Mind Map by , created over 6 years ago

Microbiology Mind Map on Leishmaniasis, created by maisie_oj on 04/24/2013.

Created by maisie_oj over 6 years ago
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1 The problem of leishmaniasis throughout tropical and subtropical regions (Epidemiology)
1.1 Global distribution/incidence of leishmaniasis
1.1.1 88 contries affected (tropics and sub-troppics)
1.1.2 2 million new cases each year
1.1.3 12 million people infected
1.1.4 350 million people at risk (will increase with global warming as insect vector migrates)
1.1.5 Spectrum of disease (mild to severe)
1.2 Transmission
1.2.1 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
1.2.2 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)
1.3 Causitive agent
1.3.1 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
1.3.2 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
2 The lifecycle of the causitive agent (Leishmania spp - L. donovani, major, infantum, braziliensis)
2.1 Sandfly takes a blood meal
2.1.1 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
3 Host cell invasion
3.1 Mechanism
3.1.1 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
3.2 Parasite ligand: GP63 + host C3b(i)
3.3 Macrophage/neutrophil target receptor: CR1 and CR3 (recognise surface bound C3b)
4 Disease pathlogy
4.1 Cutaneous leishmaniasis
4.1.1 Most common manifestation (5-10 million cases) Called; orient/bay sore, uta, baghdad/dehli/kandahar/lahore boil
4.1.2 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
4.2 Visceral leishmaniasis
4.2.1 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)
4.2.2 Most severe form 200-500,000 cases per year 50,000 deaths per year Mortality = 10-25%
4.2.3 Generalised infection of the reticuloendothelial system (phagocyte cells)
4.2.4 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
4.3 Diffuse leishmaniasis
4.3.1 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
4.4 Disease severity factors
4.4.1 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
5 Immune evasion of Leishmania spp.
5.1 There are several mechanisms used in the avoidance of the innate immune repsonse
5.1.1 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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