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Leishmaniasis
Descripción
Microbiology Mapa Mental sobre Leishmaniasis, creado por maisie_oj el 24/04/2013.
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microbiology
microbiology
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Resumen del Recurso
Leishmaniasis
The problem of leishmaniasis throughout tropical and subtropical regions (Epidemiology)
Global distribution/incidence of leishmaniasis
88 contries affected (tropics and sub-troppics)
2 million new cases each year
12 million people infected
350 million people at risk (will increase with global warming as insect vector migrates)
Spectrum of disease (mild to severe)
Transmission
Parasite is transmitted by phlebotamine sand flies
Flies live in; moist soils, stone walls, rubbish heaps - leishmaniasis found in a variety of ecosystems
Only female flies spreadnthe disease
They are pool feeders (feed of blood/lymph from an open wound - do not penetrate the skin)
Parasite not in salivary gland, but in found in the anterior portion of the gut and the pharynx
Two main modes of transmission
Zoonotic (aimals to people)
E.g. Transmission in latin america and mediterrenean via dogs
Anthroponotic (human to human)
E.g. Indian sub continent (transmission by: transplants/transfusions, congenital and sharing of needles)
Causitive agent
21 different species of Leismania (most notably L. donovani, major, infantum (aka chagasi in the new world) and braziliensis)
Morphologically indistinguishable (unlike malaria)
Molecularly distinct - detectable by...
PCR
Isoenzyme analysis (by many proteomic techniques)
Monoclonal Ab's specific to each species
Major parasite forms
Promastigote
Two subforms
Non-infectious form
Found in the insect gut/pharynx
Replicates by binary fission
Infectious metacyclic form
Invades host cells (phagocytes)
Non-replicating
15-20um in length, flagellated (motile)
Structural arrangement: posterior end-nucleus-kinetoplast/flagellal pocket-anterior end
Flagellum: long, unattached from cell body
Extracellular forms
Elongated, with long flagellum and central nucleus
Amastigote
2-4um in length, stumpy flagellated (non-motile), divides by binary fission (500+ parasites per host cell)
Intracellular form
Structural arrangement: posterior end-nucleus-kinetoplast/flagellal pocket-anterior end
Flagellum: short, barely projects beyond the flagellal pocket (non-motile)
Can invade macrophages
Transmissile from humans to insect (following blood meal)
Spherical with short flagellum and central nucleus
The lifecycle of the causitive agent (Leishmania spp - L. donovani, major, infantum, braziliensis)
Sandfly takes a blood meal
Leishmanial parasite (metacyclic promastigote in fly gut) transferred directly to the blood (unlike in chagas)
Infected sandflies have a dysfunctional valve at the junction of the pharynx and midgut
Valve cannot close meaning blood can flow backwards and forwards carrying the parasites to the wound
Reflux action -> expulsion of the parasite into the bite wound
This is aided by the secretion of a gel-like substance from the parasite which forms a physical barrier to fly feeding
Metacyclic promastigote phagocytised by host neutrophils
Trojan horse theory (for L. major)
Infected neutrophil undergoes apoptosis -> apoptotic bodies phagocytised by macrophages -> promastigote now in macrophage-> differentiate (amastigotes
Or...
Promastigote differentiates to amastigote in neutrophil -> replication -> ruputre -> amastigotes released and infect macrophages
Both ways lead to the infection of macrophages with amastigote forms
Amastigotes replicate in macrophages
Macrophage ruptures, releasing amastigotes into bloodstream to continue cycle
Sandfly takes a blood meal and ingests infected host macrophage
Macrophage rupture and amastigote release in insect gut
In the insect gut: amastigotes -> non-infectious promastigotes which attach to the gut wall by LPG (lipophosphoglycan) to avoid excretion
Non-infectious promastigotes replicate (binary fission)
Some become metacyclic promastigotes (infective) - they loose their LPG (coat change) and move to the anterior gut ready for transmission
Host cell invasion
Mechanism
Macrophage/neutrophil CR1 or 3 receptor binds to C3b(i)-bound GP63 on the parasite membrane
This stimulates phagocytosis (passive invasion of the parasite)
Cytochalasin D (inhibits phagocytosis by disrupting actin polymerisation) inhibit the invasion
Parasite is now internalised within a phagosome
Lysosomes fuse with the phagosome
Lowering the pH (~5.0)
Low pH triggers differntiation of metacyclic (infecitous) promastigote to amastigote
Amastigote replicates in the phagosome
Amastigotes are masters of modulating the phagocytes behaviour
