Pathogens (Fritz Lecture 1 - C. albicans) Flashcards
What is Candida albicans?
Dimorphic yeast that grows both in a filament form and as yeast
Does C. albicans have either a) just a cell wall b) a cell wall and a cell membrane c) just a cell membrane
B) A cell wall and a cell membrane
What are the 2 most important roles of the C. albicans cell wall?
1) Maintaining cellular shape
2) Providing resistance to environmental stress
What is the structure of the C. albicans cell wall?
Majority are complex carbohydrates:
- Innermost layer is chitin
(polymer of N-acetylglucosamine subunits)
- Then layer of beta glucans e.g B-1-3 glucans
- Then outer layer of Mannan
What is a common method to observe C. albicans?
Calcofluor white
- Binds to chitin
- Fluoresces when exposed to UV
- Very sensitive method
Is C.albicans commensal or non-commensal?
Commensal
Where does C.albicans usually reside?
In mucous membranes e.g mouth, vagina, gut and sometimes skin
C. albicans infections can be subdivided into what 2 types?
Superficial and ‘deep-seated’
Give an example of a superficial C. albicans infection
- Mild skin infections
- Infection of the tongue and oral cavity (thrush)
- Infection of the vagina (yeast infection)
How can C. albicans cause more serious infection?
Dissemination within the blood to other internal organs
Give an example of a ‘deep-seated’ C. albicans infection
Liver or kidney infections
Who is most at risk of Candida infections?
Neonates (<1 year old) and immunocompromised individuals (elderly etc)
What % of reported candida cases are in neonates and the elderly combined?
45%
What are the 4 common classes of anti fungal drugs and give an example of each
1) Polyenes (e.g amphotericin B)
2) Azoles (e.g. fluconazole)
3) Pyrimidines (e.g flucytosine)
4) Echinocandins (e.g. caspofungin)
What is empiric therapy?
Treatment applied before the confirmation of a definite diagnosis
e.g. giving antibiotics before diagnosing the specific bacterium causing the infection
Often used in fungal treatment before confirmation of infectious organism
What are some problems with current fungal treatment?
Main problem is toxicity issues!
- amphotericin B nephrotoxicity
> Drug resistant non C.albicans species
What is ergosterol and how is it synthesised in candida?
Ergosterol is a sterol found in cell membranes of fungi
Synthesised via the mevalonate pathway in candida
Name the drug type used to inhibit ergosterol synthesis (one of the 4 main types)
Azoles Mainly used: Fluconazole Newer compounds: - Itraconazole - Voriconazole - Posaconazole
What is the main advantage of using azole drugs to treat candida infection?
Some give very few side effects
How do the polyene drugs work?
Binds to ergosterol
Causes intercalation of the cell memebrane
What are the advantages and disadvantages of using amphotericin B (a polyene drug)
Advantages:
- Very broad range
- Development of resistance is rare
Disadvantages:
- Many side effects
- Nephrotoxicity
How do the echinocandins work?
Bind to and inhibit beta1-3 glucan synthase
Depletion of beta1-3 glycans in cell wall
How does flucytosine work to combat Candida infections? (Pyrimidine drug)
Converted into 2 products:
1) Deaminated to 5-fluorouracil which interferes with RNA biosynthesis
2) Other product inhibits fungal DNA synthesis
Why can flucytosine only be used in combination with another drug?
Because it gives rise to rapid development of resistance
What is the current practice for diagnosing candida infection?
- bioMerieux API Microbial Identification (colourific analysis based on substrate metabolism)
- Minimum 24-48+ hour analysis
Name some C. albicans virulence factors
C. albicans is an opportunistic pathogen Virulence factors: - Change its cell shape (polymorphism) - Secretion of hydrolytic enzymes in particular aspartyl proteases - Ability to adhere to epithelial cells
How is C. ablicans polymorphism regulated?
By pH:
pH 4.0 - yeast (circular)
pH 7.4 - filamentous
By CO2:
Approx 5.5% CO2 will induce filamentation
How is CO2 sensed by C. albicans
- Increased cellular CO2 reacts with water to produce bicarbonate (HCO3-)
- Bicarbonate activates soluble adenylyl cyclases (sACs)
- sACs generate cAMP
- cAMP signalling causes changed in gene expression resulting in filamentation
What is Laryngeal cancer?
Cancer of the head and neck squamous cells
How many people in the UK are diagnosed with laryngeal cancer each year?
2,300
How is Laryngeal cancer treated?
Most cases:
- present early
- Therefore treated with radiotherapy or laser excision
Advanced or recurrent cases require laryngectomy (removal of the larynx)
How do patients have their speech restored after a laryngectomy?
Surgical voice restoration (SVR) is the gold standard
- a speaking valve is inserted
What is the main cause of early voice prothesis failure?
Yeast infections
What is the % CO2 in air we inhale vs air we exhale?
Inhale = 0.039% Exhale = 4-5.3%
Why do speaking valves become infected with filamentous C. albicans?
Because the CO2 in exhaled air stimulates filamentation
How many aspartyl proteinases does C.albicans secrete?
10!
What protein is important for C. albicans adhesion to epithelial cells?
the Hwp1 protein
