial ligands (RNA and DNA)
Importance of TLR structure
Toll-like receptor (TLR) polypeptides comprise an extracellular sensor domain shaped like a horseshoe, a transmembrane domain, and an intracellular Toll/interleukin-1 receptor (TIR) domain that sends activating signals to the nucleus of the macrophage. The signaling domain is called TIR (Toll Interleukin-1 Receptor). Functional TLRs can form homodimers or heterodimers
Extracellular TLR domain
Horseshoe shaped and responsible for pattern recognition. It consists of a leucine-rich repeat region (LRR), a sequence motif of 20-29 amino acids and is rich in leucine.
Toll Interleukin-1 Receptor (TIR)
The signaling domain of TLRs. It sends activating signals to the nucleus of the macrophage
How does TLR4 recognize bacterial lipopolysaccharides? (There are 4 steps)
- Bacterial LPS is recognized using a complex of TLR4, MD2, and CD14.
- LPS from Gram Negative bacteria is bound by a protein on macrophage surface called CD14 which is a co-receptor of TLR4. Alternatively, LPS can be bound to LPS-binding Protein (LBP) and delivered to CD14 on the macrophage surface.
- The TLR4 dimer associates with a protein MD2 to form a complex with CD14 and LPS. This extracellular recognition of the pathogen (LPS) causes the cytoplasmic TIR domain of TLR4 to initiate signaling.
- Recognition of LPS leads to activation of transcription factor NF-KB and synthesis of pro-inflammatory cytokines
Transcription factors
They regulate (turn on/off) genes in order to make sure that they are expressed in the right cell at the right time and in the right amount. They bind to regions of DNA adjacent to the genes that they regulate. Stabilizes RNA polymerase and can make DNA more/less accessible to transcription via histone acetylation/deacetylation
Synthesis of pro-inflammatory cytokines by TLRs (8 steps)
- On recognizing LPS, TLR4 activates the transcription factor NFκB, which instructs the macrophage to produce inflammatory cytokines. These cytokines induce a state of inflammation in the infected tissue.
- The cytoplasmic tail of activated TLR4 binds the adaptor protein MyD88
- MYD88 binds the protein kinase IRAK4, which self-phosphorylates.
- IRAK4 now binds and phosphorylates TRAF6, which initiates a kinase cascade that activates the kinase IKK.
- In the absence of a signal, NFκB is bound by the IκB inhibitor, which prevents NFκB from entering the nucleus.
- In the presence of a signal, activated IKK phosphorylates IκB, causing NFκB to be released from the complex; IκB is degraded.
- NFκB enters the nucleus to activate the genes encoding inflammatory cytokines.
- Messenger RNA directs the synthesis of the cytokines in the cytoplasm, and the cytokines are secreted via the endoplasmic reticulum (ER)
Nemo deficiency symptoms
Fever, lethargy, weight loss, abnormal conical teeth, thin hair, thick skin, eczematous rashes, and reduced sweat glands. These patients also experience frequent infections which may be severe
NEMO deficiency
An incredibly rare genetic disease caused by impairment of NF-κB activation. Children lack one of the subunits of inhibitor of κB kinase (IKK). The gene for kinase subunit IKKγ or NF-κB essential modulator (NEMO) is on X-chromosome; so disease more frequent in boys. Patients are highly susceptible to pyogenic (pus-inducing) bacteria, such as Pneumococcus sp. and Staphylococcus sp. Treatment includes IV antibody infusions and antibiotic therapy
Cytokines
Small, soluble proteins used as a means of communication between cells. Innate cells respond to infection through activation (interaction with PAMPs) and secreting inflammatory cytokines in response. Cytokines are involved in regulating the development of immune effector cells and regulating the intensity/duration of an immune response. One cell type secretes a cytokine that binds to a specific cytokine receptor on the surface of another target cell. This induces signaling in the second cell.
Interleukins (IL)
Secreted by some leukocytes to act on other leukocytes
5 types of pro-inflammatory cytokines
TNF-α, IL-6, IL-12, IL-1β, CXCL8
Autocrine action
When a cytokine binds to, and has a biological effect on, the same cell that secreted it.
Paracrine action
When a cytokine binds to receptors on target cells in close proximity to the original producer cell.
