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MMI 426 > Leishmania > Flashcards

Leishmania Flashcards

1
Q

neglected tropical disease

A

leishmania

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2
Q

the Rose of Jericho

A

Leishmania

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3
Q

leishmania parasite

A
  • single cell
  • genus: Leishmania
  • flagellate
  • Trypanosomatidae family
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4
Q

vector for Leishmania

A

female sand fly

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5
Q

reservoirs for Leishmania

A

canines, rodents, humans

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6
Q

visceral leishmaniasis

A

most severe form of leishmania

often seen in countries with lower standards of healthcare

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7
Q

disease manifestations of leishmania

A

partly due to parasite = presence of RNA virus in parasite and immune response

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8
Q

life cycle of leishmania

A

2 stages
- stages in human and stages in sandfly (bio vector)
- human stage = starts after being bitten; sandflies inject saliva after bloodmeal; saliva = inflammation = calls macrophages bc parasites want to be phagocytosed to hitch a ride
- stage of parasite transmitted to humans via sand fly = promastigote
- will transform into amastigotes in macrophages (human stage)
- after bursting = sandfly stage starts; sand fly will ingest macrophages parasite
- amstogotes turn into promastogotes of sandfly
- will divide in midgut and go to proboscis waiting to take another bloodmeal

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9
Q

T or F. Leishmania has a sexual stage

A

F! not yet identified if there is one

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10
Q

leishmania disease manifestations

A

cutaneous or mucocutaneous
- L. major, L. tropica, L. aethiopica (most popular)

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11
Q

visceral leishmaniasis

A
  • most severe
  • often caused by L. donovani, L. infantum
  • Ganges, southern Nepal, Bangladesh, Brazil, etc.
  • black sickness, black fever, etc.
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12
Q

T or F. A single species of Leishmania can cause more than one type of syndrome

A

T! AND a syndrome can be caused by more than one species
it all depends on host-parasite interactions

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13
Q

two types of Leishmania promastigotes

A

these are in sandfly
- motile
- metacyclic

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14
Q

metacyclic vs motile Leishmania promastigotes

A

after amastigote stage in humans, motile promastigotes (non-infective insect form) will attach to insect gut, then transform to non-dividing infectious forms (metacyclic promastigotes)

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15
Q

transformation stimulus of Leishmania promastigotes depends on many factors, including…

A

temperature

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16
Q

risk factors Leishmania

A
  • poor rural housing conditions, cracked walls, earthen floors
  • poor sanitation = garbage attracts sandflies and dogs
  • lack of accessible medicines
  • if there is conflict = hard to perform vector control and movement of troops
  • HIV
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17
Q

how to be a good reservoir for leishmaniasis

A
  • Be in close contact with sandflies
  • Should be susceptible to the infectious agent
  • Should allow replication of the infectious agent to ensure delivery of large numbers to the victim
  • Should ideally be the main source of food for the fly
  • Disease should develop as a chronic disease giving time for the next transmission season
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18
Q

zoonotic leishmaniasis

A

rural areas
animals to humans via sandflies (mostly skin manifestations)

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19
Q

anthroponotic leishmaniasis

A

densely populated areas
- humans to humans and animals via vector (mostly visceral)

20
Q

how does Leishmania alter the feeding behaviour of sand fly

A

it makes fly hungrier
- secretes gel-like substance that forms a plug that blocks stomach = allows multiplication of parasites
- nutrient and food doesn’t get through until gel is disturbed
- timing of blood feeding correlated to numbers of metacylic promastigotes (increased biting when numbers of infective parasites increase)

21
Q

how does Leishmania adapt to 2 different hosts to complete its life cycle?

A
  • STAGE SPECIFIC VIRULENCE DETERMINANTS = PHOSPHOGUCANS
    > repeating GalB1, 4Manalpha1-PO4
    > membrane bound lipophosphoglycan (LPG) important for delaying macrophage phagosome-lysosome fusion and for attachment/detachment from insect midgut epithelium
    > number of repeating units vary in the different functional stages (ex: 15 repats in promastigotes increases to 30 repeats in metacyclic promastigotes, elongation facilitates detachment from gut)
22
Q

what are phosphoglucans

A

they are secreted acid phosphatase + phosphoglycan

23
Q

Leishmania promastigotes characteristics

A

increased surface glycoprotein GP63 (found on the parasite membrane and aids in internalization of promastigotes)
flagellated
prefers alk pH (sandfly gut)
prefers high glucose conctn

24
Q

what is GP63

A

a zinc proteinase
also called leishmaniolysin

25
Q

Leishmania amastigote characteristics

A

reduced GP63 (don’t need it in human host)
if they have flagella, it’s rudimentary
prefers acid pH (macrophages)
prefer sparse glucose conctn (shift metabolizing fats and proteins)

26
Q

T or F. Monoclonal antibodies made to one promastigotes can react with amastigotes

A

F! no cross-reaction as they have different expressions of protein, different metabolism and different drug targets should be made for different forms

27
Q

how do Leishmania parasites get in macrophages?

A

receptor-mediated phagocytosis
- macs have surface components (ex: complement receptors CR1, CR3, mannose fucose receptor) = helps the binding of cell to promastigote (MAINLY LPG POTION)
- parasites use macrophages as replication vessel

28
Q

Hsp100 is an important virulence factor for which Leishmania species?

