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