Health and Disease at Mucosal Membranes - Strand B

CFTR is activated if it is phosphorylated or dephosphoryled?

Phosphorylated.

What occurs in class IA Cystic Fibrosis?

Lack of CFTR mRNA produced.

What occurs in class IB Cystic Fibrosis?

Lack of CFTR protein produced

What occurs in class II Cystic Fibrosis?

Impaired CFTR processing and trafficking to membrane

What occurs in class III Cystic Fibrosis?

Abnormal CFTR gating

What occurs in class IV Cystic Fibrosis?

Reduced CFTR conductance

• Ability of chloride ions to move through the channel

What occurs in class V Cystic Fibrosis?

Reduced levels of CFTR

What occurs in class VI Cystic Fibrosis?

CFTR reaches the membrane and is functional but the plasma membrane keeps removing it

What occurs in a cystic fibrosis airway?

Abnormal mucociliary clearance

Ongoing infection

Progressive inflammation

How can CFTR mutations cause dehydration in airway surfaces?

Normally chloride ions are present to prevent reabsorption of all the water.

• Without chloride ions, Sodium reabsorption provides a osmotic driving force causing the mucus to become dehydrated

How does CFTR mutations cause excessive mucus secretion?

CFTR mutations can increase risk of infection and inflammation.

• This results in an overproduction of mucus

What pH dependent processes are disrupted by reduced CFTR-dependent bicarbonate secretion?

Mucus secretion

• Does not unfold properly

Regulation of ion transport

Antimicrobial activity

• Important for killing bacteria

Staphylococcus aureus is a gram positive or negative bacteria?

Gram-positive bacteria

What is typically the first pathogen to colonise CF airways?

Staphylococcus aureus

• Can cause epithelial damage which allows for later pathogens to infect

What is MRSA?

Methicillin-resistant Staphylococcus aureus (MRSA)

• Has multi-drug resistance and increasing virulence

Staphylococcus aureus usually responds poorly to antibiotics.

True or False?

False.

Staphylococcus aureus usually responds well.

• However, MRSA does not

Pseudomonas aeruginosa is a gram negative or positive bacteria?

Gram negative bacteria

How can Pseudomonas aeruginosa resist antibiotics?

Pseudomonas aeruginosa can form biofilms which are resistant to antibiotics

Why are Nontuberculous Mycobacteria (NTM) a concern for CF patients?

Infection:

• Increased risk of decline in lung function

• Difficult to treat so high patient burden

• Contra-indication for lung transplantation

  • Means lung transplants are not advisable for those infected

How early does inflammation and lung damage start in CF patients?

Can start as early as 3 months of age

• Changes on lung CTs can be detected in 1st year of life

Which type of immune cell is commonly seen in CF inflammation?

Neutrophils

In what ways does the airway remodel in CF patients?

• Hyperplasia (increase in number of cells) of the epithelium

• Thickening of the basement membrane

• Permanent scarring and enlargement of airways

In severe Cystic Fibrosis, what is often the only treatment option?

A lung transplant as the patients airways have been permanently remodelled

What gene is affected in Cystic Fibrosis?

CFTR gene.

• F508del is the most common mutation of the gene

Cystic Fibrosis only affects the lungs and respiratory tract.

True or False?

False.

Cystic Fibrosis is a multisystem disease which affects the lungs, sinuses, pancreas, renal system, GI system, etc

Why do patients with Cystic Fibrosis require prophylactic antibiotics?

Cystic fibrosis causes mucus secretions to become thick and sticky

• This increases the risk of respiratory infections in particular meaning many patients need prophylactic antibiotics to hopefully prevent bacterial infections

What can Cystic Fibrosis cause in the GI tract?

Fat malabsorption

• Including fat soluble vitamins (e.g. A, D, E and K)

Nutritional and weight issues

Bowel obstruction

How does CFTR mutations cause disease?

Bicarbonate and chloride are not able to be transported out of cells and into mucus

• This makes the mucus more acidic as less bicarbonate is being transported

  • This can impact immune responses as they are pH dependent

• Less Cl transport also makes the mucus more thick and prevents cilia from functioning

What are the signs and symptoms of Cystic Fibrosis?

• Chest infections

• Poor weight gain and malnutrition

• Salt losing syndrome

• Neonatal meconium ileus

  • Bowel blockage which is rare

CFTR mutations are autosomal dominant mutations.

True or False?

False.

CFTR mutations are autosomal recessive

How can a heel prick blood sample be used to test for Cystic Fibrosis?

Can use the blood to test for presence of Immunoreactive trypsin (IRT)

• Presence of IRT suggests the pancreas is under stress

• A genetic test can then be used to confirm if CFTR mutations are present

What is the Sweat test for CF diagnosis?