Endocrine action
When a cytokine travels through the circulation and binds to target cells in distant parts of the body.
Nod-like receptors
A family of proteins that serve as danger signals for the host cell. They are intracellular sensors of bacterial infections. They recognize bacterial degradation products in the cytoplasm. When bacteria is phagocytosed in the lysosome of the macrophage, the bacteria’s cell components are delivered to the cytoplasm, where they are detected. NLRs have a central domain called NOD (Nucleotide-binding Oligomerization Domain). Two types- NOD1 and NOD2
Nod-like receptors mechanism
- Upon recognition of bacterial products, the CARD domain of NOD receptors dimerizes with the CARD domain of the kinase RIPK2
- RIPK2 phosphorylates the kinase TAK1 which in turn activates IKK
- Activated IKK mediates degradation of IκBs (Inhibitor of κB)
- NF-κB travels to the nucleus and regulates gene expression in order to activate macrophages
Structure of Nod-like receptors
They all have a central domain called NOD (Nucleotide-binding Oligomerization Domain). Their pathogen-recognition domain is made up of LRRs on the C-terminal side of the NOD domain. Their Caspase-recruitment domain (CARD) is on the amino-terminal side
IL-1β
A major cytokine. Macrophages amplify the innate immune response by increasing the production of IL-1β, which is responsible for acute phase response and promotes inflammation. IL-1β is very potent and its production must be tightly regulated. Overexpression observed in autoinflammatory syndromes, autoimmune disorders, & degenerative diseases. Regulation is accomplished by the inflammasome
Inflammasome
A large multi-protein complex that controls when, where, and how much IL-1β is secreted by macrophages
Components of the NLRP3 inflammasome
NLRP3 molecule, Adaptor protein ASC, and Protease Caspase-1
NLRP3 inflammasome function
Enables activated macrophages to produce IL-1β from stored pro-IL-1β.
Damage-associated molecular patterns (DAMPs)
Some receptors of innate immunity can detect damage to cells or tissue that does not involve an infection. In this case, the receptor recognizes a damage-associated molecular pattern
NLRP3 inflammasome formation
Before sensing any infection, the tissue macrophage makes and stores a large quantity of pro-IL-1β in its cytoplasm. On sensing infection (exposure to PAMPs or DAMPs), NOD-like receptor protein 3 engages its microbial ligands. This stimulates each NLRP3 molecule to recruit each of the 3 necessary units, which oligomerize to form the structure of the inflammasome. Caspase-1 is synthesized as inactive pro-caspase-1 which must undergo cleavage to become active. Active IL-1β is generated after inactive pro- IL-1β is cleaved by caspase-1
Mutations in the genes encoding inflammasome components may lead to
Autoinflammatory diseases are caused by mutations in the genes encoding sensors and other inflammasome components.
How do inflammasomes amplify the innate immune response?
They amplify the innate immune response by increasing the production of IL-1Β. Exposure to IL-1β can induce macrophages to produce more inactive pro-IL-1β to be cleaved by active caspase-1. Bacterial products, ROS, uric acid crystals, and ATP can all result in the formation of an active inflammasome
How do resident macrophages respond to IL-1β?
By making and secreting inflammatory cytokines. TNF-α, IL-6, CXCL8, CCL2, and IL-12 are five crucial inflammatory cytokines that are secreted by macrophages after the release of IL-1β by an inflammasome. The cytokines recruit effector cells and plasma proteins to the infected tissue, where they work together to create a state of inflammation.
Inflammation
A localized reaction of tissue to irritation, injury, or infection, characterized by pain, redness, swelling, heat and sometimes loss of function- can be acute or chronic.
Why does inflammation cause pain?
The inflamed area is likely to be painful, especially when touched. Chemicals that stimulate nerve endings are released, making the area much more sensitive.
Why does inflammation cause redness?
