Host-Pathogen Interaction Laboratory
© 2015 - 2016 Uzonna (Created by F. Khadem)
Sepsis Syndrom / Septic Shock

Sepsis  

syndrome,  

(also  

known  

as  

systemic  

inflammatory  

response  

associated  

with  

infection,  

sepsis,

severe  

sepsis,  

and  

septic  

shock)  

is  

a  

condition  

characterized  

by  

a  

whole-body  

inflammatory  

  

state  

and  

the

presence  

of  

a  

known  

or  

suspected  

bacteria,  

usually  

gram-negative  

organisms.  

The  

  

condition  

is  

a  

common

problem  

in  

all  

age  

groups  

and  

is  

a  

leading  

cause  

of  

mortality  

in  

intensive  

care  

  

units,  

particularly  

in  

children

and  

older  

adults.  

Although  

sepsis  

causes  

a  

marked  

depletion  

of  

  

lymphocytes,  

the  

function  

of  

different

lymphocyte  

subsets  

in  

pathogenesis  

(protection  

or  

  

exacerbation)  

of  

septic  

shock  

is  

unclear.  

Interestingly,

recent   

reports   

show   

that   

one   

subset   

of   

T   

   

lymphocytes   

that   

co-express   

CD4,   

CD25,   

Foxp3   

molecules

(collectively   

known   

as   

regulatory   

T   

cells)   

   

is   

increased   

in   

sepsis.   

We   

have   

observed   

similar   

increase   

in

percentages of Tregs in a laboratory model of the sepsis.

We   hypothesize   that   Tregs   play   important   role   in   the   pathogenesis   of   sepsis/septic   shock.   Indeed,   we   have found   that   depletion   of   Treg   cells   (by   anti-CD25   mAb   treatment)   leads   to   enhanced      sensitivity   to   LPS resulting   in   acute   death   within   3-5   hr   in   an   otherwise   non-lethal   challenge.      Interestingly,   further   preliminary studies   indicate   CD4 +    T   cells   may   not   be   involved   in   this   process,      suggesting   that   depletion   of   conventional Tregs   (which   are   CD4 + CD25 + Foxp3 + )   may   not   be      responsible   for   enhanced   the   susceptibility   to   LPS   following anti-CD25   mAb   treatment.   Our   goal   is      to   understand   how   CD25 +    cells   ameliorate   lethality   associated   with LPS-induced   septic      shock.   We   aim   to   determine   whether   the   effects   anti-CD25   mAb   in   enhancing   sensitivity to   LPS   are      mediated   by   depletion   of   other   CD25-bearing   cells   such   as   B   cells,   CD8 + ,   NKT   and   T   cells,     monocytes   that   may   negatively   regulate   LPS   signaling.   Additionally,   using   molecular   approaches   we      will investigate   key   molecules   in   involved   in   LPS   signaling   (including   MyD88,   STATS,   SOCS,   TRIF      etc)   to   determine whether binding of anti-CD25 mAb to target cells enhances their activities in vitro . Sepsis   syndrome   and   septic   shock   are   common   and   frequently   fatal   clinical   conditions   in   all   age      groups   and are   leading   cause   of   mortality   in   intensive   care   units,   particularly   in   children   and   older      adults.   Therefore, understanding   the   pathogenesis   of   the   disease   is   an   important   step   towards      designing   appropriate   clinical interventions   both   for   preventive   and   treatment   purposes.   The   results      obtained   from   these   studies   would enhance    our    understanding    of    the    pathophysiology    of        sepsis/septic    shock    and    could    provide    possible therapeutic targets for clinical management of the  condition.
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.
Dr. Jude Uzonna Dr. Jude Uzonna R G
Host-Pathogen  Interaction Laboratory
© 2015 - 2016 Uzonna (Created by F. Khadem)
Sepsis Syndrom / Septic Shock

Sepsis  

syndrome,  

(also  

known  

as  

systemic  

inflammatory

response  

associated  

with  

infection,  

sepsis,  

severe  

sepsis,  

and

septic  

shock)  

is  

a  

condition  

characterized  

by  

a  

whole-body

inflammatory    

    

state    

and    

the    

presence    

of    

a    

known    

or

suspected   

bacteria,   

usually   

gram-negative   

organisms.   

The   

 

condition  

is  

a  

common  

problem  

in  

all  

age  

groups  

and  

is  

a

leading  

cause  

of  

mortality  

in  

intensive  

care  

  

units,  

particularly

in  

children  

and  

older  

adults.  

Although  

sepsis  

causes  

a  

marked

depletion    

of    

    

lymphocytes,    

the    

function    

of    

different

lymphocyte      

subsets      

in      

pathogenesis      

(protection      

or      

 

exacerbation)  

of  

septic  

shock  

is  

unclear.  

Interestingly,  

recent

reports   

show   

that   

one   

subset   

of   

T   

   

lymphocytes   

that   

co-

express  

CD4,  

CD25,  

Foxp3  

molecules  

(collectively  

known  

as

regulatory  

T  

cells)  

  

is  

increased  

in  

sepsis.  

We  

have  

observed

similar  

increase  

in  

percentages  

of  

Tregs  

in  

a  

laboratory  

model

of the sepsis.

We     hypothesize     that     Tregs     play     important     role     in     the pathogenesis   of   sepsis/septic   shock.   Indeed,   we   have   found that    depletion    of    Treg    cells    (by    anti-CD25    mAb    treatment) leads   to   enhanced      sensitivity   to   LPS   resulting   in   acute   death within      3-5      hr      in      an      otherwise      non-lethal      challenge.        Interestingly,   further   preliminary   studies   indicate   CD4 +    T   cells may    not    be    involved    in    this    process,        suggesting    that depletion   of   conventional   Tregs   (which   are   CD4 + CD25 + Foxp3 + ) may   not   be      responsible   for   enhanced   the   susceptibility   to LPS    following    anti-CD25    mAb    treatment.    Our    goal    is        to understand   how   CD25 +    cells   ameliorate   lethality   associated with   LPS-induced   septic      shock.   We   aim   to   determine   whether the   effects   anti-CD25   mAb   in   enhancing   sensitivity   to   LPS   are     mediated   by   depletion   of   other   CD25-bearing   cells   such   as   B cells,   CD8 + ,   NKT   and   T   cells,      monocytes   that   may   negatively regulate      LPS      signaling.      Additionally,      using      molecular approaches   we      will   investigate   key   molecules   in   involved   in LPS    signaling    (including    MyD88,    STATS,    SOCS,    TRIF        etc)    to determine   whether   binding   of   anti-CD25   mAb   to   target   cells enhances their activities in vitro . Sepsis     syndrome     and     septic     shock     are     common     and frequently   fatal   clinical   conditions   in   all   age      groups   and   are leading   cause   of   mortality   in   intensive   care   units,   particularly in   children   and   older      adults.   Therefore,   understanding   the pathogenesis    of    the    disease    is    an    important    step    towards      designing      appropriate      clinical      interventions      both      for preventive    and    treatment    purposes.    The    results        obtained from   these   studies   would   enhance   our   understanding   of   the pathophysiology    of        sepsis/septic    shock    and    could    provide possible   therapeutic   targets   for   clinical   management   of   the     condition.
R G