Sweat glands are abnormal in Cystic Fibrosis

• Sodium and chloride are normally reabsorbed in sweat ducts

• In Cystic Fibrosis, chloride ions are not reabsorbed meaning hypertonic sweat is produced

What structure does Haemophilus influenzae have?

Small coccobacilli (Somewhere between cocci and rods)

• Sometimes can have longer filaments

Is Haemophilus influenzae gram positive or negative?

Haemophilus influenzae is a gram-negative bacteria

What vaccine is given against Haemophilus influenzae and what does it use?

Hib vaccine (conjugate vaccine)

• Uses piece of the bacteria’s polysaccharide capsule which is conjugated with a protein carrier

Haemophilus influenzae has been isolated from birds leading scientists to think it is a mutated strain of bird flu

True or False?

False.

Haemophilus influenzae has only been isolated from humans with no animal or environmental sources identified

What two factors does Haemophilus influenzae rely on to grow?

X factor (haemin) and V factor

What is X factor (haemin)?

Required for the synthesis of cytochrome c and other iron-containing respiratory enzymes

What is V factor?

Nicotinamide adenine dinucleotide (NAD) phosphate

Essential for oxidation-reduction processes in cells

Why does Haemophilus influenzae grow poorly on ordinary blood agar?

NADase is present in ordinary blood agar and a lot of X and V factor is held within red blood cells

How can blood agar be modified to allow for better growth of Haemophilus influenzae?

Can be heated at 70-80C until the agar turns brown

• It is now called chocolate agar

This liberates X and V factor from red blood cells and removes serum NADase

Note: Haemophilus influenzae also often grows better in 5-10% CO2 conditions

Haemophilus influenzae is catalase and oxidase positive or negative?

Haemophilus influenzae is both catalase and oxidase positive.

Of the six capsular types of Haemophilus influenzae, which is the most important for health and disease?

Haemophilus influenzae type-b

Haemophilus influenzae type-b is what biotype?

Haemophilus influenzae type-b organisms are biotype I

What is a common manifestation of Haemophilus influenzae infection in children?

Meningitis is a common manifestation in children

What is Meningitis?

Infection which causes inflammation of the membranes covering the brain and spinal cord

• This can potentially cause neurological damage and sometimes death

Which type of meningitis is worse? Bacterial or viral?

Bacterial meningitis can often result in death or neurological damage even if treatment is given

How can a lumbar puncture determine if meningitis is caused by bacteria?

CSF collected will contain neutrophils which is associated with bacterial infection

• CSF protein levels will also reflect inflammation

• CSF glucose levels will also be very low

How can a lumbar puncture determine if meningitis is caused by virus?

CSF collected will contain lymphocytes which is associated with viral infection

• CSF protein levels will also reflect inflammation (less than bacteria though)

• CSF glucose levels will also be normal

Ceftriaxone is commonly used as treatment for which invasive bacterial infection?

Haemophilus influenzae infection.

90% of invasive Haemophilus influenzae infection are caused by which strains?

Type-B Haemophilus influenzae strains

90% of non-invasive Haemophilus influenzae infections are caused by which strains?

Non-capsulated strains

Why is a protein carried used for the Hib vaccine?

Bacterial polysaccharide (PRP) linked with the carrier was found to elicit a greater immune response than the polysaccharide on its own

• Protein carrier is highly immunogenic

Why should nothing be put in the mouth of a patient with epiglottitis?

Putting things in their mouth can trigger a spasm which will close the already tight airway completely

How do Non-typeable Haemophilus attack mucosal membranes?

Bind to mucus and can inhibit ciliary function/kill ciliary cells

• This allows them to grow on the mucus without being removed

Non-typeable Haemophilus influenzae strains are able to invade and survive inside of macrophages for extended periods of time

True or False?

True.

NTHi are able to survive inside of macrophages which allows them to evade immune detection

Is Staphylococcus aureus catalase positive?

Yes.

Staphylococcus aureus is catalase positive

Is Staphylococcus aureus gram positive or gram negative?

Staphylococcus aureus is gram positive.

What structure is Staphylococcus aureus?

Irregular cocci

What structure is Neisseria meningitidis   

Capsulated diplococcus

What can Neisseria meningitidis’ capsule help protect against?

The capsule can help protect against phagocytosis by immune cells

Is Neisseria meningitidis gram negative or positive?

Neisseria meningitidis is gram negative

Is Strep pyogenes catalase negative or positive?

Strep pyogenes is catalase negative

What structure does Strep pyogenes have?

Cocci structure in chains

Is Strep pyogenes gram negative or positive?

Gram positive

What structure does Corynebacterium diphtheriae have?

Rod shape which form ‘Chinese letters’ due to incomplete division

Is Corynebacterium diphtheriae gram positive or negative?

Gram positive

What causes Corynebacterium diphtheriae’s virulence?

