Leishmaniasis

Leishmaniasis

The problem of leishmaniasis throughout tropical and subtropical regions (Epidemiology)
1. Global distribution/incidence of leishmaniasis
  1. 88 contries affected (tropics and sub-troppics)
  2. 2 million new cases each year
  3. 12 million people infected
  4. 350 million people at risk (will increase with global warming as insect vector migrates)
  5. Spectrum of disease (mild to severe)
2. Transmission
  1. Parasite is transmitted by phlebotamine sand flies
    1. Flies live in; moist soils, stone walls, rubbish heaps - leishmaniasis found in a variety of ecosystems
    2. Only female flies spreadnthe disease
    3. They are pool feeders (feed of blood/lymph from an open wound - do not penetrate the skin)
    4. Parasite not in salivary gland, but in found in the anterior portion of the gut and the pharynx
  2. Two main modes of transmission
    1. Zoonotic (aimals to people)
      1. E.g. Transmission in latin america and mediterrenean via dogs
    2. Anthroponotic (human to human)
      1. E.g. Indian sub continent (transmission by: transplants/transfusions, congenital and sharing of needles)
3. Causitive agent
  1. 21 different species of Leismania (most notably L. donovani, major, infantum (aka chagasi in the new world) and braziliensis)
    1. Morphologically indistinguishable (unlike malaria)
    2. Molecularly distinct - detectable by...
      1. PCR
      2. Isoenzyme analysis (by many proteomic techniques)
      3. Monoclonal Ab's specific to each species
  2. Major parasite forms
    1. Promastigote
      1. Two subforms
        Non-infectious form
        Found in the insect gut/pharynx
        Replicates by binary fission
        Infectious metacyclic form
        Invades host cells (phagocytes)
        Non-replicating
      2. 15-20um in length, flagellated (motile)
      3. Structural arrangement: posterior end-nucleus-kinetoplast/flagellal pocket-anterior end
        Flagellum: long, unattached from cell body
      4. Extracellular forms
      5. Elongated, with long flagellum and central nucleus
    2. Amastigote
      1. 2-4um in length, stumpy flagellated (non-motile), divides by binary fission (500+ parasites per host cell)
      2. Intracellular form
      3. Structural arrangement: posterior end-nucleus-kinetoplast/flagellal pocket-anterior end
        Flagellum: short, barely projects beyond the flagellal pocket (non-motile)
      4. Can invade macrophages
      5. Transmissile from humans to insect (following blood meal)
      6. Spherical with short flagellum and central nucleus
The lifecycle of the causitive agent (Leishmania spp - L. donovani, major, infantum, braziliensis)
1. Sandfly takes a blood meal
  1. Leishmanial parasite (metacyclic promastigote in fly gut) transferred directly to the blood (unlike in chagas)
    1. Infected sandflies have a dysfunctional valve at the junction of the pharynx and midgut
      1. Valve cannot close meaning blood can flow backwards and forwards carrying the parasites to the wound
    2. Reflux action -> expulsion of the parasite into the bite wound
      1. 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
1. Mechanism
  1. Macrophage/neutrophil CR1 or 3 receptor binds to C3b(i)-bound GP63 on the parasite membrane
    1. This stimulates phagocytosis (passive invasion of the parasite)
      1. Cytochalasin D (inhibits phagocytosis by disrupting actin polymerisation) inhibit the invasion
      2. 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
2. Parasite ligand: GP63 + host C3b(i)
3. Macrophage/neutrophil target receptor: CR1 and CR3 (recognise surface bound C3b)
Disease pathlogy
1. Cutaneous leishmaniasis
  1. Most common manifestation (5-10 million cases)
    1. Called; orient/bay sore, uta, baghdad/dehli/kandahar/lahore boil
  2. Starts as raised, painless red lesion at site of bite
    1. Lesion can ulcerate
      1. Wet ulcer = L. major (typically in rural areas)
      2. Dry ulcer = L. tropica (typically seen in citites)
      3. 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
2. Visceral leishmaniasis
  1. Also known as kala azar (literally black sickness); or dumdum fever
    1. Typically caused by: L. donovani (india/pakistan) or infantum (mediterreanean; L. chagasi in latin america)
  2. Most severe form
    1. 200-500,000 cases per year
      1. 50,000 deaths per year
        Mortality = 10-25%
  3. Generalised infection of the reticuloendothelial system (phagocyte cells)
  4. Also involves; liver, spleen, bone marrow and lymph nodes
    1. Fever
    2. Hepatosplenomegaly with lymphadenopathy
    3. Anaemia, leukopaenia (WBC deficiency) and thrombocytopaenia (platelet deficiency)
    4. Progresses to; malaise, tiredness, lassitude (a state of mental tiredness) and weakness
      1. Patient exhibits wasting (even despite a good apetite)
        Common presentation = distended abdomen (hepatosplenomegaly) with wasted arm musculature
        Secondary infections are common
3. Diffuse leishmaniasis
  1. Two types;
    1. Diffuse cutaneous leishmaniasis (DCL)
      1. 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
      2. E.g. L. aethiopica and mexicana
    2. Mucocutaneous leishmaniasis (MCL)
      1. 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
      2. Mostly L. braziliensis
4. Disease severity factors
  1. Depends on the immune status of the individual
    1. T-helper lymphocytes (TH1 and TH2) response determines pathology
      1. TH1 response
        Cellular immune response stimulated (e.g. Cytotoxic T-lymphocytes)
        No/low Ab production
        Mild infection (cutaneous)
        Full recovery
      2. 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.
1. There are several mechanisms used in the avoidance of the innate immune repsonse
  1. The complement cascade (discussed in Chagas mind map)
    1. Following differentiation in the fly gut from non-infective promastigote to metacyclic (infectious) promastigote the parasite coat changes
      1. Non-infectious promastigote: short LPG chains with low levels of surface protein GP63
      2. 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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