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
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.
R G