Infection and Immunity Flashcards
Primary immune response
First encounter
Response is fairly weak and short lived but T and B memory lymphocytes are produced
Secondary immune response
Subsequent encounter with the same organism
T and B memory lymphocytes enable much faster and stronger protection
Immune hypersensitivity response
Primary response followed by secondary response harms the host
Secondary response being harmful
Can cause harmful reactions, including tissue damage
Allergy to allergens
Tissue damage due to autoimmune reactions
How are allergens detected by the immune system
Dendritic cells form the bridge between innate and adaptive immune responses
They are prototypic antigen-presenting cells of the immune system
Dendritic cells are critical for induction and regulation of adaptive immune responses
How do dendritic cells activate the adaptive immune system
Become activated and migrated to lymph nodes
Mature dendritic cells present antigen-derived peptides on cell surface MHC molecules to activate naive T cells with antigen receptors that recognizes the MHC/peptide combination
Neutrophil
12-15um
2-5 distinct nuclear lobes, abundant granules
Phagocytosis and degranulation
Basophil
9-10um
2-3 nuclear lobes, many, large oval granules. Degranulation
Monocyte
12-20um, round, oval notched, abundant granules
Phagocytosis and cytokine production in the blood
Macrophage
15-80um
Elongated, indented or oval nucleus, many granule
Phagocytosis and cytokine production in the tissues, antigen presenting cell
Mature B and T cells
9-12um
round or slightly indented nucleus, few granules
Adaptive immune responses
Plasma Cell
14-18um
round or oval nucleus, no granules
B effector cell, antibody production
NK cell
12-16um, round nucleus, many granules
Cytolysis and cytokine production
Dendritic cell
Irregularly shaped cell and nucleus, many cellular projections
Phagocytosis and cytokine production, antigen presenting cell
Mast cell
5-25um non-segmented nucleus, many large granules
Degranulation and cytokine production
Antibody structure
2 heavy chains and 2 light chains held together by inter-chain disulfide bonds
2 antigen-binding sites
1 effector function-crontilling region
Effector functions e.g complement triggering, cell receptor binding
Human heavy chain isotypes
1 of 5 possible heavy chain isotypes determine heavy chain isotype of Ig molecule
Receptors on leukocytes can bind Fc specific for Ab class
Called Fc receptors and are specific for Ab class
Types of Ig molecule
IgM, IgD, IgG, IgE, IgA
Which ig molecules mediate hypersensitivity
IgE, IgG and IgM
Fc receptors and immune hypersensitivity reactions
Receptors for antigen-antibody immune complexes. They bridge humoral and innate immune systems. They are inflammatory mediators, do phagocytosis, degranulation and antibody-dependent cell-mediated cytotoxicity ADCC
Type 1 HS
IgE medited, allergy atopy
<1-30min
Allergens cross-link IgE bound on mast cells and basophils induce degranulation
Asthma, hay fever, eczema, hives, food allergies
What is an allergen
An antigen that generates an abnormal immune response that fights off a perceived threat that would otherwise be harmless to the body
Atopic allergy
Grass pollen
Skin prick test
Immediate response (early phase reaction) with minutes
Late response (late phase reaction) a few hours later
Sensitization of Type 1 HS
Allergen breached tissue barrier
Phagocytosed by immature D cell
Travels to lymph node
Naive T cells recognise allergen derived pMHC on mature DC and become activated, differentiate into Th2 effector cells that help activate B cells. Activated B and Th2 cells leave the lymph node
Travel to where allergen entered body
Th2 cells produce cytokines that instruct plasma cells to produce IgE
IgE can bind directly to allergen or FCR on mast cells. Mast cells are sensitised for the effector stage
Excess IgE taken up by lymphatics
IgE encounters basophils in the blood and binds to FcRs to sensitise them
IgE encounters mast cells in other tissues and binds to FcRs to sensitise them