This is because the capillaries are filled up with more blood than usual. Swelling may also result from the accumulation of fluid from blood. More blood in the affected area can also make it feel hot to the touch
Initiation of inflammation of infection of the skin (3)
- A surface wound introduces bacteria, which activate resident effector cells to secrete cytokines
- Vasodilation and increased vascular permeability allow fluid, protein, and inflammatory cells to leave the blood and enter tissue
- The infected tissue becomes inflamed, causing redness, heat, swelling, and pain
Neutrophils
Also called polymorphonuclear leukocytes. Short-lived and dedicated phagocytes. They are granulocytes with numerous granules in the cytoplasm. Neutrophils are the first cells recruited to sites of infection by inflammatory mediators such as CXCL8. Neutrophils are potent killers of pathogens and are themselves programmed to die. They have a range of phagocytic receptors that recognize microbial products. They also have complement receptors that facilitate phagocytosis by opsonization and complement fixation
CXCL8
An inflammatory cytokine made by pathogen-activated macrophages, which recruits neutrophils from the blood to the site of infection in the tissue. CXCL8 is considered a chemokine since it directs the flow of leukocyte traffic throughout the body.
Chemokine
A molecule that directs the flow of leukocyte traffic throughout the body. This movement of leukocytes between blood and tissue is mediated by interactions between adhesion molecules
Which adhesion molecules are necessary for adhesion of leukocytes to the vascular endothelium? (4)
Vascular addressins, selectins, integrins, and proteins having immunoglobulin-like domains. Each family of adhesion molecules has a distinctive structure
Selectin-mediated adhesion
Allows for weak adhesion of leukocytes to the vascular endothelium, and leukocytes can roll along the endothelium. Movements of leukocytes between circulation and tissue is determined by interactions of complementary adhesion molecules. Inflammation causes endothelial cells to increase expression of selectins, ICAM-1, and ICAM-2. In the same way, neutrophils express corresponding molecules like LFA-1 and sialyl-Lewis x (carbohydrate groups of glycoproteins on neutrophil surfaces)
4 stages of extravasation
- Rolling adhesion
- Tight binding
- Diapedesis
- Migration
Which interactions allow for strong neutrophil adhesion?
CXCL8 binds to CXCR1 and CXCR2, chemokine receptors on neutrophils. Upon entering the tissue, neutrophil’s gene expression changes, making it more phagocytic
Diapedesis
When neutrophils squeeze between the endothelial cells of the blood vessels, guided by a chemokine.
Extravasation mechanism
Neutrophil secretory granules
During their development in the bone marrow, neutrophils are loaded with four types of secretory granule. The granules are loaded in the order azurophilic, specific, and gelatinase granules, followed by secretory vesicles.
Neutrophil killing of bacteria
For neutrophils to kill bacteria, the phagosome must fuse with 3 types of secretory granules. Upon engulfing, degradative enzymes and toxic substances are released to rapidly kill the pathogen. The bacterium is engulfed to form an endosome that then fuses with the azurophilic, specific, and gelatinase granules of the neutrophil. The components of NADPH oxidase provided by the specific granules facilitate a respiratory burst. This raises the pH of the vesicle, which now becomes a phagosome. The antimicrobial proteins and peptides are activated by the change in pH, and they kill the bacterium. The phagosome fuses with lysosomes containing acid hydrolases, which lowers the pH and activates the hydrolases to degrade the bacterium completely. The neutrophil dies and its remains are phagocytosed by a macrophage. One neutrophil will kill many bacteria before its arsenal of weaponry and capacity for phagocytosis are exhausted.
3 types of preformed neutrophil granules
- Primary (or azurophilic)- has myeloperoxidase, lysozyme, defensins, cathepsin G
- Secondary (or specific)- has lactoferrin protein, lysozyme, components of NADPH oxidase
- Tertiary (or gelatinase)- has gelatinase enzyme
Respiratory burst
Neutrophils rely on respiratory burst to kill bacteria. Occurs when O2 consumed by phagocytes is converted within phagosomes to toxic reactive oxygen species (ROS). Occurs via action of the enzyme NADPH phagosome oxidase
How does the respiratory burst kill pathogens?