Leishmania inhibit host cell PKC which prevents NADPH oxidase complex formation
Reducing the overall oxidative stress
Leishmania activate SHP1 (a host cell tyrosine phosphatase)
SHP1 dephosphorylates cytokine receptor-bound JAK (inactivating the JAK-STAT pathway)
STAT no longer expresses genes that promote an inflammatory response
Supression of the inflammatory response
Lysosomes acidify the phagosome, add digestive enzymes (lysosymes: proteases, nuclease and lipases) and also induce oxidative stress
Phagosome membrane enzyme NADPH oxidase complex produces free radicals (H2O2 and hypochlorate - which produce hydroxyl radicals un reacting with iron)
Nitric oxide synthase produces nitric oxide which reacts with superoxide free radicals - producing peroxynitrite
All are deadly to pathogens
Parasite ligand: GP63 + host C3b(i)
Macrophage/neutrophil target receptor: CR1 and CR3 (recognise surface bound C3b)
Disease pathlogy
Cutaneous leishmaniasis
Most common manifestation (5-10 million cases)
Called; orient/bay sore, uta, baghdad/dehli/kandahar/lahore boil
Starts as raised, painless red lesion at site of bite
Lesion can ulcerate
Wet ulcer = L. major (typically in rural areas)
Dry ulcer = L. tropica (typically seen in citites)
No pus (unless bacterial infection follows)
Ulcer self-heals, leaving a scar (esp. L. major)
Oce healed - individual is immne for life
Can become diffuse
Visceral leishmaniasis
Also known as kala azar (literally black sickness); or dumdum fever
Typically caused by: L. donovani (india/pakistan) or infantum (mediterreanean; L. chagasi in latin america)
Most severe form
200-500,000 cases per year
50,000 deaths per year
Mortality = 10-25%
Generalised infection of the reticuloendothelial system (phagocyte cells)
Also involves; liver, spleen, bone marrow and lymph nodes
Fever
Hepatosplenomegaly with lymphadenopathy
Anaemia, leukopaenia (WBC deficiency) and thrombocytopaenia (platelet deficiency)
Progresses to; malaise, tiredness, lassitude (a state of mental tiredness) and weakness
Patient exhibits wasting (even despite a good apetite)
Common presentation = distended abdomen (hepatosplenomegaly) with wasted arm musculature
Secondary infections are common
Diffuse leishmaniasis
Two types;
Diffuse cutaneous leishmaniasis (DCL)
Limited to cutaneous surfaces - but metastasises over the entire body
Non-ulcerated, scaley,lesions (nodular)
Caused by a lack of immune response (anergy)
Amastigotes abundant in lesions
E.g. L. aethiopica and mexicana
Mucocutaneous leishmaniasis (MCL)
Primarily a cutaneous form that metastasises to the mucocutaneous junctions (e.g. Mouth/nose/soft palate or anus/genitalia)
Can occur weeks or years after initial infection
Tissue is grossly destroyed causing disfigurement
Secondary bacterial infections are common
Mostly L. braziliensis
Disease severity factors
Depends on the immune status of the individual
T-helper lymphocytes (TH1 and TH2) response determines pathology
TH1 response
Cellular immune response stimulated (e.g. Cytotoxic T-lymphocytes)
No/low Ab production
Mild infection (cutaneous)
Full recovery
TH2 response
Stimulates a humoral (Ab) immune response
High Ab production
Succumb to infection (visceral form)
Particularly nasty species (e.g. L. donovani) actually trigger a switch from TH1 to TH2 response
Immune evasion of Leishmania spp.
There are several mechanisms used in the avoidance of the innate immune repsonse
The complement cascade (discussed in Chagas mind map)
Following differentiation in the fly gut from non-infective promastigote to metacyclic (infectious) promastigote the parasite coat changes
Non-infectious promastigote: short LPG chains with low levels of surface protein GP63
Infectious metacyclic promastigote: has much longer LPG chains (conceal the membrane proteins) and a higher level of GP63 surface protein
Long LPG
Blocks the MAC forming within the parasite membrane
Lipophosphoglycan (LPG) - around 3-5million copies per cell
Structure
Oligosaccharide capping complex
Phosphoglycan domain
Recurring motif of [galactose-mannose-phosphate]n
Features side chains (Galactosyl sidechains)
These galactosyl side chains bind galectin in the insect gut (during differentiation into the infectious promastigote these side chains are capped)
Arabinosyl caps (prevents binding of infectious form in the insect gut)
GP63
Binds to activated C3b and inactivates it
Preventing C3 convertase formation
However, used the bound C3b(i) to attract macrophages for invasion
Macrophages phagocytose anything that is bound to C3b (detected by CR1 and CR3 receptors)
This is called opsonisation
CR = comement receptor
Zinc metalloproteinase
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