Leishmania Flashcards
What type of protozoan is Leishmania?
Kinetoplastid
Leishmania can only replicate in which cell type?
Macrophages
What do intracellular parasites need to overcome?
- They must have a method of cell entry- invasion
- They must have a method of evading the host cell immune responses
- They must have a method of obtaining nutrients
What intracellular parasites do you need to know?
Plasmodium, Trypanosoma cruzi, Leishmania and Toxoplasma
What intracellular mechanisms need to be avoided by intracellular parasites?
- Display of antigens on MHC
- Phagolysosomal degradation
- Reactive oxygen and nitrogen intermediates
- Autophagy
- Induction of apoptosis
Leishmania is spread by?
Sandflies
Describe the lifecycle?
Sandfly injects promastigotes
Promastigotes are taken up by macrophages
Differentiation of promastigotes into amastigotes in the macrophage
Replication of amastigotes
Macrophage lysis and release of amastigotes
Amastigotes then invade other macrophages or are taken up by a sandfly bite
The amastigotes differentiate into promastigotes in the sandfly gut
The promastigotes move to the mouthparts of the sandfly
What are the three forms of Leishmaniasis?
Cutaneous
Mucocutaneous
Visceral
What is visceral leishmaniasis?
It impacts the organs and can be fatal
What is cutaneous leishmaniasis?
It may cause lesions on the skin and is the most common form of Leishmaniasis
What is mucocutaneous leishmaniasis?
Causes destruction of mucosal membranes of the nose, mouth and throat cavity. Can cause disfiguration which can cause a person to be rejected by their communities
What are the definitive and intermediate hosts of Leishmaniasis?
Definitive: Sandfly
Intermediate: Human
How do promastigotes enter the macrophages?
Opsonisation by Cb3 and recognition by CR3 on the macrophage, leading to phagocytosis
How do amastigotes enter the macrophages?
Opsonisation by IgG and recognition by FcR on the macrophage, leading to phagocytosis
Properties of the promastigote?
Flagellum
GP63 protease
LPG on its surface
Properties of the amastigote?
Has no LPG
Has little GP63
Lacks a flagellum
What is LPG?
Lipophosphoglycan
LPG is attached to the cellular membrane via?
GPI anchor
What is the function of LPG?
Can prevent MAC formation
Mediates actin recruitment which can delay phagolysosomal fusion
What is the importance of delaying phagolysosomal fusion?
Allows time for the promastigote to differentiate into the more acid resistant amastigote form of the parasite
How is phagolysosomal fusion delayed?
LPG inserted into the phagosome membrane
Via LPG mediated actin recruitment
Leishmania trojan horse?
Can enter the macrophages through a neutrophil trojan horse
Infection of neutrophils can lead to induction of apoptosis or damage which causes the parasitised neutrophils to be phagocytosed by macrophages
What prevents Cb3 from forming the MAC?
GP63 protease
How does GP63 work?
It is a protease
Can cause C3b to become iC3b
This is an inactivated proteolytically inactive form of C3b, can still opsonise the parasite but cannot interact with factor B and cannot lead to amplification or assembling of the C5 convertase
iC3b?
This is an inactivated proteolytically inactive form of C3b, can still opsonise the parasite but cannot interact with factor B and cannot lead to amplification or assembling of the C5 convertase
Amasitogotes are more what than promastigotes?
Amastigotes are more acid resistant than promastigotes, less vulnerable to degradation
How are macrophages classically activated?
They are classically activated through IFN-g produced by Th1 cells
Why are amastigotes opsonised by IgG rather than complement proteins?
As amastigotes have little GP63
They are also produced later on in infection once the adaptive immunity has been elicited
What can elicit adaptive immunity?
Exogenous antigens presented by dendritic cells
What does classical activation of macrophages achieve?
Macrophages produce IL-12 which creates a positive feedback loop
Macrophage microbicidal activity is increased
Macrophage lysosomal degradation and production of reactive oxygen and nitrogen intermediates is increased
How are reactive oxygen species produced?
From oxygen
How is nitric oxide produced?
L-arginine precursor is transformed by iNOS into NO
iNOS?
Inducible nitric oxide synthase
Th1 response causes L-arginine to become?
NO
Th2 response causes L-arginine to become?
L-ornithine
L-ornithine can give rise to?
Polyamines which can be used for nutrients
What causes L-arginine –> L-ornithine?
Arginase
How can Leishmania reduce NO production?
Inducing the macrophage to produce arginase or by producing its own arginase
How does Leishmania obtain nutrients?
It is in the phagolysosome which is fusogenic
Fusion of ER membrane, endosomes and autophagosomes provides lots of nutrients
Leishmania replicates where?
In the fusogenic phagolysosome
Summary of Leishmania immune evasion?
- GP63 converts C3b–> iC3b
- LPG prevents MAC formation
- LPG mediated actin recruitment delays phagolysosome fusion
- Intracellular
- Arginase producing L-ornithine provides nutrients for growth and reduces NO production
- Leishmania can inhibit JAK/STAT signalling
Leishmania can block which signalling?
JAK/STAT signalling