Effector stage of Type 1 HS (early stage)
Allergen enters tissue where sensitised mast cells are present
Allergen binds IgE molecules attached to mast cells via FcRs
Mast cells degranulate and secrete cytokines/chemokines
Breakdown of mast cells releases platelet-activating factor
Tissue-specfic symptoms of allergic response
Additional leukocyte recruited (eig eosinophils and sensitised basophils)
Differences of mast cell granulations due to route of allergen entry (Gastrointestinal tract)
increased fluid secretion and peristalsis - diarrhoea and vomiting
Differences of mast cell granulations due to route of allergen entry (Eyes, nasal passages and airways)
Decreased airway diameter, increased mucus secretion
Congestion and blockage of airways (wheezing, coughing phlegm) Swelling and mucus secretion in nasal passages. Ocular itching and sneezing
Differences of mast cell granulations due to route of allergen entry (Blood vessels)
Increased blood flow, increased permeability
Increased fluid in tissues causing increased flow of lymph to lymph nodes, increased cells and protein in tissues, increased effector response in tissues. Hypotension potentially leading to anaphylactic shock
Determinants favouring atopy
Genetic determinants and environment determinants trigger events which leads to clinical atopy upon exposure to allergen
Type II HS
Direct antibody- mediated cytotoxic HS
Antibody (IgG or IgM)
5-8hr
IgM or IgM bind to cell-bound antigen, cell is destroyed by phagocytosis, complement activation or ADCC
Hemolytic anemias, Goodpasture’s syndrome
Antibody-mediated cytotoxic hypersensitivity
Autoantibodies against cell surface Ag
Complement-dependent cell lysis
C3b-opsonised phagocytosis
FcR-mediated antibody-dependent cell-mediated cytotoxicity, ADCC (NK cells and macrophages)
Type III hypersensitivity
Immune complex-mediated HS
Antibody (IgG or IgM)
4-6 hr
Immune complexes trigger complement activation; phagocyte FcR engagement leads to release of lytic mediators
Arthus reaction, aspects of rheumatoid arthritis and systemic lupus erythematosus
Immune complex-mediated hypersensitivity
Ab binds antigen in the blood (IC). Insoluble ICs form by cross-linking that lodge in small vessels. ICs enter tissues (kidneys, joints), drives local inflammation/tissue damage
What is immunological tolerance?
Immunological tolerance is a state of unresponsiveness to an antigen
When a lymphocyte encounters an antigen it can either be activated, leading to an immune response, or inactivated/eliminated, lead to tolerance.
Self reactive lymphocytes
Have the potential to respond to self antigens (or autoantigens) are called autoreactive lymphocytes
What happens if immunological tolerance fails to remove self-reactive lymphocytes
Autoimmune diseases can occur if the resulting autoimmune response leads to tissue damage.
Central tolerance
Deletion of strongly self-reactive T and B cells during their development
Where are lymphocytes developed
Primary lymphoid organs are sites in the body where lymphocytes develop
Thymus for T cells and bone marrow for B cells
Positive selection
Lymphocytes are positively selected based on their affinity of interaction with the self MHC complex expressed on cortical thymic epithelial cells. A T cell which does not recognise self at all will undergo death by neglect.
Negative selection
Lymphocytes are negatively selected based on their affinity of interaction with self antigen-MHC complexes presented by dendritic cells, macrophages and cortical/medullary epithelial cells. A T cell which receives very strong signals will undergo apoptotic death
Autoreactive cells can escape
How does pos and neg selection occur?
Positive selection occurs in the cortex when thymocytes are double positive for CD4 and CD8.
Thymic cortical epithelial cells mediate positive selection.
Developing T cells bearing antigen receptors that recognise self MHC with sufficient affinity survive.
T cells bearing TCRs that strongly recognise self peptide, self MHC are negatively selected.
