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

Our research

The   other   infectious   disease   we   are   researching   is   African   trypanosomiasis,   also   known   as   sleeping   sickness or   Nagana.      African   sleeping   sickness   is   caused   by   a   variety   of   trypanosomatids   including   Trypanosoma   brucei brucei ,   Trypanosoma   vivax ,   Trypanosoma   congolense ,   Trypanosoma   brucei    gambiense   and   Trypanosoma   brucei rhodesiense .      The   species   we   work   on   are   Trypanosoma   congolense    and   Trypanosoma   brucei   brucei ,   which   cause diseases   in   livestock.      Trypanosomiasis   is   a   major   problem   for   the   cattle   industry   in   many   African   countries where   it   is   estimated   that   the   disease   costs   $1340   million   to   livestock   producers   and   consumers   every   year.     As   in   leishmaniasis,   there   is   no   vaccine   for   trypanosomiasis   and   although   there   are   very   good   drugs   for treatment of the disease in livestock, the battle against drug resistant parasites is very real.     African   trypanosomiasis   is   transmitted   by   the   tsetse   fly   when   the   fly   takes   a   blood   meal.      The   parasites   are extracellular   and   extensively   activate   the   complement   and   humoral   immune   systems.      They   replicate   in   the bloodstream   causing   massive   proinflammatory   responses   and   eventually,   if   untreated,   invade   the   central nervous   system   causing   death.      Trypanosomes   are   masters   of   immune   evasion.      The   host   immune   system   is very    good    at    clearing    (almost)    the    infection    due    mostly    to    an    antibody    response    to    parasite    surface molecules.      However,   the   parasite   has   evolved   the   ability   to   switch   the   variant   surface   glycoprotein   to   any   one of   hundreds   of   thousands   possible   combinations.      For   this   reason,   trypanosomiasis   is   characterized   by undulating   fever;   when   the   host   has   cleared   most   of   the   parasites   the   fever   is   low,   but   when   the   new   variant replicates   the   pathology   increases   again.      A   very   good   website   for   learning   more   about   the   biology   of   African trypanosomes    and    trypanosomiasis    is    Dr.    George    Cros's    research    website    at    Rockefeller    University: http://tryps.rockefeller.edu/Default.html   BALB/c   mice   infected   with   Trypanosoma   congolense   are   unable   to   control   their   first   wave   of   parasitemia   and die   acutely   with   a   mean   survival   time   of   8   ±   1   day.   Acute   death   of   infected   BALB/c   mice   is   associated   with   high levels   of   proinflammatory   cytokines.   We   have   found   that   treatment   of   infected   mice   with   Berenil   on   day   5 post-infection   leads   to   clearance   of   parasitemia   and   indefinite   survival.   Interestingly,   the   levels   of   IL-1   beta,   IL- 6,   IL-12   and   TNF   were   significantly   lower   in   serum   from   Berenil-treated   mice.   Thus   Berenil   treatment   blocks the   production   of   deleterious   proinflammatory   cytokines   in   T.   congolense   infected   mice.   In   vitro   pretreatment of   bone   marrow   derived   macrophages   (BMDM)   and   dendritic   cells   (BMDC)   with   Berenil   also   inhibits   LPS- induced   proinflammatory   cytokine   production   in   a   dose-dependent   pattern.   Berenil   also   suppressed   CpG ODN-induced     proinflammatory     cytokine     production     and     costimulatory     molecules     (CD40     and     CD86) expression   on   BMDCs,   suggesting   possible   global   effects   on   Toll-Like   Receptor   (TLR)   signaling.   Collectively, these   findings   suggest   that   Berenil   can   inhibit   antigen   presenting   cell   abilities   and   impair   priming   of   adaptive immune response.   We    hypothesize    that    Berenil    modulates    host    immune    response    by    altering    the    responsiveness    of macrophages   and   dendritic   cells   to   microbial   stimuli.   We   are   investigating   the   effects   of   Berenil   on   responses of    macrophages    and    dendritic    cells    in    vitro    in    order    to    determine    whether    Berenil    globally    alters    the expression   of   TLRs   and   costimulatory   molecules   on   macrophages   and   DCs.   In   addition,   we   will   determine   the molecular   and   signaling   mechanisms   through   which   the   drug   alters   responsiveness   of   macrophages   and dendritic cells to LPS and CpG.
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. 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)
African Trypanosomiasis