A

L. donovanii and L. major

29
Q

steps to internalization of Leishmania promastigotes

A
  • LPG influence on the phagocytic mechanisms: attachment & hindering endosome-lysosome fusion
  • Promastigotes internalized in phagosome (survival is dependent on LPG which activates F actin and proteins that delay the interaction of phagosomes with endosomes and lysosomes)
  • Production of heat shock proteins to protect parasite & contribute to resistance to oxidants
    Differentiate into amastigotes in phagosomes
30
Q

how does Leishmania destroy macrophages?

A
  • Replicating Leishmania destroy macrophages
  • Depending on the species, they stay in the lymphatics (cutaneous and mucocutaneous) or disseminate through the reticuloendothelial system (macrophage system) to liver, spleen, and cause further damage and recruitment of T cells (visceral) (granuloma formation)
  • Decreased numbers of tissue and circulating macrophages cause a type of immunosuppression and shift to Th2 response which furthers the spread of infection
  • Visceral leishmaniasis is a problem in HIV + individuals
31
Q

Role of the immune system in protection from leishmaniasis

A
  • Abs have no protrective effect; associated with non-healing type of disease syndrome
  • control of infection has to be mediated by CMI = CD4 T cells esp. important!!
  • spleen = major site for killing parasites and removal of infected macs and neutrophils
32
Q

tegumentary vs visceral leishmaniasis

A

disease progression:
cutaneous to mucocutaneous to visceral
lab diagnosis difficult = unless bone marrow aspirate shows macs with parasites
NEGLECTED DISEASE in Africa

33
Q

ATL (american tegumentary leishmaniasis)

A

Disease manifestations:

LCL: immunocompetent patients, normally 1-10 ulcerated lesions

Diffuse CL: nodules on at least 2 body parts

MCL: extensive lesions prone to relapse

Disseminated L: immunodeficient patients, numerous nodules, papules and plaques

34
Q

this RNA virus is correlated to clinical severity of leishmaniasis

A

LRV1

35
Q

localized cutaneous leishmaniasis characteristics

A
  • Well-defined round painless ulcer with raised edges and central crust
  • May heal spontaneously after ~2 months
  • Ulcer develops to a typical epitheloid granuloma, predominance of Th1 response
  • Often leaves a hypopigmented smooth thin scar
36
Q

diffuse cutaneous leishmania characteristics

A
  • ofteen seen in anergic individuals (don’t response to immune system), lifelong
  • Subcutaneous nodules that do not usually ulcerate unless trauma
  • No cell-mediated immunity that responds to leishmania but might have some antibody production
  • Invasion of nasal mucosa if disease persists
37
Q

disseminated cutaneous leishmaniasis

A
  • worst of cutaneous leishmaniasis
  • 10-300 pleomorphic lesions in > 2 different sites of the body
  • Mucocutaneous lesions found in about 30% of the cases
38
Q

mucocutaneous Leishmanaisis characteristics

A
  • Upper respiratory tract mucosa commonly affected: destruction of walls of oral-nasal and pharyngeal cavities
  • Usually L. braziliensis; often seen in south America
  • Can appear years after onset of cutaneous leishmania
39
Q

visceral leishmaniasis

A
  • spleen and liver enlarged
  • Kala-azar (black fever or fatal illness in Hindi)
  • Usually “old world leishmaniasis” caused by L. donovani and L. infantum
  • .5 million new cases/yr, most in India/Nepal
  • Systemic and most severe form of leishmania
  • If untreated ~100% mortality rate
40
Q

PKDL

A

post kala-azar dissimentated leishmaniasis

  • chronic
  • granulomatous syndrome that happens after treated VL
  • we don’t know why this happens, autoimmune?; 10% of treated VL
41
Q

HIV & Leishmania

A
  • HIV has changed the profile of Leishmania disease, both diseases target similar immune cell; together are much worse than individually
  • HIV infection increases risks of getting VL and reduces the chances for successful treatment
  • VL progresses faster in HIV positive individuals
  • Co-infected patients are a possible source of drug resistant parasites
42
Q

why is leishmania diagnosis a challenge?

A
  • Disease can mimic malaria, typhoid fever, tuberculosis, sporotrichosis, etc
  • Parasites sequestered in spleen and lymph nodes = invasive biopsies required to get a good specimen
  • Molecular techniques are very good, but not practical in many areas with leishmaniasis – resources are not there.
  • Antibodies – not always present, especially in immunocompromised. Cannot reliably diagnose recurrent disease
  • Severity is due to several factors – including state of the adaptive immune system and presence of the LRV1 virus in the parasite.
43
Q

how to diagnose leishmania

A
  • could confirm if there is lesion! but very insensitive!!
  • only 10-30% sensitive by direct smear
  • ~50% by culture;
  • PCR is best but only done in reference centres
  • indirect method = antibodies
    > BUT sensitivity low, some cross-reactivity with other organisms; IFA, ELISA

problem = many species!

44
Q

treatment of leishmania

A
  • can clean with topical antiseptics
  • can treat 2ry bacterial infections
  • reconstruct damaged tissues

treatment failure common due to complex factors = host, parasite species, drug factors, simultaneous infection of parasite with LRV1

45
Q

important vaccine considerations for Leishmania vaccine

A
  • vaccine must be feasible since patients get immunity to the particular parasitic species after an infection
  • need to activate the Th1 arm: (IFNy and IL-12 = CELL IMMUNITY) and not Th2 (Ab)
46
Q
A

MMI 426 (20 decks)

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