Quiz 2

what fills the gap between physical barriers and the adaptive immune system

the innate immune defenses

What is the mechanical barriers in the skin, gut, lungs, eyes/nose/oral cavity

epithelial cells joined by tight junctions

what kind of cells are skin and mucous membranes made up of

flattened epithelial cells

What connects epithelial cells in the skin and mucous membranes

tight junctions that continually shed

skin and mucous epithelial cells are impenetrable to microbes unless_____

broken due to wound or burn

What are the mechanical barriers in the skin and gut

longitudinal flow of air or fluid

What are the mechanical barriers in the lungs

movement of mucus of cilia

What are the mechanical barriers in the eyes/nose/oral cavity

tears and nasal cilia

What are unnoticeable (autonomic/semi-autonomic) mechanical defenses

blinking, tears, swallowing, peristalsis, mucociliary escalator

What are energetic mechanical defenses

coughing, sneezing, urination

What are violent mechanical defenses

vomiting and diarrhea

What are the two mechanisms of the mucociliary escalator

Mucus secretion by the goblet cells combined with the timed beating of cilia on epithelial cells

What is the purpose of the mucociliary escalator

to push debris and microbes in a unidirectional manner out of the respiratory tract

How does cystic fibrosis affect the mucociliary escalator

defects in the mucus layer prevent this defense mechanism

What are the chemical barriers in the skin

fatty acids

What are the chemical barriers in the gut

low pH and antimicrobial enzymes

What are the chemical barriers in the lungs

pulmonary surfactant

What are the chemical barriers in the eyes/ nose/ oral cavity

antimicrobial enzymes in tears and saliva

What are the chemical barriers in the skin, gut, lungs, eyes/nose/oral cavity

antimicrobial peptides

What are defensins

peptides 30-40 amino acids in length, lots of arginine residues, 3 antiparallel beta-sheets

What is the important feature of defensins

amphipathic (containing both hydrophobic and hydrophilic regions), which allows it to disrupt membrane integrity of pathogens

What do defensins promote

protein unfolding and denaturation of bacterial toxins

what are pentraxins

plasma molecules that bridge betwen pathogens and phagocytes

what do pentraxins do

promote engulfment of pathogens by phagocytes, short form includes SAP and C-reactive protein (CRP)

What are the microbiological barriers in the skin, gut, lungs, and eyes/nose/oral cavity

normal microbiota

When does colonization of commensal bacteria occur

Some time around birth and is impacted by delivery mode and antibiotic use

How is commensal bacteria a microbiological defense

The presence of the microbiome makes it harder for pathogenic microbes to invade by competing for nutrients and space. The microbiome is required for immune homeostasis and proper barrier function

What is the Complement system

a complex system of at least 30 proteins

What does the complement system do

interact to kill invading microbes, trigger inflammation, and regulate immunity

what is the star of the complement system and why

complement component 3 (C3) because it does complement fixation, which is the irreversible attachment of C3b to pathogens

how many activation pathways and major downstream outcomes are there

three of each

substrate modulation

Enzymes (proteases) cannot act on their substrate until they themselves become activated, which leads to a chain of activation and substrate cutting. This ensures that the activation of complement enzymes is highly regulated

C3 activation before cleavage

C3 has a reactive thioester bond that is normally on the inner side of the protein and protected from hydrolysis

C3 activation after cleavage

once C3 is cleaved, the thioester bond is exposed, and most C3b is immediately hydrolyzed by water. Some C3 covalently binds to the surface of the pathogen via a hydroxyl or amino group

what are the three pathways of complement activation

alternative, lectin, and classical pathways

the alternative pathway

the most common (80-90% of complement activation), C3 convertase is initiated by spontaneous hydrolysis of the thioester bond

what does C3 convertase do

cleaves other C3 molecules into C3a and C3b

The lectin pathway

Triggered when mannose-binding lectin (MBL) or other lectins bind to carbohydrates on the microbial surface. MBL binds and activates MBL-associated serine protease (MASP), triggering the formation of a C3 convertase

The classical pathway

triggered when antibodies or C-reactive protein (CRP) bind to bacterial surface and recruit the C1 complex (C1q, C1r, C1s) to trigger the C3 convertase

where do the new C3b fragments from complement activation go

produce additional C3 convertases (amplification), bind phagocytic cell receptors (opsonization), generate C5 convertases (promotes pathogen lysis through membrane attack complex)

where do the C3a fragments from complement activation go

they serve as attractants of innate cells (anaphylotoxin)

opsonization

C3b-coated pathogens can be bound by complement receptor 1 (CR1) to promote phagocytosis

perforation of pathogen cell membranes starts with activation of C5

all pathogens generate a C5 convertase that leads to the formation of a membrane-attack complex (MAC), which disrupts cell membranes

what is the membrane attack complex made up of

1 C5b, 1 C6, 1C7, 3C8, 18C9

recruitment of inflammatory cells

anaphylatoxins: C3a, C5a recruit leukocytes to the site of infection and trigger additional inflammatory signals that induce contraction of smooth muscle and vascular permeability

soluble complement regulatory proteins

factor H and Factor I work together to cleave C3b and iC3b which can opsonize but cannot form a C2 convertase

membrane-bound complement regulatory proteins

decay accelerating factor (DAF)/ CD55-prevents formation of C3 convertase, Membrane cofactor protein (MCP) helps to inactivate C3b by binding Factor I

C3 deficiency

occurs in Brittany spaniels as a result of a mutation in the C3 gene, results in increased susceptibility to disease, most notably bacterial pneumonia, inherited as an autosomal recessive condition

