23 Pathogenicity-fungi immune evasion Flashcards
what is the most common type of superficial fungal infections
Dermatophytosis
where does dermatophytosis infect
- Stratum corneum (upper skin surface)
- Nails
- Hair (scalp)
what does dermatophytes infect
humans
animals
saprophyte in soil
what is anthropophilic
infects humans
what is zoophilic
infects animals
what is geophilic
generally saprophyte in soil
what is the Stratum corneum
- Epidermal layer of dead cells
- Rich in keratin
- Protects underlying tissues
what increases risk of zoonotic infections
Direct contact with these infected animals
what do antropophilic fungi cause
generally chronic infections with low inflammation
what do zoonotic infections usually come with
accompanied by inflammatory host response
what do dermatophytic fungi require
ability to degrade keratin staining
what does keratin form
alpha helical structure and builds filaments
what is keratin
protein
how flexible is keratin
Amount of cysteine residues determine the rigidity of keratin fibrils
what is cystine
Disulfide bond from two cysteines = cystine
what are dermatophytes rich in
proteases
what do dermatophytes make from cysteine degradation
sulfite
what happens when sulfite is secreted
reduces cysteine bridges (cystines)
= Proteins become accessible for degradation by proteases
how are fungal infections diagnosed
Cultivation of fungi
Staining and visualisation of hyphae in infected tissues
Diagnostic PCR
how are fungal infections treated - superficial skin
topical application of azoles or terbinafine
how are fungal infections treated - scalp infections
azoles, sometimes systemic application
how are fungal infections treated - nail infection
Topical + systemic treatment and nail removal to be considered
how long does therapy last for fungal infection
takes between 2 and 48 weeks of treatment, depending where it is located
what are major risk factors in fungal infection
- Immunosuppressive regimen (graft versus host disease, leukaemia)
- Chronic granulomatous disease (CGD)
- Other inborne immunodeficiency
- AIDS (HIV infection)
what is Histoplasma capsulatum
Environmental dimorphic fungus
where is Histoplasma capsulatum found
Strongly enriched in droppings of birds and bats
what does Histoplasma capsulatum infect
immunocompromised and healthy individuals
how does Histoplasma capsulatum avoid immune mechanisms
- Immune cells generally detect β-glucans in the fungal cell wall via Dectin-1
- Dectin-1-mediated phagocytosis elicits an inflammatory immune response
- α-glucan is not immune stimulatory
- α-glucan overlays the β-glucan layer
what does Histoplasma capsulatum acquire
essential nutrients from the host and replicates within macrophages
Histoplasma capsulatum and antimicrobial defense molecules
Detoxifies antimicrobial defense molecules
how does condida get into body
uptake by inhalation (lung alveoli)
what happens once entered cell
Adherence to macrophage β-integrins
what are CD18
complement receptors
what blocks phagocytosis
Antibodies against HSP60
when are the first symptoms of Histoplasmosis
about two weeks after conidia inhalation
what are the symptoms at start
Silent manifestation (no symptoms)
what happens in the acute phase of Histoplasmosis
non-specific respiratory symptoms (cough or flu-like)
what happens in the chronic phase of histoplasmosis
similar symptoms as tuberculosis
what can Histoplasmosis
lead to in immunocompromised patients
especially AIDS = reduced T-cells
what is the problem with HIV and macrophage function
HIV reduces number of CD4+ cells that activate CD8+ killer cells
CD8+ killer cells are essential to recognise and kill infected macrophages
what is the therapy for Histoplasmosis
Primary therapy with amphotericin B
Secondary therapy with azoles (may need one year for clearance of infection)
what is PCP
Pneumocystis pneumonia
what is throphozoit
Pneumocystis trophic form
what is cyst
Pneumocystis cyst form
what is special about Pneumocystis
species are specialised towards their host
what is the pneumocystis life cycle
Trophic form (asexual) multiplies by binary fission Cysts result from sexual crossing, meiosis and mitosis
what are the cysts cell walls like
thick cell wall mainly made of β-glucans, chitin, mannoproteins
what do β(1,3/1,6)-glucans cause in cysts cell wall
severe inflammatory response by immune recognition
what us the trophic cell wall like
without β-glucans and very thin cell wall
what is the flexibility of trophic cell wall
Flexible in the cell wall (as no beta glucan)
what does trophic express
integrin like molecule PcInt1
what does integrin interact with
extracellular matrix of epithelial cells (fibronectin and vitronectin)
what is reduced in trophic cell wall
Expression of surfactant phospholipids by epithelial cells reduced
why is AIDS cause a major problem to Pneumocystic infection
Implies major role of CD4+ cells in clearance, but mainly through cytokine response
CD8 T cell depletion does not increase risk for infection