DP cells express a successfully rearranged TCR with CD4 and CD8 on their surface
Positive selection rescues the T cell from default ‘death by neglect’
Those with high affinity interactions with dendritic cells presenting self MHC with self peptide undergo negative selection
T cell education
Most thymocytes bear TCRs that fail to bind self MHC (80%)
Most thymocytes with TCRs that bind strongly to self peptide: MHC are removed by negative selection (20%)
Leaves 1-2% of positively selected thymocytes and ensures strongly autoreactive clones removed from T cell repertoire
Education of B cells
Educated to not recognise self antigens during their development,
Developing B cells with BCRs strongly recognize multivalent cell-surface self antigen undergo selection
B cell precursor rearranges its immunoglobulin genes
Immature B cell bound to self cell-surface antigen is removed from the repertoire
Mature B cell bound to foreign antigen is activated
Activated B cells give rise to plasma cells and memory cells
What happens when an APC presents self-peptide
DCs present self antigens derived from host cells, in the absence of pathogen attack
In the absence of pathogen attack the DC is not activated
DC encounters an autoreactive T cell that recognises the self MHC, self peptide combination it inactivates it
Suppression-regulatory T cells
Specialised autoreactive T cells
If Tregs encounter self antigen on APC they can inhibit surrounding autoreactive T cells by producing inhibitory cytokines like IL-10 and TGF-b
Ignorance-sequestered antigen release
Sympathetic ophthalmia
- Damage to an immunologically privileged site (eye)
- Release of sequestered eye antigens can result in an autoimmune response against eye proteins in both eyes
Requirements for autoimmune disease
Escape of autoreactive clones from central tolerance
Autoreactive clones encounter self-antigens
Peripheral tolerance failure
Autoreactive tissue damage
Where does type II Hs act?
Organ-specific
Antibody - mediated (cytotoxic)
Where does type III Hs act?
Systemic
Immune complex-mediated
Organ-specific autoimmunity diseases
Goodpastures syndrome
Myasthenia gravis
Pemphigus
Goodpasture’s syndrome
Antibodies against type IV collagen in basement membrane (glomeruli and alveoli)
Kidney dysfunction, bleeding in lungs
Myasthenia gravis
Antibodies block acetylcholine receptors
Muscle weakness
Pemphigus
Antibodies against intercellular adhesion (desmogleins) between keratinocytes causing blisters
Can lead to fatal infections
Thyroid autoimmune diseases
Graves disease
Hashimoto’s disease
Graves disease
Autoantibodies bind the thyroid stimulating hormone receptor
Acts as agonist
Hyperthyroidism
Hashimoto’s disease
Autoantibodies against thyroglobulin and thyroid peroxidase
Complement activation and cytotoxic T cell - driven attack hypothyroidism
Systemic autoimmune disease
Soluble antigen and antibodies in optimal concentration
-> Precipitation
-> Vessel deposition (Type III hypersensitivity)
Kidneys - glomerulonephritis
Skin - rash
Joints - arthritis
Systemic Lupus Erythematosus
Inflammation in the skin, joints, blood vessels, kidneys
Photosensitivity
Antinuclear autoantibodies, anti-DNA, anti-RNA, anti-nuclear proteins
Molecular mimicry
Some T and B cells may bear antigen receptors that recognise both the self epitope and the pathogen and epitope
Acute Rheumatic fever
Group A streptococcal post-infection complication
M proteins share epitopes with proteins in synovium, heart muscle, and hear valve. Antibody-mediated Type II hypersensitivity generates tissue damage and inflammation.
Arthritis and heart valve damage
Factors influencing autoimmunity
Genotypes can be predisposed to autoimmunity
There are replacement and suppression treatments.
How to do a gram stain
Heat-fixed slide stained with crystal violet (purple)
Stain attaches to peptidoglycan in bacterial cell wall.
