Bacteria & Infection response Flashcards by Hayaka Amada

What does overgrowth of Clostridium difficile lead to?

Antibiotic-associated colitis (AAC)

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What are bacteria?

Prokaryotes (lack cell nucleus) –> DNA is free in the cytoplasm of the cell

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What are the two types of bacteria?

Gram positive and gram negative

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What is distinguished by Gram stain?

structure of bacterial cell wall

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What is the process of gram stain?

Bacteria stained with crystal violet stain and iodine

2. Cells washed with alcohol and counterstained with safarin

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How do gram positive bacteria appear?

Purple - they retain the crystal violet iodine copmlex

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How do gram negative bacteria appear?

Pink - complex is removed by the alcohol wash and stained with safarin

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What is the structure of a gram positive cell wall?

Thick cell wall made up of peptidoglycan on the outside of the cell membrane which retains the crystal violet dye

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What is the structure of a gram negative cell wall?

Have a thin layer of peptidoglycan sandwiched between two cell membranes
Outer membrane is heavily modified with sugars to produce lipopolysaccharide (LPS) or endotoxin

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What is LPS responsible for?

LPS is a very potent activator of the immune system and is largely responsible for endotoxic shock (e.g. in meningococcal sepsis)

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What is the peptidoglycan cell wall required for?

Integrity of the cell

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What is the significance of the production of peptidoglycan?

It is the target for several commonly used antibiotics e.g. penicillin

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What does MALDI-TOF MS stand for?

Matrix-assisted laser description ionisation-time of flight mass spectrometry

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What does MALDI-TOF MS involve?

The bacteria colony is exposed to a laser beam which ionises the sample. Analysis of the mass of the fragmentation products generated allows the identification of the organism by comparison to a data base.

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What are the 5 things bacteria need to do to cause disease?

Attach to the host
Invade the tissue
Acquire nutients and grow
Avoid the host immune response
Cause damage (–> symptoms)

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What are virulence factors?

Factors that allow bacteria to cause disease to the host

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How can bacteria attach to the host?

Appendages (pilli/fimbrae)
By attaching to specific host receptors the bacteria can induce their own uptake into pathways to allow intracellular survival rather than killing

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What do bacteria have that help with invasion into host cells?

Type 3 secretion systems

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What is an example of nutrient acquisition in cells?

Iron

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What are siderophores?

Molecules produced by bacteria which have high affinity for iron and can scavenge iron from host molecules

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How is immune evasion achieved?

Inhibition of apoptosis
Inhibition of phagocytosis
Inhibition of complement activation
etc

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What are the two mechanisms by which damage to the host can be mediated?

Direct and indirect mechanisms

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What does the direct mechanism of damage involve?

Usually mediated by production of toxins e.g. membrane damaging toxins, neurotoxins such as tetanus and botulinum

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What does the indirect mechanism of damage involve?

Overactivation of inflammation. Molecular mimicry where microbial components are similar to host e.g. Group A streptococci and acute rheumatic fever where antibodies to streptococcal proteins cross react with heart, lung and kidney antigens.

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What is toxic shock syndrome associated with?

Staphylococcal aureus toxin

What are some examples of gram positive bacteria?

Staphylococcus

What are some examples of gram negative bacteria?

H. pylori Vibrio cholerae Salmonella

What are the four main ways pathogens can enter the body?

1. Skin breach 2. Gastrointestinal tract 3. Respiratory tract 4. Genito-urinary tract

What type of epithelium lines the mouth, pharynx and upper oesophagus?

Stratified squamous epithelium

What is a common cause of renal failure in children?

Failure or the vesicourteric valve to prevent reflux of urine into the ureter

How does the innate immune system recognise pathogens?

Through Pattern recognition receptors and complement

How does the adaptive immune system recognise pathogens?

MHC molecules, T cell receptors, B cell receptors (antibody)

What do Pattern Recognition Receptors (PRRs) recognise?

General patterns on non-mammalian cells - Pathogen Associated Molecular Patterns (PAMPs)

What are Toll-Like Receptors (TLRs)?

A major group of PRRs

What are the 3 surface TLRs?

TLR-2, TLR-4, TLR-5

What does TLR-2 recognise?

Peptidoglycan, bacterial lipoproteins, lipoteichoic acid, porins

What does TLR-4 recognise?

lipopolysaccharide (LPS) from gram(-) cell wall, fungal mannans, parasitic phospholipids, heat-shock proteins, viral envelope proteins

What does TLR-5 recognise?

Bacterial flagellin

What are the intracellular/endosomal TLRs?

TLR-3, TLR-7, TLR-8, TLR-9

What does TLR-3 recognise?

viral dsDNA

What does TLR-7 recognise?

viral ssRNA

What does TLR-8 recognise?

G-rich oligonucleotides

What does TLR-9 recognise?

viral and bacterial unmethylated CpG sequences of DNA

What are other common PRRs?

NOD-2, RIG-I, MBL

What does NOD-2 recognise?

muramyl dipeptide from bacterial peptidoglycan

What does RIG-I recognise?

viral RNA

What does MBL (Mannose Binding Lectin) recognise?

microbial glycoproteins and glycolipids,can be soluble and trigger complement activation or attached to macrophages and trigger phagocytosis

What is the end result of TLRs binding to PAMPs?

upregulation of inflammatory cytokines

What do genetic defects in Myd88 or IRAK4 result in?

immunodeficiency characterised by recurrent pyogenic infection

What are the three ways in which the complement cascade can be triggered?

Classical pathway, lectin binding pathway, alternative pathway

How is the classical pathway activated?

