Immune response to, and immune evasion by fungi and parasites Flashcards
Common fungal diseases
- Fungal nail infections - common infections of the fingernails or toenails
- Athletes foot, “Jock rash” – caused by Tinia pedis or Tinia cruris
- “Thrush” /Vaginal candidiasis - caused by the yeast. Candida albicans, also called a “vaginal yeast infection”
- “Oral thrush” - Candida infections of the mouth, throat, and oesophagus
- Ringworm - A common fungal skin infection that often looks like a circular rash
More serious fungal infections (opportunistic)
*Invasive candidiasis
- A serious infection that can affect the blood,
heart, brain, eyes, bones and other parts of the
body
*Aspergillosis
- An infection 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, causing meningitis
*Pneumocystis pneumonia (PCP)
Serious fungal infections are a consequence of compromised immunity
Describe this phenomenon
- Compromised immunity is the most important
predisposing factor for clinically significant fungal infections. Neutrophil deficiency as a result of bone marrow suppression or damage is frequently associated with such infections - Secondary infections associated with severe viral infections (Aspergillosis and ‘flu or COVID infections)
- Opportunistic fungal infections are also associated with immunodeficiency caused by HIV and by therapy for disseminated cancer and transplant rejection
How well do we understand Immune responses to fungi
Less is known about antifungal immunity than
about immunity against bacteria and viruses.
This lack of knowledge is partly due to the paucity of animal models for mycoses and partly due to the fact that these infections
typically occur in individuals who are incapable of mounting effective immune responses
What makes fungi efficient activators of innate immunity?
- Glucans are the most abundant polysaccharides in the cell walls of fungi, and their structures are highly variable
- Glucans comprise glucose moieties joined through either alpha (α) or beta (β) linkages; they can be either linear or branched, and amorphous or microfibrillar
Fungal cell walls are recognised by PRRs
in DCs and macrophages
Describe these PRRs
The TLR family again plays an important role in this process, along with the mannose receptor
and complement receptors:
* TLR2 (which can cooperate with the b-glucan receptor dectin-1) recognizes fungal phospholipomannans, C. albicans yeasts, and A. fumigatus hyphae and conidia, and linear beta-1,2-oligomannoside structures ;
* TLR4/CD14 recognizes C. albicans, Aspergillus
fumigatus, and the glucuronoxylomannan capsule of C. neoformans. TLR4 is activated upon ligation of C. albicans O-linked mannans
* C-type lectin receptor family recognizes glucan and
mannan
What is the innate Immune responses to fungi?
The basic protective features of the skin and normal commensal flora are important in resistance to fungi.
Defensins have antifungal properties, and collectins such as MBL and the surfactant
proteins A and D can bind, aggregate, and opsonize fungi for phagocytosis. Phagocytes, particularly neutrophils and macrophages, are essential for killing fungi, either by:
* degranulation and release of toxic materials onto large indigestible hyphae; or
* ingestion of yeast or conidia.
The oxidative burst plays a crucial role in some antifungal responses
Recognition of fungi via this receptor promotes phagocytosis, triggers the respiratory burst and elicits inflammatory cytokine, chemokine and prostaglandin responses. TNF is one of these important cytokines
T cell-mediated immunity is critical for resistance to fungi
Describe this phenomenon
the dominant protective role of TH1 (and perhaps also TH17 T cells) and phagocyte activation, rather than antibody-mediated responses.
dependent upon T cell-mediated immunity, particularly CD4+ TH1 cells secreting IFNg and to a lesser extent CD8 T cells
The clinical relevance of TH1 versus TH2 responses is also clear for some human mycoses, for example:
* individuals with mild paracoccidioidomycosis have TH1-biased immune responses; whereas
* individuals with severe, disseminated infection have high levels of TH2 cytokines such as IL-4 and IL-10, and eosinophilia.
Describe the Immune evasion strategies of fungi
Fungal pathogens avoid detection by masking
pathogen-associated molecular patterns, such as cell wall carbohydrates:
* C. albicans masks b-glucan layer underneath a
coat of mannoprotein, which would otherwise be efficiently recognized by host dectin-1
Fungal pathogens can avoid detection by
downregulating 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)
- Cell size is an effective deterrent to ingestion: the multinucleate hyphal forms of C. albicans and Aspergillus fumigatus are not efficiently
internalized - Once detected, various species interfere with
phagocytosis and intracellular trafficking, and
can repress production of antimicrobials like
nitric oxide (NO) - dermatophytes suppress host T cell responses to delay cell-mediated destruction.