Iodine binds to crystal violet and traps it in the cell
Add ethanol or acetone
-> Then stain with safranin or carbol fuchsin (pink)
-> Gram pos - retain crystal violet dye
-> Gram neg- doesn’t retain crystal violet dye
Gram negative
Outer membrane composed of lipopolysaccharides (LPS). Have an outer membrane
Gram positive
Thick peptidoglycan cell wall
Lack an outer membrane
Ziehl Neelsen stain
Carbol fuchsin (red) in phenol driven into bacilli with heat
For mycobacterium tuberculosis
Motility of bacteria
Swarming
Twitching - use appendages, has pilus
Swimming
Gliding
Sliding - bind & unbinding
Aerotolerance
Obligate Aerobes -tolerant to oxygen. ATP production by aerobic respiration
Obligate Anaerobe - not tolerant to oxygen. ATP production by fermentation
Biofilms
Sticky matrix - protection from immune system & antibiotics
Highly organized microbial communities
Genetic variability
Genetic material is in a chromosome or plasmid
Core + accessory genes = pan genome
There are big colonies and small colonies which evade immune system
Transformation of bacteria
Uptake of naked DNA from surrounding environment into the genome of the bacterial cell
Transduction of bacteria
Bacteria DNA is transferred from one cell to another via bacteriophages (viruses) acting as vectors
Conjugation of bacteria
Process of direct cell to cell transfer of genetic material mediated by conjugative plasmids (extrachromosomal DNA elements)
Found in guts or soil
Pathogen
Microbe capable of causing damage to host
Infection
Colonisation/invasion of a host by a pathogen
Sources of pathogens
Self and others
Food and drink
Environment, including soil, plants and water
Air
Inanimate objects
Insects and animals
Modes of transmission of disease
Airborne
Drinking and eating
Bodily fluids
Direct contact
Insect bite
Surgery
Risk factors
Age
Existing/underlying medical conditions
Genetics
Hospitalisation/surgery
Medication
Contact
How to cause an infection
Establish a foothold
Evade host defences
Proliferate
Cause damage
Why do bacteria stick
Prevent being washed away and anchor at a preferred niche
How do bacteria stick
Non-specific adhesion molecules (often reversible)
Specific adhesins - Gram-negative bacteria - Pili and Fimbriae. Outer membrane adhesins
Gram positive bacteria - cell wall proteins - Microbial surface components recognising adhesive matrix molecules
Enteropathogenic E.Coli attachment
Initial contact with intestinal cells mediated through bundle forming pilus (BFP)
Attaching - effacing lesion
- characterised by effacement of brush border microvilli and intimate attachment of bacteria to cell.
Locus of enterocyte effacement
Codes for Type III secretion system
Inject bacterial proteins into cell to change cell function
Neisseria meningitidis
Pili attach to receptor on nasopharyngeal cell surface
Pili retract allowing adhesion of outer membrane adhesin to receptor on cell surface
Staphylococcus aureus attachment
Lipoteichoic acids mediate initial attachment to cell surface
MSCRAMMS mediate stronger interaction with matrix proteins e.g fibrinogen, fibronectin, collagen
Host defences
Skin, mucosal barriers
Antibacterial compounds in sections
Iron restriction
Complement
Phagocytes
Antibodies
Invasion by Listeria
Entry
Lysis of the vacuole
Intracellular movement
Cell to cell spread
Lysis of the two-membrane vacuole
Ways of resisting antimicrobial fluids
Altering surface charge so as to repel cationic peptides
Producing proteases e.g to cleave sIgA
Producing physical barrier e.g capsule, s-layer, outer membrane
Evading the immune system
Using mask or hiding
Immune defense do not see the invader as NON-SELF
Masking and hiding - capsule
Surface exposed protein antigens are recognised by antibodies. Complement deposited on surface of bacterium. Easily phagocytosed (opsonised) complement mediated lysis
Many vaccines composed of capsular polysaccharide so pathogen is easily recognised
Masking and hiding - invading
Invades host cells like mycobacterium tuberculosis inside macrophages
Mimicking the host -appearing as SELF
Mimicking
Antibodies recognise foreign antigens on surface of bacterium
Promotes destruction and disposal of pathogen
Mimicking - binding Ig and Staph
Staph - Protein A binds to antibody Fc region
Inhibits the activation of complement, phagocytosis and ADCC
Cell now covered in layer of host proteins = recognised as self
Mimicking - binding host proteins
MSCRAMMS bind to extracellular matrix proteins
Recognises as self
Mimicking - binding factor H
If C3b forms on a cell it can target it for complement-mediated damage.
