human fungal infections - part 2 Flashcards
WHO fungal priority pathogens list
critical
- cryptococcus neoformans
- candida auris
- aspergillus fumigatis
- Candida albicans
candida species
opportunistic yeast (C.albicans, C.glabrata)
- commensals of the gut, oral and genitourinary tracts
this is a common component of the human microbiota, but it can also turn bad and it’s the most common cause of invasive yeast infection.
since the 90s there has been an increase in the infections caused by candida glabrata, which unfortunately is resistant to a lot of the drugs that are used against candida species.
mucosal candidiasis (mouth or vagina)
- common in infants
- 75% of women suffer at least one episode of vaginitis
- often occurs following changes in resident microflora or defects in cell-mediated immunity
risk factors: AIDS (CD4 T cell deficiency), antibiotics
disseminated candidiasis
- often originates at a gastrointestinal site and/ or might occur as a result of physical breach, or impaired innate immunity
risk factors: surgery, indwelling catheters, chemotherapy
C.Albicans virulence factors
yeast cells are able to adhere to host surfaces using adhesins
- the contact of the fungus with host cells triggers the yeast to hyphae transition
- once the hyphae are starting to grow they can direct the growth on top of the epithelium so that they break the tissue and They can get into the cells via the expression of invasins
- uptake via induced endocytosis
- fungal driven active penetration
-can also secrete a series of fungal hydrolysis that help in breaking down barriers
- formation of biofilms
- phenotypic plasticity
- metabolic flexibility and adaptation response to stress and nutrient/ trace elements
C.albicans yeast to hyphae transition - facilitating infection
Transition is really important in promoting and facilitating infection
- it’s a switch that is genetically regulated in response to Clues such as nutrient deprivation, pH
- candida can adopt a range of morphologies from yeast to filamentous hyphae
○ And this has very important advantages in the establishment of disease
○ because hyphae are more pathogenic - they can penetrate more efficiently through the epithelial layers and they are more resistant to defensive systems.
what are hyphae
hyphae are these tentacles that are basically able to infiltrate into the barriers and reach the blood vessels to then disseminate.
- So the first thing that hyphae facilitates is tissue penetration and colonization
C.albicans yeast to hyphae transition - facilitating evasion
transitioning from one shape to the other means different cell walls, different components that are exposed to the host.
- promoting tissue invasion, tissue penetration, and colonisation
- the yeast to hyphae transition facilitate the masking of pathogen Associated molecular patterns from immune cells
- helping the fungus to avoid recognition from the host cells which would try to engulf it and kill it.
- also promotes escape from within immune cells following phagocytosis
what does nutrient starvation promote in Candida albicans
C.albicans experiences nutrient starvation inside the macrophage phagolysosome (but not in neutrophils), prompting germination, hyphal formation and escape
- The hyphae punch their way through kill the cell that had tried to ingest it and eliminate it
candidalysin
This is a cytolytic peptide toxin, which originally had been discovered in candida albican
it causes the Lysis of the cells
- and it’s been demonstrated that strains that are lacking this toxin are not able to activate a response in epithelial cells or to damage epithelial cells
- and this results in a virulent Strains in animal models
mode of action of candidalysin
- candida albicans is a commensal on our skin
has a dual mechanism.
- It’s secreted at sublytic concentrations normally as the fungus starts to grow as an hyphae
- when it’s secreted at sub lytic concentration it elicits an immune response that is not damaging
- It turns bad when more fungus Grows and forms Pockets into the cells invade and more toxins accumulate in these pockets
- it will exceed a threshold which then becomes dangerous and damaging.
○ Once it exceeds these thresholds it accumulates and forms pores in the membrane of the host cell
- And that means that it’s releasing its content - causes cell to die
So it goes from commensal to opportunistic
aspergillus species
- filamentous fungi
- major components of the airborne microflora
(100s spores inhaled daily)
aspergillus fumigatus
- the most potent of infectious moulds (over 90% of human disease)
- sporulates abundantly
- slow fall rate of spores
- viable spores per cubic metre rarely exceeds 100 (not the most prominent of the spores that we inhale)
- the fungi most often cultured from the airways of chronically ill humans
- the spores are so small that they can arrive very deep into our respiratory system
into our alveoli and cause disease
outcomes of A.fumigatus spore inhalation - human immunity
human immunity serves a dual purpose in protection following spore inhalation:
1. clearing through physical and cell-mediated mechanisms
2. preventing or dampening potentially harmful inflammatory responses
what can A.fumigatus spore inhalation cause
in immunocompromised hosts, it can progress very fast and be fatal - acute - (days) 300,000
in chronic lung disease or mild immunocompromised people, or in cavitary lung disease - CHRONIC - months (3,000,000)
in astham, cystic fibrosis - ALLERGIC - years (11,000,000)
A.fumigatus virulence factors that helps them to be dispersed in the environment, To arrive deep into the lungs to resist in the lungs, finder a niche where they can then grow and cause disease
- small, thermotolerant and hydrophobic spores
- conidia: melanin, rodlets and negatively charged siliac acid
A.fumigatus virulence factors after dispersed
- adaptation to stress and nutrients/ trace elements limitation
- production of potent secondary metabolites
- secretion of proteases - degrading the tissue to find more nutrients to sustain more growth
- production of catalases, superoxide dismutases, and glutathione transferases - enzymes that are important to detoxifying from an environment
A fumigatus - melanin
Melanin is a polymer that is produced in a variety of microbes and eukaryotes even from in us and humans
in the case of fungi, it helps to the fungi to defend themselves from various environmental insults.
when the fungus is Melanised and is taken up by macrophages this leads to the macrophages to not be able to act and try to break down what they have ingested.
melanin shedding during A.fumigatis germination
activates autophagy (LC3 - associated phagocytosis (LAP)), which promotes fungal killing
- melanin deficient A.fumigatus is attenuated in macrophages and in vivo
- melanin inhibition of LAP promotes A.fumigatus virulence in vivo
gliotoxin
the genes that are responsible for the production of gliotoxin are all clustered together
a member of the epipolythiodioxopiperazine class of toxins and is both the major and the most potent toxin produced by A.fumigatus
cryptococcus species
- encapsulated yeasts
- the most common lethal fungal infection in patients with AIDS worldwide
- reservoirs exist in nature
acquired via inhalation - reside latently and become pathogenic following subsequent immune suppression
- it has a preference for invading the central nervous system provoking infection there
- virtually all cases of cryptococcosis are caused by cryptococcus neoforman And cryptococcosis gattii
C.neoformans virulence factors
- thermotolerance
- melanin (promotes intracellular survival)
- capsule (antiphagocytic, inhibits leukocyte migration and dysregulate cytokine secretion
- intracellular lifestyle
C.neoformans intracellular lifestyle
alveolar macrophages play paradoxical roles in defence against cryptococcus infections
1. clearance by collaborative innate and adaptive responses
but C.neoformans can also survive and multiply inside the macrophage phagolysosome and escape
2. latency
3. Cn survival, CNS entry and infection
