Host-Pathogen Interaction Laboratory
© 2015 - 2016 Uzonna (Created by F. Khadem)
Leishmaniasis

Leishmaniasis,

  

also  

known  

as  

kala-azar,  

Dumdum  

fever,  

Oriental  

sore,  

Baghdad  

boil,  

etc.,  

are  

a  

spectrum

of  

diseases  

caused  

by  

protozoan  

parasites  

belonging  

to  

the  

genus  

Leishmania.  

  

The  

disease  

is  

endemic  

in  

88

countries  

and  

affects  

1  

to  

2  

million  

people  

worldwide  

each  

year  

with  

an  

estimated  

12  

million  

more  

at  

risk.  

 

There are three major forms of the disease:

Cutaneous leishmaniasis, Visceral leishmaniasis,  Mucocutaneous leishmaniasis.

Cutaneous  

leishmaniasis

   

causes   

skin   

lesions   

that   

are   

usually   

self-healing   

but   

can   

cause   

extensive

scarring.  

However,  

treatment  

is  

usually  

given  

to  

accelerate  

cure,  

reduce  

scarring  

especially  

at  

cosmetic  

sites,

and   

to   

attempt   

to   

prevent   

dissemination   

(e.g.,   

mucosal   

disease)   

or   

relapse.   

Self-   

cure   

of   

cutaneous

leishmaniasis usually results in life-long protection from the disease.

Visceral  

leishmaniasis

   

is   

the   

most   

severe   

form   

of   

the   

disease   

and   

affects   

visceral   

organ   

systems

including  

the  

spleen,  

liver  

and  

bone  

marrow.  

The  

signs  

and  

symptoms  

of  

visceral  

leishmaniasis  

are  

non-

specific  

but  

include  

fever,  

weight  

loss,  

mucosal  

ulcers,  

fatigue,  

anemia  

and  

highly  

visible  

enlargement  

of  

the

spleen  

and  

liver  

termed  

splenomegaly  

and  

hepatomegaly,  

respectively.  

If  

left  

untreated,  

visceral  

leishmaniasis

(unlike  

the  

cutaneous  

disease)  

will  

almost  

always  

result  

in  

the  

death  

of  

the  

host.  

Of  

particular  

concern,

according to the WHO, is the emerging problem of HIV/VL co-infection, particularly in the Indian subcontinent.

Mucocutaneous  

leishmaniasis

  

also  

known  

as  

espundia,  

affects  

the  

mucus  

membranes  

and  

leads  

to

severe  

destruction  

of  

underlying  

tissue  

of  

the  

skin,  

mouth  

and  

nose.  

Because  

parasites  

are  

usually  

rare  

in  

the

lesions,  

tissue  

destruction  

is  

possibly  

related  

to  

uncontrolled  

immunological  

mechanisms.  

At  

present  

90%  

of

all mucocutaneous leishmaniasis occurs in Bolivia, Peru and Brazil.

Our research The   main   species   of   Leishmania   we   work   with   in   our   lab   are   Leishmania   major    and   Leishmania   donovani   (which cause   cutaneous   and   visceral   leishmaniasis,   respectively).   Both   parasites   are   transmitted   by   the   bite   of   a female   Sandfly,   similar   to   transmission   of   malaria   parasites   by   the   mosquito.      When   an   infected   Sandfly   takes a   blood   meal   from   an   uninfected   person,   the   elongate   flagellated   parasites   (termed   promastigotes)   are injected   into   the   host,   enter   the   bloodstream   and   primarily   invade   macrophages   and   dendritic   cells.      Within these   cells,   the   parasites   quickly   transform   into   the   mammalian   stage   (termed   amastigotes).   They   replicate inside   these   cells   until   the   cells   are   lysed   and   free   parasites   are   released   and   ready   to   invade   new   cells.      The next   time   the   host   is   bitten   by   a   Sandfly,   the   parasites   are   ingested   and   they   differentiate   back   into   the   more infective   promastigote   form.   You   can   view   a   life   cycle   diagram   for   leishmaniasis   and   find   more   information here: http://www.who.int/leishmaniasis/en/ http://www.who.int/tdr/diseases/leish/lifecycle.htm There   is   no   vaccine   for   leishmaniasis   and   current   medications   are   toxic   and/or   have   serious   side   effects. Interestingly,   recovery   from   natural   or   experimental   infections   with   L.   major   results   in   long-   lasting   immunity against   reinfection.   This   so   called   infection-induced   resistance   is   the   strongest   anti-   Leishmania   immunity known.   We   believe   that   understanding   the   factors   that   regulate   the   induction,   maintenance   and   loss   of infection-induced    resistance    is    critical    for    rational    vaccine    designs    and    vaccination    strategies    against leishmaniasis.    We    hypothesize    that    parasite    dose,    virulence    (determined    by    the    rate    of    replication    in macrophages   after   infection)   and   initial   rate   of   T   cell   expansion   are   key   determinants   that   regulate   the magnitude    and    quality    of    memory    T    cell    responses    during    infection    or    vaccination.    In    general,    some questions the lab is currently addressing include: Are persistent parasites required to maintain anti-Leishmania immunity? Are   there   differences   (in   function,   phenotype   and   migratory   properties)   of   CD4 +    memory   cell   subsets (central and effector, Tcm and Tem, respectively) following infection with low and high dose L. major How   long   do   memory   cells   persist   in   the   absence   of   live   parasites?         Can   non-replicating   parasites maintain   memory   (both   Tcm   and   Tem)   cells   induced   by   vaccination   with   non-replicating   (avirulent)   live parasites?  What is the nature of memory T cell subsets induced following vaccination with heat killed  parasites?  How do Tcm and Tem cells mediate secondary anti-Leishmania immunity?  What   is/are   the   immunodominant   antigens   that   maintain   the   memory   T   cell   pool   following      recovery from primary infection? Using   various   reverse   immunology   and   proteomic   studies,   we   have   recently   identified   a   variety   of   peptides and   antigens   applicable   for   vaccinations.   These   highly   immunogenic   and   protective   antigens   were   shown   to produce   striking   protection   in   vaccinated   mice   and,   with   the   help   of   collaborators,   we   have   demonstrated   this strong   response   in   infected   and   healed   human   patients.   These   immunological   and   proteomic   techniques subsequently     led     to     the     development     of     first     Leishmania-specific     tetramers     capable     of     identifying Leishmania-specific   T   cells   at   clonal   level   over   an   entire   course   of   infection.   This   reagent   will   be   critically relevant    in    the    study    of    memory    responses    in    Leishmania    infection    at    a    clonal    level.    We    are    currently developing   T   cell   receptor   (TCR)   transgenic   mice   that   express   these   unique   TCRs   with   the   view   to   answering the   one-million   dollar   question   of   whether   persistent   parasites   are   required   for   the   maintenance   of   anti- Leishmania immunity in healed animals.
Professor, Manitoba Health Research Chair Professor in Immunology, Department of Immunology, Department of Medical Microbiology, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba. Address: Department of Immunology, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, 750 McDermot Avenue, 425 Apotex Centre, Winnipeg, Manitoba, R3E 0T5. Phone: 1-204-977-5659 Fax: 1-204-789-3921 Email: jude.uzonna@umanitoba.ca
Dr. Jude Uzonna Dr. Jude Uzonna R G