Serum factor H binds to our cells and degrades any C3b forming on the surface to protect us from damage
Phagocytic killing
Attraction
Recognition and phagocytosis
Phagosome/lysosome fusion
To either bacterial killing or toxin production which leads to phagocyte death and bacterial survival
Detoxifying the phagocyte
After formation of a phagosome, detoxified ROI or prevention of fusion means bacterial survival
Complement factor proteolysis
Complement factor proteolysis refers to the cleavage or breakdown of complement proteins by proteolytic enzymes, which is a crucial step in the activation and regulation of the complement system.
Complement disruption
Complement disruption refers to the interference or inhibition of the complement system, a crucial component of the immune system involved in host defense, inflammation, and the clearance of pathogens
Antigenic variation
Invading population mutates and is not recognised by immune system
Outer membrane blebs
Blebs of outer membrane containing lipopolysaccharide and outer membrane proteins released as immune decoys
Iron resources
Transferrin in blood
Function in enzymes
Stored as ferritin in cells
Siderophores
Specific binding proteins
Peptic ulcer disease
Break in the lining of stomach/small intestine
Symptoms: Upper abdominal pain
Belching
Vomiting
Weight loss
Bleeding
H. Pylori prevalence
From asymptomatic to deadly
Gastritis (80-90%)
Peptic ulcer (10-20%)
Gastric cancer (1-2%)
MALT lymphoma (<1%)
Estimated that 50% of world’s population is infected
H. pylori: transmission
Gastro-oral
Fecal oral
Sexually?
H pylori: disease progression
Infection
Superficial gastritis (Days - weeks)
Chronic gastritis (Months - years)
Antral gastritis, pangastritis, chronic active gastritis (Decades)
Duodenal gastric metaplasia, Atrophy intestinal metaplasia, chronic active gastritis (decades)
Duodenal ulcers
Gastric cancers & ulcers
MALT lymphoma
Flagellum
H. pylori uses it to swim fast to mucus layer
Helical shape
Gives ‘screw-like’ movement which allows it to penetrate mucus
H. pylori acid resistance
Uses urease to produce a ‘cloud’ of ammonia to neutralise acid
H. pylori: mucus ‘de-gels’
H. pylori raises ph, mucin de-gels
H. pylori gastric coloniser
Attaches to gastric epithelium via Lewis b carbohydrate receptor with BabA adhesin
Chronic infection: Immune evasion
Evade host defense
LPS = poorly recognised by TLR4 -> low levels of cytokine production
Flagellum subunits = poorly recognised by TLR5 -> low levels of cytokine production
Vacuolating toxin A (VacA)
Inhibits phagosomal maturation. T/B cell proliferation, iNOS generation
Coating with plasminogen and cholesterol -> mimic host
Chronic infection and inflammation
Loss of function of cells in the inflamed area
Ulcers
a lesion found on the mucous membrane
Peptic ulcer
ulcer in the lining of the stomach or duodenum, where hydrochloric acid and pepsin are present
Gastric ulcer
in stomach
Duodenal ulcer
in duodenum
Stomach acid production
Food/thought of food
G cells produce gastrin
ECL cells produce histamine
Parietal cells produce acid
H. pylori infection of antrum
Inflammation
Loss of function of somatostatin cells
Increased gastrin production and acid production
Acid enters duodenum
Inflammation of duodenum
Duodenal ulcer & acid hypersecretion
H. pylori infection of corpus
Inflammation
Loss of function of parietal cells
Loss of acid production
Intestinal-like cells in stomach
Inflammation
Gastric ulcer & acid hyposecretion
H. pylori and genetic instability of epithelial cells
Irregular AID expression