- Histoplasma capsulatum is an obligate intracellular pathogen that evades macrophage killing by entering the cell via CR3 and then altering the normal pathways of phagosome maturation
Common helminths and parasites
Protozoa
* Entamoeba
* Leishmania (intracellular)
* Toxoplasma (intracellular)
* Trypanosomes (intracellular)
* Giardia
* Trichomonas
* Malaria (intracellular)
Helminths
* Nematodes
* Ascaris
* Schistomiasis
* Filaria
Ectoparasites
Ticks, fleas, lice
What is the Immune responses to parasites?
The principal immune response to intracellular protozoa is phagocytosis, which is much enhanced by cell-mediated immunity particularly macrophage activation by Th1 cell–
derived cytokines
Recognition of parasites is through surface molecules
Describe this
Some protozoa express surface molecules that are recognized by TLRs and activate phagocytes. Plasmodium species, Toxoplasma gondii, and Cryptosporidium species (a major cause of diarrheal disease in HIV-infected patients) all express glycolipids that can activate TLR2 and
TLR4.
- T. gondii binds TLR11 via profilin and associates with TLR3, TLR7, and TLR9 via the endoplasmic reticulum protein UNC93B1;
- TLR9 mediates innate immune activation by the malaria pigment hemozoin;
Many parasites are resistant to phagocytic killing and may even replicate within macrophages
Describe the Evasion by Leishmania
During primary infection in vivo, Leishmania
recruits neutrophils to the site of inoculation
following a sandfly bite, and survival within
these cells is important for productive infection.
IFN-g-induced MHCII and iNOS are blocked
by L. donovani, which disrupts nuclear
translocation of STAT1α by blocking the
interaction between STAT1a and importin-a5.
Leishmania are also potent inhibitors of IL-12
production by macrophages in vitro and in
vivo; as this cytokine plays a pivotal role in
Th1 responses, this activity is likely extremely
important in persistence in vivo.
Describe the Evasion by Toxoplasma gondii
Penetration of T. gondii into the host cell
results in formation of a membrane bound
vacuole that is primarily derived by
invagination of the host cell plasma membrane.
Toxoplasma is unique in being able to actively
penetrate both phagocytic and nonphagocytic
cells and set up residence in a nonfusigenic
vacuole. Residence in this vacuole is relatively
resistant to NO, ROI-mediated killing
The acute infection is characterized by fast
growing forms called tachyzoites, which lyse
their host cells within 24–48 hrs 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, which resides within
an intracellular cyst and is largely invisible to
antibodies
Describe the Evasion by Trypanosomes
T. cruzi infects and replicates in 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 antibody response to
the surface VSG protein
Describe the Immunity to malaria
- It was thought for many years that antibodies
were the major protective mechanism against
malaria, and early attempts at vaccinating
against this infection focused on generating
antibodies - It is now apparent that the CTL response
against parasites residing in hepatocytes is an
important defence against the spread of this
intracellular protozoan
Eosinophils and mast cells are needed to
clear helminth infections
Describe this
- Most helminth parasites are too large to be phagocytized, and the IgE system is believed to have evolved as a mechanism for dealing with these larger invaders
- IgE is the link that connects eosinophils to the outer surface of a parasitic worm
- IgE-bound pathogens bind to high affinity FceRI and FceRII receptors found on the surface of eosinophils and mast cells (and basophils)
- The large cytoplasmic granules of eosinophils contain a variety of proteases and toxic proteins that, in aggregate, can often kill larval intestinal parasites to which the eosinophils are attached
- Mast cells (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 the smooth muscle cells of the intestinal walls as a physical mechanism for expelling the worms from the digestive tract.
Describe Th2 cells
- Th2 cells help to control parasitic infections by
promoting IgE production and by promoting the function of eosinophils and mast cells - Produce IL-4, IL-5 and IL-13
Immune responses to Helminths
