Lecture 7 - the immune responses to fungal and parasitic infections Flashcards
Whats Candida albicans?
A commensal fungus that colonises the normal human oral, gastrointestinal and urogenital mucosa.
Disruption of mucosal barriers leads to persistent superficial infection.
What is the name of the infection that candida albicans can commonly lead to in patients with HIV?
Thrush and candida esophagitis
How does candida albicans reproduce?
Asexually by budding
What can cause candida albicans to switch from budding yeast form to filamentous hyphae form?
Microenvironmental signals that accompany tissue invasion e.g. changes in pH, cell density, exposure to serum and iron deprivation
What is innate recognition of fungi mediated by?
Interactions with conserved cell wall constituents e.g. glucans, mannans, galactans
What is dectin-1?
a highly conserved natural killer (NK)-cell-receptor-like C-type lectin.
What does dectin-1’s c type lectin domain recognise?
beta 1,3- and beta 1,6- linked gluons on the surface of intact cells and zymosan
What does engagement of dectin-1 cause?
Phosphorylation of its cytoplasmic immunoreceptor tyrosine-based activation motif (ITAM)
What does activation of Dectin-1 produce?
Induction of the production of inflammatory cytokines and the production of reactive oxygen species (ROS)
What comprises the structure of a fungal cell wall?
beta 1,6- glucan Fungal cell wall (chitin) Phospholipid bilayer of fungal cell membrane Ergosterol beta 1,3- gluten synthase mannans galactans
What is the name for the collection of molecules responsible for making distinctions between apoptotic particles generated by normal tissue turnover and particles that are indicative of infection?
Toll like receptors (TLRs)
What does stimulation of immune cells through their TLRs lead to?
Synthesis and secretion of pro-inflammatory cytokines, thereby initiating the inflammatory response that recruits both soluble immune components and immune cells from the blood
What type of immune response does TLR stimulation of DCs induce, innate or adaptive?
adaptive
What are the _ steps of toll like receptor activation?
- DCs recognise PAMPs such as LPS via their TLRs e.g. TLR4
- LPS is transported by LBP to the cell surface and deposited onto CD4
- Maturation of the DC and migration to the lymph
- Activation of acquired immune response
How do TLRs signal? (Pathway)
- Activation of TLR by fungal cell wall components and CD14
- MyD88 (an adaptor protein) binds TLR
- Signalling cascade initiated that culminates in transcriptional activation of cytokine genes by NK-kB
What occurs in collaborative signalling for cytokine production?
TLR binds to the cells surface along with dectin-1.
TLR and Dectin-1 recruit adaptor proteins MyD88 and phosphorylate Syk respectively.
Both of these promote downstream signalling pathways which enhance cytokine and chemokine production.
Expression of adhesions and mannoproteins by candida activate what pathway?
Lectin pathway of complement
Mannose binding lectin (MBL) is a collectin, and one of a number of serum proteins collectively known as ______
Opsonins
What does MASPS stand for?
Mannose binding lectin associated serine proteases
What do MASPS do?
Couple collections to the complement pathway
What does the binding of multiple carbohydrate recognition domains of MBL to the microbial cell surface lead to?
Conformational changes in the molecule which promotes proteolytic activation of the MASPS which then initiate the complement cascade
How does the body protect itself against candida infection?
- Activation of complement which results in phagocytosis by neutrophils and macrophages
- Phagocytosis triggers the production of ROS
- Interactions of ell wall components such as mannoproteins an b-glucan with phagocyte receptors such as TLR2 and dectin-1 stimulate release of cytokines including IL-1, IL-6 and TNF
- this all promotes maturation of DCs and allows activation of the adaptive immune system
What is chromoblastomycosis and fonsecaea pedrosoi?
Causative agents of a non fatal disease of the skin and subcutaneous tissues
Frequently occurs in tropical and sub tropical regions of America, Asia and Africa
Infection occurs following transcutaneous trauma
Causes chronic disease that is difficult to treat and can take decades to develop
What does TLR2 recognise?
Fungal cell wall components
What does F.pedrosi signal through?
TLR2 and Mincle as opposed to dectin
What are helminths?
Large, multicellular organisms that reproduce sexually to create larval stages that mediate pathogenic transmission.
These helminths don’t generally replicate with a mammalian host, but gain passage through intermediate hosts or require soil or water
Name 3 examples of helminths
Nematodes (roundworms)
Trematodes (flukes)
Cestodes (flatworms or tapeworms)
What type of parasite is a schistosoma?
Parasitic trematode or fluke which infects humans
What are the stages of the life cycle of a schistosome?
- In fresh water, eggs hatch to yield motile miracidia
- Miracidia infect snails
- In their intermediate snail hosts, the miracidia undergo mutation and multiplication to release infectious cercariae
- These cercariae can shed their tails and use a combination of proteases and the muscular action of their oral sucker to penetrate the host’s skin
- After penetration, the immature schistosomula enter the bloodstream and travel the circulation until the eventually become embedded in the hepatic portal vein, where they mature
- adult females reside intimately within a canal in
the ventral body of the male, and release eggs - These eggs elicit a granulomatous inflammatory response, which allows them to reach the bladder and intestines, for excretion via the urine or stool respectively
* sometimes the eggs can become retained in the tissue and calcify causing chronic schistosomiasis
What immune response profile does the early stages of an infection directed against a schistosomula demonstrate?
Th1 profile
In schistosomiasis, what triggers a change from Th1 response to a vigorous Th2 response?
Presence of egg antigens
Along with the presence of Th2 cytokines, what other features characterise the late stages of a response to schistosomiasis?
Eosinophilia, elevated IgE and the presence of tissue granulomas sounding eggs
What are the characteristics of a Th1 profile?
Th1 cell binds macrophage, along with binding of coreceptors CD154/CD40
Release of the following cytokines: IFN-g GM-CSF TNF-a IL-3 TNF-b
What are the characteristics of a Th2 profile?
Th2 cell binds antigen specific b cell, along with binding of coreceptors CD154/CD40
Release of the following cytokines: IL-4 IL-5 IL-10 IL-3 TGF-b
How are type 2 granulomas characterised?
AN organised circumferential infiltrate of Th2 cells, eosinophils, macrophages and fibroblasts with a dense collagen rich matrix
What are protozoa?
Diverse group of unicellular pathogens that typically cause chronic infections, including a high degree of evolutionary adaptation e.g. malaria
What is the most common theme that underlies the capacity of these organisms to persist the host?
Antigenic variation
What two groups can protozoan infections be divided into?
- those introduced by bites or tissue injury
2. Those introduced by ingestion of contaminated water
What is the initial immune response to infection by t.brucei characterised by?
Release of inflammatory cytokines IFN-g and TNF, associated with a Th1 response
The presence of which cell type is a hallmark of infection with trypanosomes?
Macrophages