Double-strand DNA breaks
Impaired DNA mismatch repair
Irregular DNA methylation
miRNA regulation
cag pathogenicity island
Region of DNA involved in pathogenicity
>30kb
28 genes
T4SS
cag pathogenicity island correlates with increase virulence and disease severity in humans
Intimin
Attachment to host cells
Formation for attachment and effacement lesions on surface of host cells
H. pylori CagA
Phosphorylated in gastric cell
CagA-P stimulates phosphorylation cascades, apoptosis, morphological change, cytokine production, cell proliferation
Promotes release of ROS from mitochondria. Stimulates oncogenic pathways
H. pylori virulence factors
Flagella - bacterial mobility & chemotaxis to colonise under mucosa
Urease - neutralize gastric acid. Gastric mucosal injury by ammonia
Lipopolysaccharides - adhere to host cells inflammation
Outer proteins - adhere to host cells
Type IV secretion system - pilli-like structure for injection for effectors
Exotoxins - vacuolating toxin (vacA) gastric mucosal injury
Secretory enzyme - mucinase, protease, lipase - gastric mucosal injury
Bacteria migration
Bacteria migrate most between corpus and fundus
Low acid production
Pangastritis - atrophic gastritis - gastric cancer
H. pylori leads to
Chronic gastritis
High acid production
antral-predominant gastritis - peptic ulcer disease
Treatment
First line therapy = one-week “triple therapy”. Proton pump inhibitor such as omeprazole + antibiotics such as clarithromycin and amoxicillin
Disease action
Pathogen establishes a niche on/in host’s body
Pathogen causes disease (e.g aided by toxins)
= infectious disease
Intoxication action
Pathogen produces a toxin ex vivo
Person ingest toxin & toxin causes disease
= microbial intoxication
Microbial intoxication
May result from eating food where bacteria have previously grown and produced a toxin
Staphylococcal food poisoning
Botulism
Staphylococcal food poisoning
Produces a family of related toxins
Heat and protease resistant
Able to survive harsh conditions of the stomach
Very quick onset - few hours
Vomiting, diarrhoea & stomach cramps
Quick recovery 1-2 days
No treatment
Molecular mechanisms unknown
Sources of Staphylococcal
Animal products
Lack of hygiene
Cholera
Infection of small intestine with Vibrio cholerae
Faecal-oral route
Eating/drinking food/water contaminated with faeces
Cholera facts
Highly infectious
Incubation period
No or mild symptoms
20% - rice water diarrhoea
Cholera toxin
Cholera rice water
Fluid loss severe - 40L a day
Dehydration and electrolyte imbalance
Cholera toxin AB5 familiy
A subunit - bind to stimulatory G protein after golgi and ER modification
B-subunit - binds to ganglioside receptor which allows entry into cell
Guanine nucleotide-binding (G) proteins
Binding of hormone produces a conformational change in receptor.
Receptor binds to G protein
Binding induces a conformational change - GDP is replaced by GTP.
Gs dissociates from rest of G
Gs binds AC synthesis of cAMP; hormone dissociated
Hydrolysis of GTP to GDP causes Gs to disassociate from AC and bind to the rest of G
Cholera toxin mechanism
Locks G protein cause NAD+ -> ADP-ribose
ADP-ribosylation of Gsa causes constant activation of cyclase, resulting in increased levels of cAMP.
This activates Protein Kinase A
causes active secretion of chloride ions via CFTR and loss of water by osmosis
Cholera review
Toxin mediated disease
AB5 and acts intracellularly 5xB subunits: binding and entry
1xA subunit: enzymatic activity
Causes chloride secretion
Profuse diarrhoea
No physical damage and reversible.