Following recognition of antigen-antibody complexes, and through CRP

What is the main pathway of complement activation during the adaptive immune response to a pathogen?

Classical pathway

What do local macrophages release following infection?

cytokines that alert the immune system of attack

What do IL-1B and IL-6 do?

Released into tissue fluids and act on the liver to induce the release of soluble acute phase proteins

What are the two acute phase proteins involved in the lectin pathway?

Mannose Binding Lectin (MBL) and C-Reactive Protein (CRP)

What do MBL and CRP do?

They are soluble PRRs that recognise common constituents of bacterial cell walls, triggering complement activation

What does MBL recognise and bind to?

mannose

What does CRP recognise and bind to?

Phosphorylcholine

During the innate response, which pathway does the lectin pathway support?

The alternative pathway

What is the main complement activation pathway when infected with a previously unknown pathogen?

alternative pathway

What is the alternative pathway activated by?

endotoxin and bacterial cell walls

What does the activation of alternative pathway rely on?

Soluble C3 spontaneously hydrolysing to insoluble C3b

What does insoluble C3b bind to?

any nearby microbial/membrane surface

What is the result of C3b binding?

Activation of the rest of the complement cascade | Microbe becomes covered in C3b molecules, promoting opsonisation

Where is C3 convertase found?

On the surface of the mirobe

What does C3 convertase do?

Split molecules of soluble C3 to insoluble C3b

How does C3b help in the amplification loop?

Bound C3b molecules form more C3 convertases (via the alternative pathway)

How is the complement system controlled?

Inhibition by control enzymes

What do the control enzymes of complement cascade do?

cleave C3b to an inactive form called iC3b

What are 2 examples of control enzymes?

Factor H, Factor I

What is absence of control enzymes associated with?

Low levels of circulating C3 and an increased risk of infections esp. Neisseria meningitidis

A patient with 2 episodes of Neisseria meningitid has complement investigations undertaken. A defect in what factor/test is most likely?

Alternative pathway defect

What does C3b activate?

C5 convertase

What does C5 convertase activate?

the terminal lytic pathway components C5-9

What makes up the Membrane Attack Complex (MAC)?

C5b-9

What is the MAC?

A transmembrane channel

How does the MAC cause destruction?

Allows water uptake into the cell resulting in swelling and ultimately destruction of the cell

What are the 4 function of complement activation?

Opsonisation, cell lysis, mast cell degranulation, neutrophil chemotaxix

What causes opsonisation?

Surface bound C3b and iC3b

What is C3b recognised by?

Complement Receptor 1 (CR1)

What is iC3b recognised by?

Complement Receptor 3/4 (CR3/4)

Where are CR1 and CR3/4 expressed?

On neutrophils and macrophages

What causes cell lysis?

formation of MAC

What causes mast cell degranulation?

C3a

How do C3a act on mast cells?

Mast cells express C3a receptors

What causes neutrophil chemotaxis?

C5a is able to attract neutrophils to site of complement activation

What are the two main complements tests undertaken frequently?

C4 and C3

What does a high complement level reflect?

Infection, not a natural response

What do patients with a low C4 suffer from?

Recurrent infection

What type of bacteria do patients with a low C4 suffer from?

Encapsulated bacteria

Which pathway is responsible for killing bacteria such as pneumococcus?

Classical pathway

How many alleles is C4 made up of?

What is a common immune complex disease?

Lupus

What could cause a low C4?

C1 inhibitor deficiency (Hereditary angioedema)

When is C1 inhibitor used?

At the beginning of the classical pathway, to block C1 formation Also an enzyme that works in the bradykinin pathway

What does bradykinin do to vessels?

Increase intravascular permeability (as well as vasodilation)

What does bradykinin result in?

Oedema (swelling) due to fluid movement

What are the acquired causes of a low C4?

Consumption or increased activation of the classical pathway - lupus, cryoglobulinaemia, rheumatoid vasculitis, ANCA positive vasculitis

What does a low C3 often present with?

Meningitis

What is the most common acquired low C3?

Post-streptococcal glomerulonephritis in paediatrics

What are the cells of the innate immune system?

Dendritic cells, monocytes, macrophages, neutrophils, eosinophils, basophils, mast cells, NK cells

Where are dendritic cells found?

all tissues

What is the main function of dendritic cells?

presentation of antigen to naive T cells

How can dendritic cells be activated?

Local tissue injury - to take up fluid and particles from their surroundings

What does activation of dendritic cells cause them to do?

Migration to secondary lymphoid tissues

What do dendritic cells do in the secondary lymphoid tissues?

Present to T lymphocytes the antigen derived peptide/MHC complexes

What are the 3 functions of dendritic cells?

1. Pick up and process antigens, and present them on their MHC class I and class II molecules 2. Migrate to the T cell rich areas of secondary lymphoid tissues where naive and memory T cells circulate, and where they present antigens to specific T cells 3. Transmit danger signals through molecules like TLR that help determine the type of T cell response that is programmed

What do follicular dendritic cells capture?

They capture native non-degraded antigens through complement and antibody and presents this antigen to B cells in B follicles

Where are dendritic cells most abundant?

Body surface

What are Langerhans cells?

Tissue dendritic cells that have not taken up antigen

What induces Langerhans cells to start to take up material from their surroundings?

Local tissue injury which causes release of chemical mediators

How do Langerhans cells take up material?

In pinocytotic vesicles

What do Langerhans cells have that help with phagocytosis?

Receptors that allow them to recognise bacteria and induce phagocytosis

Which type of cell can engulf cells, including phagocytes, which are undergoing apoptosis?

Langerhans cells