Our research

The    other    infectious    disease    we    are    researching    is    African trypanosomiasis,   also   known   as   sleeping   sickness   or   Nagana.     African     sleeping     sickness     is     caused     by     a     variety     of trypanosomatids      including      Trypanosoma      brucei      brucei , Trypanosoma     vivax ,     Trypanosoma     congolense ,     Trypanosoma brucei    gambiense   and   Trypanosoma   brucei   rhodesiense .      The species     we     work     on     are     Trypanosoma     congolense      and Trypanosoma   brucei   brucei ,   which   cause   diseases   in   livestock.     Trypanosomiasis   is   a   major   problem   for   the   cattle   industry   in many   African   countries   where   it   is   estimated   that   the   disease costs    $1340    million    to    livestock    producers    and    consumers every    year.        As    in    leishmaniasis,    there    is    no    vaccine    for trypanosomiasis   and   although   there   are   very   good   drugs   for treatment   of   the   disease   in   livestock,   the   battle   against   drug resistant parasites is very real.     African   trypanosomiasis   is   transmitted   by   the   tsetse   fly   when the   fly   takes   a   blood   meal.      The   parasites   are   extracellular   and extensively   activate   the   complement   and   humoral   immune systems.      They   replicate   in   the   bloodstream   causing   massive proinflammatory     responses     and     eventually,     if     untreated, invade      the      central      nervous      system      causing      death.        Trypanosomes    are    masters    of    immune    evasion.        The    host immune   system   is   very   good   at   clearing   (almost)   the   infection due    mostly    to    an    antibody    response    to    parasite    surface molecules.      However,   the   parasite   has   evolved   the   ability   to switch     the     variant     surface     glycoprotein     to     any     one     of hundreds    of    thousands    possible    combinations.        For    this reason,   trypanosomiasis   is   characterized   by   undulating   fever; when   the   host   has   cleared   most   of   the   parasites   the   fever   is low,    but    when    the    new    variant    replicates    the    pathology increases   again.      A   very   good   website   for   learning   more   about the   biology   of   African   trypanosomes   and   trypanosomiasis   is Dr.   George   Cros's   research   website   at   Rockefeller   University: http://tryps.rockefeller.edu/Default.html   BALB/c    mice    infected    with    Trypanosoma    congolense    are unable    to    control    their    first    wave    of    parasitemia    and    die acutely   with   a   mean   survival   time   of   8   ±   1   day.   Acute   death   of infected     BALB/c     mice     is     associated     with     high     levels     of proinflammatory   cytokines.   We   have   found   that   treatment   of infected   mice   with   Berenil   on   day   5   post-infection   leads   to clearance   of   parasitemia   and   indefinite   survival.   Interestingly, the   levels   of   IL-1   beta,   IL-6,   IL-12   and   TNF   were   significantly lower    in    serum    from    Berenil-treated    mice.    Thus    Berenil treatment        blocks        the        production        of        deleterious proinflammatory   cytokines   in   T.   congolense   infected   mice.   In vitro    pretreatment    of    bone    marrow    derived    macrophages (BMDM)   and   dendritic   cells   (BMDC)   with   Berenil   also   inhibits LPS-induced   proinflammatory   cytokine   production   in   a   dose- dependent     pattern.     Berenil     also     suppressed     CpG     ODN- induced        proinflammatory        cytokine        production        and costimulatory    molecules    (CD40    and    CD86)    expression    on BMDCs,     suggesting     possible     global     effects     on     Toll-Like Receptor   (TLR)   signaling.   Collectively,   these   findings   suggest that   Berenil   can   inhibit   antigen   presenting   cell   abilities   and impair priming of adaptive immune response.   We     hypothesize     that     Berenil     modulates     host     immune response   by   altering   the   responsiveness   of   macrophages   and dendritic   cells   to   microbial   stimuli.   We   are   investigating   the effects   of   Berenil   on   responses   of   macrophages   and   dendritic cells   in   vitro   in   order   to   determine   whether   Berenil   globally alters   the   expression   of   TLRs   and   costimulatory   molecules   on macrophages    and    DCs.    In    addition,    we    will    determine    the molecular   and   signaling   mechanisms   through   which   the   drug alters   responsiveness   of   macrophages   and   dendritic   cells   to LPS and CpG.
R G