Up to 40L a day
Cholera resurgence
Climate change - cyclones, flooding, drought
Political
Limited healthcare and availability of vaccine
Ongoing health emergencies
Enterohaemorrhagic E. coli
Type 3 secretion system
Produces Shiga-like toxin
Faecal oral route
3-8 days
Severe, bloody diarrhoea and abdominal cramps
Haemolytic uremic syndrome
7 days after symptoms
Anaemia caused by destruction of RBC (haemolytic anaemia)
Acute kidney failure (uremia)
Low platelet count (thrombocytopenia)
5-10% mortality and in children
Shiga toxins
STx: Shiga toxin from Shigella dysenteriae
STx1: Shiga-like Toxin 1 from E.coli - 1 amino acid difference from STx
STx2: Shiga-like Toxin 2 from E.coli - 56% identity from STx and STx1. Most common cause of human disease
Enteropathogenic
Acute diarrhoea (children)
Enterohaemorrhagic
Bloody diarrhoea
Haemolytic uraemic syndrome (anaemia and kidney failure)
Shiga-toxin producing and verotoxin-producing
Haemolytic uraemic syndrome
Shiga-like toxins
Toxins that cause cell death
Bind to Gb3 in digestive tract = bloody diarrhoea
and kidney = HUS (kidney failure)
Cattle, swine and deer
Don’t have receptor
Carry bacteria without any toxic effect, while shedding them in their faeces
Mechanisms of action of Shiga toxins
B subunits bind to Gb3 in cell membrane
A subunit transported to ER
Subunit cleaved by protease to make enzymatically active
Removes a single adenine from 28s rRNA = irreversibly inactivates ribosome inhibiting protein synthesis
Results in cell death
Alternative mechanism of action of shiga toxin
B subunits bind to Gb3 in cell membrane
Inactivates ADAMTS 13
Accumulate multimers of Von Willebrand’s Factor on endothelial surface, leads to clumping of platelets
Alternative Alternative mechanisms of action. Shiga toxin
Bind to Factor H
Prevent inactivation of C3b
Persistent C3b activity
Increased alternative pathway complement activation, leads to increased endothelial inflammation
Shiga-like toxin
Toxin mediated disease
Shiga-like toxin belongs AB5 family
5xB subunits: binding and entry
1xA subunit: enzymatic activity
Transported from cell surface to cytosol via Golgi and ER
Stops protein translation
Inflammation of intestinal epithelium and apoptosis, loss of barrier function
Physical damage
Digestive tract = bloody diarrhoea
Kidney = HUS
Cytolysins
Form a pore through the cell membrane
Results in cell death or induction of apoptosis
Haemolysis - cytolysins that destroy RBC
Why destroy host cells?
Spreading: destruction of tissue allows bacteria to move
Immune evasion: killing immune cells helps bacteria escape immune response
Nutrition: cells full of useful nutrients
Exoenzymes
Proteins secreted by microorganisms
Lipases
Proteases
DNAse
Hyaluronidase
Lipases
Staphylococcus aureus b toxin/Shingomyelinase C - immune evasion factor, destroys leukocytes
Clostridium perfringens Zn-metallophospholipase C - spreading factor, involved in invasive disease (myonecrosis)
Clostridial myonecrosis - Gas gangrene
Proteases
Pseudomonas aeruginosa elastase - degrade collagen, elastin and other host proteins e.g IgG, complement, chemokines
LasA = serine protease (nicks proteins)
LasB = Zinc metalloprotease (fully degrades nicked proteins)
Burn wound infections
Elastases causes damage leading to acute inflammation & work with other toxins and enzymes leading to tissue necrosis
Degradation of tissue allows spread of the bacteria and the disease (septicaemia)
DNAses & NETS
Bacteria destroy NETS using DNAse which helps spreading and immune evasion
Pus
Bacteria and leukocytes
Release of chromosomal DNA from leukocytes increases viscosity
Bacterial DNases cleave DNA and decrease viscosity
Facilitates bacterial spreading
Tissue damage
Chemical change in interstitial fluid leads to mast cells releasing histamine and heparin. Dilation of blood vessels, increased blood flow, increased vessel permeability. Leads to area becoming red, swollen, warm and painful and clot formation
Tissue repair
Histamine and heparin attract phagocytes, especially neutrophils. Specific defenses and removal of debris by neutrophils and macrophages, stimulation of repair lead to tissue repair
Inflammation & infection
Bacteria enter wound
Platelets release wound clotting proteins at wound site
Mast cells secrete factors that mediate vasodilation and vascular constriction
Increased delivery of blood plasma & cells to injured area
Neutrophils secrete factors that kill and degrade pathogens
Neutrophils and macrophages remove pathogens by phagocytosis
Macrophages secrete cytokines (IL-8)
More immune cells attracted activates cells involved in tissue repair
What does tissue damage/infection lead to?
