Immune response to and immune evasion by fungi and parasites Flashcards
Where are fungi found?
Commensals on our skin, in our mouths and throat
Spores in the air
Spores in our food
Our immune system has co-evolved with them
What are common fungal diseases?
Fungal nail infections
Athletes foot caused by Tinia pedis or Tinia cruris
Thrush (Vaginal candidiasis) caused by yeast Candida albicans
Oral thrush - Candida infections of mouth, throat and oesophagus
Ringworm - common fungal skin infection that often looks like a circular rash
What are some more serious fungal infections?
Invasive candidiasis - affects blood, heart, brain, eyes, bones and other parts of the body
Aspergillosis - caused by Aspergillus, a common mold that lives indoors and outdoors
Candida auris - emerging, often multidrug-resistant fungus found in healthcare settings
Cryptococcus neoformans - can infect the brain and cause meningitis
Pneumocystis pneumonia (PCP)
What causes serious fungal infections?
They are a consequence of compromised immunity
Neutrophil deficiency as a result of bone marrow suppression or damage is frequently associated with such infections
What are secondary infections associated with?
Severe viral infections e.g. Aspergillosis with flu or COVID infections
What are opportunistic fungal infections associated with?
Immunodeficiency caused by HIV and by therapy for disseminated cancer and transplant rejection
What are glucans?
Most abundant polysaccharides in the cell walls of fungi and their structures are highly variable
Glucan comprise glucose moieties joined through either alpha or beta linkages - they can either be linear or branched and amorphous or microfibrillar
What recognises fungal cells walls?
PRRs in DCs and macrophages
What does TLR2 recognise?
Fungal b-glucans of several fungal species including C. albicans
Also recognises phospholipo-mannans (PLMs) and linear beta-1-2-oligomannoside structures that are unique to C. albicans
What activates TLR4?
Ligation of C. albicans O-linked mannans
What does C-type lectin receptor family recognise?
Glucan and mannan
What are immune responses to fungi?
Release of IL-22 stimulates epithelial cells to produce antimicrobial peptides
Release of IL-17 recruits neutrophils to the site of infection
What are immune evasion strategies of fungi?
Fungal pathogens avoid detection by masking PAMPs such as cell wall carbohydrates
e.g. C. albicans masks b-glucan layer underneath a coat of mannoprotein
Downregulate complement cascade
Cell size is an effective deterrent to ingestion
Once detected, various species interfere with phagocytosis and intracellular trafficking and can repress prod of antimicrobials like NO
How do fungi downregulate the complement cascade?
Cryptococcus neoformans secretes App1, a small protein which binds to and inhibits complement receptors
C. albicans inhibits complement activity by binding several complement regulatory factors, including Factor H, FHL-1 and C4b-binding protein (C4BP)
Name some common protozoa
Entamoeba
Leishmania - intracellular
Toxoplasma - intracellular
Trypanosomes - intracellular
Giardia
Trichomonas
Malaria - intracellular
Name some common helminths
Nematodes
Ascaris
Schistosomiasis
Filaria
Name some common ectoparasites
Ticks
Fleas
Lice
What is the principle immune response to intracellular protozoa?
Phagocytosis, which is enhanced by cell-mediated immunity - particularly macrophage activation by Th1 cell-derived cytokines
How are parasites recognised?
Through surface molecules
Some protozoa express surface molecules that are recognised by TLRs and activate phagocytes
Give examples of protozoa that express surface molecules
Plasmodium species (responsible for malaria)
Toxoplasma gondii (causes toxoplasmosis)
Cryptosporidium species (major cause of diarrhoeal disease in HIV-infected patients)
All express glycolipids that can activate TLR2 and TLR4
Describe how Leishmania evade immune response
During primary infection Leishmania recruits neutrophils to the site of inoculation following a sandfly bite
IFN-g-induced MHC II and iNOS are blocked by L. donovani, disrupting nuclear translocation of STAT1-a by blocking interaction with importin-a5
What are Leishmania potent inhibitors of?
