Lecture 6: Fungal Infections Flashcards
Fungal Infections regularly seen in
HIV infected patients
Cancer patients undergoing chemotherapy
Transplant patients on immunosuppressive medication
Patients taking long term corticosteroids
Facts about fungi
Examples
Functions
Eukaryotic micro organisms
Includes yeast, moulds, polypores, plant parasitic rusts and smuts
Important role as decomposers, pathogens (plants and animals), carbon cycling in soils and mediate mineral nutrition in plants
Fungal diseases are called myscoses and are characterised based on:
Site of infection
Route of infection
Virulence - the severity or harmfulness
Fungal Disease: Site of infection different mycoses
1.Superficial mycoses: Caused by fungi known as dermatophytes and are usually restricted to the non-living keratinized components of the skin, hair and nails
2.Subcutaneous mycoses: Driven by saprophytic fungi which cause chronic nodules or ulcers in subcutaneous tissues following trauma. Eg. Chromomycosis, sporotrichosis & mycetoma
3.Respiratory mycoses: Infections caused by soil sprophytes producing acute lung infections or granulomatous lesions eg. Coccidioidomycosis
4.Candidiasis: Caused by candida albicans (ubiquitous commensal) causes superficial (rarely systemic) infections of the skin and mucosal membranes
Fungal Disease: route of infection types
Endogenous – presence of fungi in the gut/human microbiota
Exogenous – Inhalation of fungi from environment
Fungal Disease: Virulence
Primary – pathogenic organism
Opportunistic – commensal organism
predisopsing factors for specific fungal pathogens
- Candida (mucosal)
= impaired cellular immunity, neutropenia - Candida (disseminated)
= impaired muscoa, neutropenia
3.Aspergillus
= Neutropenia, high dose corticosteroids
4.Cryptopcoccus
= impaired cellular immunity, corticosteriods
- Zygomycetes
= Neutropenia, corticosteroids, diabetic ketoacidosis - Fusarium
= Neutropenia, corticosteriods, impaired skin - Scedosporium
= neutropenia - Trichosporon
= Neutropenia, impaired skin
Candida
Pneumocystis
Histoplasma Capsulatum
Blastomyces Dermatitidis
Malassezia
Cryptococcus
Source and Diseases caused
Candida
Commensal on skin, GI, vagina
Vaginitis
Skin/nail infections
Oropharyngeal infections
Pneumocystis
Host specific
Pneumonia
Histoplasma Capsulatum
In soil, contaminated birds/bats, infected by inhalation of spores
Acute pneumonia
Self-limited flu like symptoms
Disseminated disease
chronic pulmonary disease
Blastomyces Dermatitidis
Soil, decaying wood. infected by inhalation of spores
Skin lesions/subcutaneous nodules, disseminated disease, acute/chronic pulmonary disease
Malassezia
Commensal of skin
Cutaneous infections
Allergic atopic eczema
Cryptococcus
Soil, pigeons, trees
Pneumonia
Meningitis
virulence factors that allow fungal survival and persistence in the host (5)
- complementary structures - adherance to host tissues and the extracellular matrix
2.production of phospholipases, proteases and elastases that cause tissue damage and impairment of host defences
- switch to metabolic pathways that are required for intracellular survival
- thermotolerance (the ability to grow at 37°C)
5.exist in different forms and to reversibly switch from one to the other during infection
Eg: dimorphic fungi, which transform from saprobic filamentous moulds to unicellular yeasts in the host
some species of Candida can grow in different forms, such as yeasts, blastospores, pseudohyphae and hyphae, depending on infection sites
3 mechanisms of fungal immunity
Tolerance
protection
clearance
The TLR-PAMP recognition system
Lecture Slide
Draw the fungal wall
And functions of B-glycans, Chitin and Mannans
Lecture Slide
Β-glycans
β1,3 - scaffolding
β1,6 –branches
Chitin (provides structural stability)
Mannans – often linked to proteins
The innate response to fungi serves two main purposes:
depends heavily on?
Surveillance and elimination
depends heavily on phagocytic cells
Especially neutrophils, macrophages & dendritic cells
Macrophages mediate the first steps of an effective antifungal host defense
Neutrophils essential in elimination
Innate recognition of fungi: Dendritic Cells and macrophages
bind to components of fungal cell walls usingpattern recognition receptors(PRRs)
C-type lectin receptors(CLRs, e.g. Dectin-1)
Toll-like receptors(TLRs, e.g. TLR2)
What happens when PRRS bind to PAMPS
when PRRs bind fungi they induce intracellular signalsor associated molecules (FcRγ).
These intracellular signals will in turn initiate:
1.phagocytosis
2.Initiation of killing mechanisms(e.g. production of reactive oxygen species)
3.helps drive thedevelopment of adaptive immunity
Innate cellular components: Epithelial Cells, Macrophage, Neutrophil, dendritic and platelet roles
+ DIAGRAM
Fungi can invade tissue by inducing endocytosis or actively penetrating the epithelium. Epithelial cells can produce antimicrobial peptides with antifungal activities and proinflammatory cytokines that can recruit other immune cells, such as monocytes, which will also contribute to fungal clearance.