Activation of mast cells
Mast cells release heparin and histamine
Vasodilation and increased permeability of blood vessels
Leukocytes extravasate from blood and migrate to site of injury/infection
Migration guided by chemokine interleukin-8 (IL-8) produced by activated macrophages
Bacterial triggering of inflammation
Immune cells recognise conversed structures on bacteria
-PAMPS
- LPS on Gram Negative
-LTA on Gram positive
Flagellin - protein part of bacterial flagellum
Peptidoglycan - polymer of peptides and sugar forming bacterial cell wall
Bacterial DNA
Endotoxin
Alternative name for LPS but also refers to LOS (lipooligosaccharide)
Anchored in outer membrane
Not secreted like exotoxins
Lipooligosaccharide
No O-antigen
Limited to 10 saccharide units
Major glycolipids expressed on mucosal Gram negative bacteria
Sepsis
Life threatening complication of an infection
Inflammation triggered throughout the body
Can lead to organ damage and multiple organ failure
Endotoxins & sepsis
Infection
Bacteria in bloodstream (bacteremia)
Cell lysis - release of endotoxin
Cytokine storm - sepsis
TLR signalling
LPS binding protein binds to LPS/LOS, delivers to CD14 then to TLR-4 which induces pro-inflammatory cytokines (IL-1B, TNF-a)
IL-1B
Macrophages are activated and release cytotoxic effectors (ROS, enzymes)
Vasodilation blood vessels
Hypotension
Intravascular coagulation
TNF-a
Brain - increased body temp and loss of appetite
Vasodilation blood vessels
Hypotension
Intravascular coagulation
Bacterial infections resulting in strong inflammatory response
Meningococcal disease
Superantigen-triggered toxic shock
Meningococcus
Enter through nasal pharyngeal route
Have LOS and capsule
Meningococcal disease
Meningococcemia or meningitis
Meningococcemia
Blood infection
Bacteria enters through the nose & throat
Purplish rash
Cold hand and feet
Breathing fast
Limb, joint and muscle pain
Meningitis
Spinal cord/brain infection
Passage through blood-brain barrier
Severe headache & stiff neck signal infection
Bacteria in spinal cord & brain membranes
Sensitivity to bright light
Seizures
Severe headaches
Stiff neck
Lipid A of LOS
Causes extensive inflammatory response
Causes most damage and symptoms
Outer membrane blebs
Bacteria also releases blebs out outer membrane
Contain LOS
Acts as immune decoy
Meningococcal disease
Very sleepy and vacat
High sleepy and vacat
High fever
Confused and delirious
Vomiting
Immune damage of meningococcal disease
Alteration of coagulation pathways
Intravscular coagulation
Weakened epithelium
Bleeding under skin
Phagocytic cells release ROI and enzymes
Extensive tissue damage and necrosis
Treatable with antibiotics
Multiple organ failure
No vaccine protects against all types
Super antigen-triggered toxic shock
Caused by exotoxins
No enzymatic activity but instead causes huge systemic inflammatory response
Can result in multiorgan failure
Mortality:
S aureus 40-50%
S pyogenes 50-70%
T cell activation
Antigen-presenting cell presents antigen specific to T-cell. Activated T-cell produces cytokines
<0.01% activated
Superantigens
Activates 2-30% of T cell population
Massive production of proinflammatory cytokines
No enzymatic activity
Act from outside cell by binding to MHC class II on APC and TCR on non-specific T cells
Systemic acute inflammation, toxic shock syndrome
Autoimmunity
Antibodies produced in response to infection cross-react with host antigens
Bacterial infection leads to…
Innate immune response
Adaptive immune response (generation of antibodies)
Antibody cross reacts with human antigen (molecular mimicry)
Acute Rheumatic fever
Group A Streptococcus leads to pharyngitis/skin infection. Generation of antibodies against proteins in joints/heart muscle. Acute rheumatic fever is inflammation and leads to rheumatic heart disease.
Migratory polyarthritis
Most common symptom in ARF patients
Inflammation (pain) starting in one joint
After a time, inflammation reduces and start in another joint. Caused by auto-reactive antibodies against collagen in joints