These reactions raise the pH of the phagosome to 7.8-8.0 within a couple minutes, and antimicrobial peptides get activated at this pH. The pH slowly goes down, reaching 7.0 after 10-15 min after which phagosome-lysosome fusion occurs
Neutrophil extracellular tarps (NETs)
Extracellular fibers, primarily composed of DNA from neutrophils, which bind pathogens to prevent dissemination. The pathogens are also exposed to antimicrobial proteins. In this way, neutrophils protect against pathogens even after they die (they are short lived, and cannot replenish their enzymes after they are used)
Death of neutrophils
Mature neutrophils cannot replenish their granule contents; once they are used up, they die. Some die by apoptosis and are then phagocytosed by a macrophage. Others die by a process called NETosis
TNF-alpha
Induces blood vessels to be more permeable, enabling cells, fluid, and soluble effectors to enter infected tissue
IL-6
Induces fat and muscle cells to metabolize, generate heat, and raise the temperature in infected tissue. It is involved in the acute-phase response, changing the spectrum of plasma proteins made by the liver. Concentrations increase for 30 proteins that contribute to innate immunity, but decrease for other plasma proteins like albumin
CCL2
Recruits monocytes from the blood and directs them to the infected tissue
IL-12
Recruits and activates natural killer cells to secrete cytokines that strengthen macrophages’ response to infection
Chronic granulomatous disease
Genetic syndrome caused by defective forms of genes encoding the NADPH oxidase subunits. No respiratory burst → No killing of pathogens. These patients are more susceptible to certain infections
Granulomas
Chronic infections are characterized by granulomas- small areas of inflammation in tissue. This is a way to wall off bacteria the body is unable to clear. Found in tuberculosis, A. fumigatus, and other bacterial/fungal infections
Time course of inflammation
Edema begins in less than a day, neutrophils respond in around a day, and monocytes, macrophages peak around 2-3 days, taking longer to disperse
Chronic inflammation
Prolonged duration (weeks or months) in which active inflammation, tissue destruction, and attempts at repair are proceeding simultaneously. It arises during persistent infections (HIV), prolonged exposure to toxic agents, or autoimmunity. Attempts at healing lead to fibrosis (scaring).
Macrophages and the secretion of pro-inflammatory cytokines are implicated. Inflammation is connected to several human diseases. The immune response is specific (where the immune response is activated).
Acute vs chronic inflammation
Acute inflammation is short term, over a period of days, while chronic inflammation is long term (weeks to months). Acute inflammation is nonspecific while chronic inflammation is specific. In acute inflammation, there is active vasodilation and increased permeability, while chronic inflammation causes new vessel formation (granulation tissue).
Pyrogens
Molecules that induce fever (IL-1β, IL-6, TNF-α and other molecule)
Effects of IL-1β, IL-6, and TNF-α on organs (4)
- Liver- acute phase proteins (C-reactive protein and mannose binding lectin) cause activation of complement and opsonization
- Bone marrow endothelium- neutrophil mobilization, causing phagocytosis
- Hypothalamus- increased body temperature, leading to decreased viral and bacterial replication
- Fat and muscle- protein and energy mobilization to generate increased body temperature
Acute-phase response
The cytokine-induced increase in the concentration of around 30 proteins within hours after inflammatory stimulus. Causes a systemic inflammatory response and increases the supply of the pathogen-recognition receptors of innate immunity. Proteins that change their concentration by 25% or more are called acute-phase proteins. C-reactive protein (CRP) and serum amyloid A’s concentrations rise by several hundredfold during the response. This effect is so strong and predictable that CRP is measured clinically to test for infection, inflammation, and tissue damage
C-reactive protein (CRP)
Member of the pentraxin family of proteins. It is a pentameric molecule with a hole in the middle. CRP binds to bacteria, fungi, yeasts, and parasites, and acts as an opsonin, triggering the classical pathway of complement activation
Serum amyloid A protein
A 100 amino acid protein that associates with HDL proteins. It interacts with TLRs and scavenger receptor to activate cells to produce cytokines, and data suggests it can activate the inflammasome. Induces chemotaxis of phagocytic cells
Mannose-binding lectin (MBL)
A C-type lectin that binds to mannose-containing carbohydrates of pathogens- it is a member of a family of soluble proteins called collectins. It is an acute phase protein that triggers the lectin pathway upon binding to the pathogen. Can act as an opsonin, facilitating the uptake of bacteria by monocytes
Mannose-binding lectin (MBL) structure
Structure resembles a flower and each stalk is a triple helix made of 3 identical polypeptides. The stalks are rigid collagen-like triple helices, with one site that can flex; each bud or flower comprises three carbohydrate-binding domains. Each polypeptide contributes a carbohydrate-recognition domain. MBL circulates in plasma as a complex with 2 zymogens: MBL-associated serine protease (MASP) 1 and 2
Activation of the lectin pathway by mannose-binding lectin
When MBL complex binds to mannose-containing macromolecules at a pathogen surface, MASP-2 gets activated (protease). Activated MASP-2 cleaves C4 into C4a and C4b. Some C4b covalently binds to the microbial surface. Activated MASP-2 will also cleave C2 to C2a and C2b
C2a function in the lectin pathway
After C2 is cleaved by MASP-2 into C2a and C2b, C2a binds to surface C4b, forming the classical C3 convertase C4b2a
C4b2a
A C3 convertase of the lectin pathway. Binds C3 and cleaves it to C3a and C3b. C3b binds covalently to the microbial surface.