Tissue resident macrophages can phagocyte and kill fungal pathogens;
neutrophils can also produce ROS (reactive oxygen species) and release neutrophil extracellular traps (NETs) that capture fungi and contain antimicrobial proteins that inhibit their growth.
Dendritic cells can migrate to lymph nodes and activate specific T-cell responses depending on the microbial morphology and site of infection. Innate lymphoid cells can also produce proinflammatory cytokines (IL-22) that contribute to mucosal antifungal responses.
Finally, in the last steps of infection, fungi breach the endothelium allowing them access to the bloodstream where they can activate platelets to produce cytokines and molecules with antifungal activity (CCL5 and PF4).
Adaptive Response cells and roles
Major Adaptive immune cell subset involved are CD4+ Th1 and Th17 cells
Th1 cells secrete IFN-y & TNF-a and are responsible for fungal clearance and inflammation
Th17 cells secrete IL-17a & IL-17F and are responsible for neutrophil recruitment and inflammation
Innate and adaptive immunity to fungal infections diagram
lecture slide
Functions of antibodies in response to fungi
1.opsonization of fungi
2. complement activation,
3.antibody-dependent cell toxicity
4.Immunomodulation
5.neutralisation of fungal PAMPS
Role of TNF-α, IFN-γ, and IL-17A and IL-17F
TNF-α, IFN-γ, and IL-17A and IL-17F. These cytokines stimulate the antifungal effector functions of phagocytes, as well as the generation of optimal T-cell-dependent immunity.
IFN-γ and help for opsonizing antibodies
IL-17A to mobilize neutrophils and induce defensins may contribute to a prompt and efficient control of the infection at the different body site
3 steps and description of fungal avoidance mechanisms of immune system response
1.Stealth— hide from detection
2.Control
-activate host immune inhibitory mechanisms
-guide immune responses toward types that are not especially effective against the microorganism
3.Attack— produce molecules that destroy host immune defences
fungal avoidance mechanisms diagram and examples
Stealth:
Dimorphism
Biofilm
Capsule
Melanin
Control:
Complement inhibiton
Avoiding phagocytic process
Apoptosis induction
Manipulation of phagosome maturation
Attack:
Destruction via ROS and RNS
Stealth:
Explain Dimorphism in more detail with specific example of fungi
Explain Biofilm in more detail with specific example of fungi
Dimorphism - Histoplasma capsulatum andBlastomyces dermatitidi
The cell wall is altered; the filamentous form contains both β- and α-glucans, but conversion to the yeast form is accompanied by increased production of α-(1,3)-glucan (much less immunogenic) and has been correlated to reduced virulence.
Biofilm - C. albicans
Biofilms are microbial communities that are attached to surfaces and held together by an extracellular matrix. Growth in a mass increases the resistance of the organisms to environmental stress, their resistance to antifungal activities and also effectively shields them from attack by phagocytes.
Control:
Explain Complement inhibition in more detail with specific example of fungi
Explain Avoiding phagocytic process in more detail with specific example of fungi
Complement inhibition -
To avoid elimination by the complement pathway, it is known thatC.albicansandAspergillusspp. secrete proteins onto their surface that bind to regulatory complement proteins. When attached to the fungal surface, these proteins inhibit the complement cascade and thus allow the evasion of complement attack
Avoiding phagocytic process - C. albicansundergo efficient phagocytosis; however, they are also able to develop hyphae inside and outside the macrophage, multiplying intracellularly, destroying the phagocytic cell, and escaping ingestion. During this transition,C. albicansproduces hyphae within macrophages to kill the cell or outside the macrophage to avoid phagocytosis and limit the recruitment of additional macrophages.
Attack:
Explain the purpose of RNS and ROS
If host defense mechanisms cannot be avoided completely or controlled sufficiently, the last resort for a pathogen is simply to survive or destroy the defences by the destruction of reactive oxygen species (ROS) and reactive nitrogen species (RNS). ROS and RNS have combined powerful antimicrobial effects and are sufficient to eliminate pathogens
Draw a diagram and explain Cryptococcus neoformansinfection in humans AND the mechanisms used to avoid immune response
(1) Killing and clearance by macrophages after phagocytosis,
(2) The encapsulated fungi are able to escape from phagocytosis and further establish virtual infection after pulmonary colonization, from asymptomatic latency period to pneumonia,
(3) Part of the phagocytosed fungi could escape killing and further parasitize the host cells like a Trojan horse which transports the pathogenic fungi into the CNS via circulation. After crossing the BBB, Cn that accumulates in the CNS would result in lethal cryptococcal meningitis especially in susceptible hosts.
Lecture slide