IL-12 production by macrophages in vitro and in vivo
Describe evasion by Toxoplasma gondii
Penetration of T. gondii into host cell results in formation of membrane bound vacuole - primarily derived by invagination of host cell plasma membrane
Toxoplasma actively penetrates phagocytic and nonphagocytic cells and reside in nonfusigenic vacuole - residence in this vacuole is relatively resistant to NO, ROI-mediated killing
What is T. gondii acute infection characterised by?
Fast growing forms called tachyzoites - they lyse their host cells within 24-48hrs to release large numbers of progeny
These are very immunogenic
In response to immune pressure, the parasite differentiates into a slow growing form called a bradyzoite - resides in an intracellular cyst and is largely invisible to Abs
Describe evasion by trypanosomes
T. cruzi infects and replicates into the cytoplasm and is therefore relatively resistant to NO, ROI-mediated killing
T. cruzi release from infected cells generates strongly immunogenic material and host species generate a robust Ab response to the surface VSG protein
How do parasites evade protective immunity?
By reducing their immunogenicity
They change their surface antigens during their life cycle in vertebrate hosts
What are two forms of antigenic variation?
- Stage-specific change in antigen expression such that the mature tissue stages of parasites produce antigens different from those of the infective stages
e.g. infective sporozoite stage of malaria parasites is antigenically distinct from merozoites that reside in the host and are responsible for chronic infection - Continually changing surface antigen expression - e.g. Trypanosomes and Entamoeba
Describe antigenic variation in T. brucei
Parasite is covered with variant surface glycoproteins (VSGs) recognised by host’s immune system
VSG is so densely packed that it obscures other cell surface components from immune recognition
VSG coat is highly antigenic and stimulates a very strong immune response that wipes out most of the parasite population
A few parasites switch the VSG gene expressed so as previous variants are recognised and cleared, newly switched variants emerge, resulting in characteristic waves of parasitaemia
How do VSGs generate diversity?
The diversity of the VSGs required to maintain an extended infection exceeds the number of functional genes responsible for encoding them
VSG genes rearrange to generate this diversity
What is an important defence against spread of malaria parasites?
CTL response against parasites residing in hepatocytes
What are the principle mechanisms of protective immunity for plasmodium species?
Antibodies and CD8+ CTLs
Plasmodium species cause malaria
What are the principle mechanisms of protective immunity for plasmodium species?
Antibodies and CD8+ CTLs
Plasmodium species cause malaria
What are the principle mechanisms of protective immunity for Leishmania donovani?
CD4+ Th1 cells activate macrophages to kill phagocytosed parasites
What are the principal mechanisms of protective immunity for Trypanosoma brucei?
Antibodies
T. brucei cause African trypanosomiasis
What are the principle mechanisms of protective immunity for Entamoeba histolytica?
Antibodies, phagocytosis
E. histolytica causes Amebiasis
What immune cells are needed to clear helminth infections?
Eosinophils and mast cells
What mechanism deals with larger invaders that are too big to be phagocytosed?
IgE system
IgE is the link that connects eosinophils to the outer surface of a parasitic worm
What do IgE-bound pathogens bind to?
High affinity FceRI and FceRII receptors found on the surface of eosinophils and mast cells (and basophils)
What do the cytoplasmic granules of eosinophils contain?
A variety of proteases and toxic proteins that aggregate to kill larval intestinal parasites to which the eosinophils are attached
What do mast cells do?
Activated by IL-5 and coated by IgE
Degranulate and release histamine, serotonin and leukotriene at the site of infection
These can cause contractions of smooth muscle cells of the intestinal walls as a physical mechanism for expelling worms from the digestive tract
What do Th2 cells do?
Help to control parasitic infections by promoting IgE production and function of eosinophils and mast cells
Produce IL-4, IL-5 and IL-13