Adaptive B-cell response important for clearance
Macrophages and neutrophils phagocytose and inactivate cysts and trophozoits
what causes major disease transmission in Pneumocystis
cysts
what does Pneumocystis not produce (unlike other fungi)
ergosterol
what are the problems with treating Pneumocystis
- Natural resistance against azoles
- Low sensitivity against amphotericin B
- don’t have beta glucan = no trophozoits
what is important for transmission control in Pneumocystis
Echinocandins active against cysts, but need co-application of sterols
what is Cryptococcus neoformans divided into
four serotypes A, B, C, D
who are the individuals at risk to Cryptococcus neoformans
mainly infects immunocompromised individuals
- Highest risk for HIV infected patients with AIDS
- Transplant recipients identified as emerging group at risk
what does Asexual Cryptococcus form
yeast cells
how do Asexual Cryptococcus infect
by inhalation of
- Blastoconidia
- Desiccated spores
what causes Cryptococcosis
released from bird droppings
why does cryptococcosis not infect birds
birds don’t get infected as their body temperature is too high – cannot proliferate in the tissues, but can survive and proliferate in intestine – in bird droppings
what is the major virulence factors of cryptococcus
Polysaccharide capsule
what is the polysaccharide capsule made of
galactoxylomannan (GXM)
what does the polysaccharide capsule do
Protects from cell-wall recognition and immune activation
what is melanisation in crypotococcus
Activation of host diphenolic compounds
what does melanisation stabilise
fungal cell wall
what does melanisation reduce
susceptibility to antifungal agents
what can melanin scavenge
reactive oxygen species
what can some cryptococcus cells form
titan/giant cells
when are titan cells made
formation is stimulated when both mating partners cause infection
what cant occur to titan cells
cannot be phagocytosed – surrounded by large capsule (cannot be opsonised)
Promotes survival within the host
what is the the main disease from cryptococcus
acute meningitis
what can occur in cryptococcus infections
Latent infection frequent (no complete clearance) = Reactivation possible
dendritic cell role in cryptococcus clearance
phagocytose Cryptococcus and present antigens to T-cells
adaptive T cell role in cryptococcus clearance
Adaptive T-cell response from CD4+ and CD8 cells play major role in clearance
- Low CD4+ counts in HIV patients major risk factor
what is the therapy for acute meningitis
Initial therapy with combination of two
Maintenance therapy with another
Echinocandins are not effective
what are Aspergillus species
environmental saprophytes
where are Aspergillus species
common in soil and on decaying organic matter
where is Aspergillus terreus
Common in soil and on decaying organic matter
what is Aspergillus terreus problem
Natural Amphotericin B resistance
what is frequent in Aspergillus terreus
dissemination
what is the thermotolerance of Aspergillus terreus
Moderately thermotolerant (42°C)
where is Aspergillus fumigatus
Common in soil and on decaying organic matter
what is the thermotolerance of Aspergillus fumigatus
Highly thermotolerant (55°C)
what is dissemination of A. terreus interaction with DC
Activation of DCs leads to transmigration to lymph nodes
Present antigens mainly to T-cells (and B-cells)
Mediators between innate and the adaptive immune response
Phagocytosis of A. fumigatus and A. terreus by DCs
DCs phagocytose A. fumigatus faster than A. terreus
A. fumigatus escapes from DCs
A. terreus mainly persists
what is the germination of A. fumigatus like
a very low nutrient threshold
what is the germination of A. terreus like
speed is dependent on nutrient availability
what is the survival of A. fumigatus conidia after DC phagocytosis
inactivated
what is the survival of A. terreus conidia after DC phagocytosis
remain viable
what is the survival in presence of antimycotics and DCs - A. fumigatus conidia
not protected from antifungals
what is the Survival in presence of antimycotics and DCs - A. terreus conidia
Persistent A. terreus conidia are protected
does A. fumingatus cause DC activation
Viable A. fumigatus candida trigger DC activation and transmigration
does A. terreus cause DC activation
do not elicit DC activation
does A. fumingatus cause cytokine production by DC
trigger an inflammatory immune response
does A. terreus cause cytokine production by DC
no
where can A. terreus conidia persist
macrophages and DCs and TNF-α stimulated DCs
what does TNF-alpha stimulate
transmigration of A. terreus infected DCs
what is a suitable vehicle for A. terreus
DCs
A. fumigatus infections strategies
rapid acute pulmonary disease
- A. fumigatus follows a “germinate and escape” strategy
- Rapid progression is life-threatening
A. terreus infections strategy
“sit and wait” strategy
- A. terreus conidia can hitchhike innate immune cells for dissemination
- Disseminated infection has mortality rates > 90%