C4bC2a and C3bBb
The C3 convertase produced by the classical and lectin-mediated pathways is C4bC2a. They are homologous, functionally similar enzymes that cleave C3 to activate its thioester bond. This causes C3b to become covalently bound to the pathogen surface.
Complement component C1
C1 molecule consists of a complex of C1q, C1r, and C1s.
C1q contains 6 identical subunits, each with one binding site for the Fc region of antibodies (IgM, IgG). CRP binds to the C1q stalks, leading to the cleavage of C1r and C1s, resulting in activation of classical pathway of complement activation
C1s
CRP binds to the C1q stalks, leading to the cleavage of C1r and C1s. C1s then goes on to cleave C4 and C2. The C2a and C4b fragments combine to form the C3 convertase of the classical and lectin pathway of complement activation: C4b2a
Toll-like receptors (TLR) sensors that detect viral infections (3)
- TLR3 senses double-strand (ds) RNA
- TLR7 and TLR8 sense ssRNA
- TLR9 senses hypomethylated CpG DNA.
Cytosolic DNA sensors that detect viral infections (3)
AIM2 (Absent in Melanoma-2), IFI16, and cGAS
Cytosolic RNA sensors that detect viral infections (2)
- Retinoic acid inducible-I (RIG-I)
- Melanoma differentiation-associated protein 5 (MDA5)
RIG-I and MDA5
Cytosolic RNA virus sensors which signal via a unique adaptor called mitochondrial antiviral signaling (MAVS; also known as IPS). These receptors mediate NF-κB and IRF (IFN regulatory factor)-dependent transcription of inflammatory genes.
RIG-1 like receptors (RLRs) mechanism (4)
- Viral replication in an infected cell produces uncapped RNA with a 5’-triphosphate
- RIG-1 binding to viral RNA induces association with MAVS
- MAVS associations initiate signal via TRAG6 that activates IRF3 and IRF7
- IRF3 and IRF7 turn on the synthesis and secretion of IFN-beta and IFN-alpha, respectively
AIM2
Absent in melanoma-2, recognizes viral double-stranded DNA. Induces IL-1β secretion
Cyclic GMP-AMP synthase (cGAS)
Recognizes viral DNA. It activates ER protein STRING to trigger type 1 interferon production
Interferon-response factor 3 (IRF3)
Works with NF-κβ and AP-1 to turn ON IFN-β synthesis
IFN-β actions (2)
- Autocrine: IRF7 and IFN-α secretion
- Paracrine: increased resistance to viral infection
Plasmacytoid dendritic cells
Plasmacytoid dendritic cells are factories for making large quantities of type I interferons. They combine features of lymphocytes and myeloid dendritic cells and are present in blood and lymphoid tissue. They detect viral infection by using TLR7 and TLR9- MyD88 signaling leads to the activation and translocation of IRF7 to nucleus. Results in transcription of Type I IFN gene. Type I Interferon prevents the spread of infection
Important functions of NK cells (3)
- Kill the cell infected with virus
- Increase inflammation in the infected tissue
- Secrete inflammatory cytokines that act on macrophages to make them activated
Natural killer (NK) cells
Natural killer cells are the main circulating lymphocytes that contribute to the innate immune response. NK cells are large active lymphocytes that are induced rapidly in response to infection. Abundant in blood (5-25%)
Induced innate immune response
The innate immune response to a pathogen that has overcome the immediate defenses of the body. Pathogens that expand their population at a greater rate than the pathogen is being killed or eliminated require the induced innate immune response to be triggered. This induced component can take up to 4 days to be activated
3 phases of an immune response to a pathogen
- Initial phase- begins as soon as the pathogen invades. Sufficient to terminate most infections
- Induced innate response
- Adaptive immune response- occurs after 4 days of infection if the immediate and induced responses aren’t effective
Phagocytosis by macrophages
Cell-surface receptors in macrophage are used to capture pathogens and deliver them to the acidic endosomes through the process of receptor-mediated endocytosis. From an endosome, the pathogen is taken through a series of vesicles where the pathogen is killed and partly degraded. The lysosome is the ultimate destination, where extreme acidity and degradative enzymes completely degrade the pathogen.