Virulence is caused by it’s endotoxin

How can Corynebacterium diphtheriae cause obstruction of airways?

Corynebacterium diphtheriae can develop a pseudo-membrane on the tonsils and pharynx which can spread up or down leading to obstruction of the airways

Is Haemophilus influenzae gram negative or positive?

Gram negative

What structure does Haemophilus influenzae have?

Small coccobacilli (Somewhere between cocci and rod shaped)

Is Moraxella catarrhalis gram negative or positive?

Gram negative.

What structure does Moraxella catarrhalis have?

Diplococcus shape

Is Moraxella catarrhalis catalase positive or negative?

Moraxella catarrhalis is catalase positive

• Its also oxidase positive

S. Aureus, N. Meningitidis, S. Pyogenes, C. diphtheriae, H. Influenzae and M. catarrhalis all infect the lower respiratory tract.

True or False?

False.

All those bacteria infect the upper respiratory tract

• Although Moraxella catarrhalis can sometimes cause disease in the lower respiratory tract

Strep. Pneumoniae and Mycobacterium tuberculosis cause disease where?

Lower respiratory tract.

Type C Influenza viruses can cause major pandemics.

True or False.

False.

Type A Influenza viruses can cause major pandemics because of antigenic shift.

Type C viruses are antigenically stable and only cause sporadic disease

Why is Mycobacterium tuberculosis unique compared to other bacteria?

Mycobacterium tuberculosis rods are not classified by a gram stain

• They have special outer lipid layer which contains waxy components

What causes Mycobacterium tuberculosis’ virulence?

Virulence depends on its cell wall

• Mycobacterium tuberculosis produces no toxins

What is the cause of most upper respiratory tract infections?

Most upper respiratory tract infections are caused by viruses

What is Epiglottitis?

Inflammation of the epiglottis

• Causes difficulty breathing, muffled speech and noisy breathing

What is Laryngotracheitis?

Inflammation of the larynx and trachea

• Can cause rapid breathing and blueish colouration of the skin due to a lack of oxygen

What are most common colds caused by?

Mainly caused by Rhinoviruses

• However sometimes caused by other viruses like coronaviruses

What is Sinusitis?

Sinusitis is the inflammation of one or more of the sinuses of the nasal cavity

Acute sinusitis often follows a common cold

What is the primary function of the nasal sinuses?

To warm, moused and filter air which enters the nasal cavities.

What commonly causes chronic sinusitis?

A mixed infection of aerobic and anaerobic organisms

What is Otitis media?

Infection and inflammation of the middle ear

• This is especially common in young children and usually causes acute ear-ache confined to one side

Otitis media (middle ear infection) usually follows upper respiratory infections. How does this occur?

Infection from spread from the nasopharynx area to the middle ear via the eustachian tube

How is Otitis media (middle ear infections) typically diagnosed?

Can look into the ear canal with an otoscope and can look for a bulging, reddened ear drum

• Sometimes, if the infection has lasted a while, there may be perforation in the ear drum

What are grommets and why are they given to people with a history of recurrent ear infections?

They help drain the ear and allow the eustachian tube to reopen

• This reduces the risk of a renewed infection and so helps people with recurrent ear infections

What is it called when both the pharynx and tonsils are infected?

Pharyngotonsillitis

Swelling of lymph nodes during Pharyngitis and Tonsillitis is common in ________ infections.

Common in bacterial infections.

Why is there a challenge with treating Tonsilitis?

We don’t want to overuse antibiotics

• E.g. viral tonsilitis doesn’t require antibiotics to treat

However, we also don’t want to not treat Strep A tonsilitis which requires antibiotic treatment

• Patients won’t want to wait days for confirmation on if it’s viral or bacterial

Sometimes there can be a mixed infection of both a virus and a bacteria

Which bacteria can cause Pharyngitis and Tonsilitis and can also cause lethal complications?

Group A β-haemolytic streptococci

• Can lead to Rheumatic fever (damages heart), toxic shock and glomerulonephritis (damages kidneys)

Do viruses or bacteria cause most cases of Laryngitis?

Most cases are caused by viruses

Why does the voice become hoarse or ‘lost’ in Laryngitis?

The vocal cords become inflamed which can affect the sound of the voice

• If the inflammation is severe enough, the voice can be ‘lost’

What is Pneumonia?

Lung infection of the alveoli

• Causes them to fill with fluid/pus

What type of infection usually causes pneumonia?

Usually caused by bacterial infections however influenza and other viruses can also be the cause

What type of culturing is used for diagnosing respiratory infections?

Sputum cultures

Blood cultures

• Usually done for invasive diseases

Ziehl Nielsen staining is used for diagnosis of which particular pathogen?

Tuberculosis.

• However is frequently ‘false negative’