Factor H deficiency

occurs in pigs, autosomal recessive, uncontrolled activation of the alternate pathway results in massive amounts of C3 being deposited in the kidneys, glomerular capillary wall thickening, results in renal failure and death

cytokines

small secreted proteins that act locally on other cells (or the same cell), interleukins (IL), interferons (IFN), tumor necrosis factor (TNF)

chemokine

small secreted proteins that recruit immune cells to sites of inflammation, CCL2, CCL3, CCL4, CXCL8, CXCL10

What do cytokines and chemokines allow the cell to do

quickly communicate with each other

pattern- recognition receptors (PRR)

recognize pathogen-associated molecular patterns (PAMPS) presented by microbes, including lipids, nucleic acids, and proteins

what are the two types of membrane-bound receptors

Toll-like receptors (TLRs) and scavenger receptors (SRs)

toll-like receptors

surface and endosomal, recognize lipid, protein, and nucleic acid patterns

scavenger receptors

surface, recognize a broad range of microbial and host ligands (lipoproteins, carbohydrates, phospholipids)

what are the two types of cytoplasmic receptors

NOD-like receptors (NLRs), RIG-I-like receptors, and cGAS-STING receptors

NOD-like receptors

cytoplasmic, recognize degraded bacterial products (peptidoglycans)

RIG-I-like receptors

cytoplasmic, recognize viral RNA

cGAS-STING

recognizes viral dsDNA and bacterial components

what is the structure and domains of Toll-like receptors

function in dimers and are composed of 2 domains: pathogen-recognition domain (leucine-rich repeat regions- LRRs: 20-29 amino acid segments enriched for leucine residues) and TIR domain (toll/interleukin-1-receptor)

what is the ligand of the TLR1:2 or TLR2:6 heterodimer

peptidoglycan and lipoproteins

what is the ligand of the TLR3 homodimer

dsRNA (endosomal)

what is the ligand of the TLR4 homodimer

lipopolysaccharide (LPS)

what is the ligand of the TLR5 homodimer

flagellin

what is the ligand of the TLR7 and TLR8 homodimers

ssRNA (endosomal)

what is the ligand of the TLR9 homodimer

unmethylated CpG DNA (endosomal)

receptor signaling works by oligomeric scaffolding

engagement of PRRs leads to an intracellular signaling cascade, oligomeric assembly brings weak interactions together quickly, intracellular signaling cascade through MyD88 and eventually NF-kB leads to gene transcription and cytokine production

what does binding of scavenger receptors (SRs) lead to

phagocytosis of microbes

what does binding of NOD-like receptors lead to

recognition of products of bacterial degradation to induce cytokine production

What does binding of RIG-I-like receptors lead to

generates production of cytokines called type I interferons, RLRs recognize viral dsRNA, RLR binding leads to production of Type I interferons (IFN-alpha, IFN- beta)

what happens when cGAS is activated

it is activated by viral dsDNA to produce cGAMP, and cGAMP and bacterial c-diGMP/AMP bind to STING

what happens when intracellular LPS is detected

1. Cytosolic LPS is recognized by caspase-4

2. Caspase-4 activates Gasdermin D

3. Gasdermin D induces assembly of a pore in the plasma membrane

4. The Gasdermin D pore causes death of the cell by pyroptosis

what recognizes intracellular LPS

caspase-4

what is called the executioner protein

Gasdermin D

what is pyroptosis

inflammatory or fiery cell death

Damage-associated molecular patterns (DAMPs) can also be recognized by receptors

the products of broken cells, altered self, released by damaged or stressed tissues, mitochondrial products resemble bacterial PAMPs

what does Type I interferons produce

anti-viral proteins and amplify the response through paracrine action

autocrine

a cell produces a signal that acts on its own receptor

paracrine

a cell produces a signal that acts on another cell

plasmacytoid dendritic cells (pDCs)

plasmacytoid dendritic cells are the biggest producers of Type I interferon (IFN-alpha, IFN-beta) pDCs express TLR7 (viral RNA) and TLR9 (bacterial/viral CpG motifs in DNA)

Innate cells detect non-self and altered-self patterns

1. Engulfment and destruction of the pathogen

2. secretion of cytokines and chemokines that activate other cells in the immune system

3. Killing of the infected cell: the cell itself (i.e., a macrophage) or a neighboring cell (i.e., an NK cell)

innate effector cells

macrophages, neutrophils, dendritic cells

macrophages

tissue-resident myeloid cells found in almost every organ in the body, they often serve as sentinels for invasion by pathogens, produce inflammatory cytokines, in addition to innate immune functions, macrophages are responsible for tissue maintenance

what is the main function of macrophages

phagocytosis

phagocytosis

the process by which cells ingest or engulf particles, microorganisms or other material

what types of cells are phagocytes

macrophages and neutrophils

what are the stages of phagocytosis

1. Binding to the pathogen

2. ingestion

3. degradation in the endosome/phagosome

4. further degradation in the phagolysosome

neutrophils

polymorphonuclear cells (PMN), a common feature is all have a segmented, many-shaped (polymorpho) nucleus, are short-lived, circulate rapidly, recruited to the site of infection by chemokines, known for respiratory burst and production of NETs

how are neutrophils recruited into the site of infection

through chemokine signaling

how do neutrophils get out of the bloodstream

interactions with the blood vessel endothelium

what are the 4 stages of extravasation

rolling adhesion, tight binding, diapedesis, and migration

selectins

initiate rolling adhesion

integrins

initiate tight binding