Adaptor protein
Protein in an intracellular signaling pathway that has no enzymatic or other activity in itself but brings two other components of the pathway together so that they can interact
Allotypes
A naturally occurring variant of a protein. Allotypes are encoded by different alleles of the same gene
Genetic polymorphism
The existence of two or more alleles of a given gene within a population, leading to variation between individuals
TLR4 polymorphism
Polymorphism is more common in TLRs that recognize surface determinants of proteins. TLR4 polymorphism influences severity of disease. For example, the rarer TLR4 allotype with glycine 299 confers a greater susceptibility to septic shock than the more common allotype with asparagine 299
NOD1
Soluble cytoplasmic receptor. Recognizes a degradation product of the peptidoglycan of gram-negative bacterial cell walls. Expressed in many cell types
NOD2
Soluble cytoplasmic receptor. Recognizes a degradation product of bacterial peptidoglycan. Expression is restricted to myeloid and cytoplasmic cells
Caspases
A type of protease that is involved in generating some cytokines from their inactive pro-proteins as part of the inflammasome. Caspases also have many non-immune functions
Type 1 interferons
A collective name for interferons alpha and beta. They are cytokines produced by virus-infected cells that interfere with viral replication by the infected cell. They also signal to neighboring infected cells to prepare to resist infection. Type 1 interferons have functions similar to those of cytokines
Interferon receptors
They are constitutively expressed on human cell surfaces, ready to bind interferon in response to infection
Interferons
A general name for a family of cytokines that induce cells to resist viral infection. They signal to neighboring cells to prepare to resist infection. Also, they alert the immune system that infection is present and cause virus-infected cells to become more vulnerable to attack by NK cells. All nucleated human cells can be infected by viruses, and they all make interferon. Interferons are barely detectable in the blood of healthy people but will increase when infection is present
Pyroptosis
A type of programmed cell death that results in inflammation and is the means by which large amounts of cytokine IL-1β are released from storage in macrophages. Pores are formed in the cell membrane through which the cytokines and cell contents leak out, resulting in the eventual death of the macrophage. Only a small amount of macrophages in infected tissue will die in this way. The cytokines released by one pyroptotic macrophages are usually enough to activate multiple other macrophages
Autoinflammatory diseases
A type of disease characterized by chronic and recurrent bouts of systemic inflammation mediated by cells of innate immunity. These diseases do not involve adaptive immunity.
Adhesion molecules
Any cell-surface proteins that allow human cells to bind to each other. Movements of leukocytes between blood and tissue are determined between complementary pairs of adhesion molecules- one is present on the leukocyte surface and the other is present on a tissue-cell surface
What triggers neutrophils to interact with the vascular endothelium?
In the absence of infection, neutrophils move rapidly through capillaries and don’t interact with the vascular endothelium. In infected tissue, inflammatory cytokines instruct the blood vessels to dilate, while inducing the endothelial cells to express selectin adhesion molecules. Blood flow decreases, which allows the neutrophils to contact the vascular endothelium within post-capillary venules. There are transient interactions between selectins on the endothelium and the sialyl-Lewisx carbohydrate of glycoproteins on the neutrophil surface. These interactions impede the neutrophils, causing them to roll along the endothelial surface
Importance of fever
It impairs the growth and replication of bacteria and viruses. In the presence of fever, tissue cells become more resistant to damage by TNF-alpha , which is an inflammatory cytokine. Other cytokines induce the lethargy, fatigue, and anorexia that come along with fever. This also helps to fight infection by preventing the body from using energy on other functions.
