2010 Annual Report - Institute for Molecular Bioscience - University ...

37 imb researchers: molecular genetics and development
MATT SWEET
PATHOGEN SURVEILLANCE, INNATE IMMUNITY
AND INFLAMMATION
ALL MULTICELLULAR ORGANISMS
are equipped with an immune system,
which provides protection against
infectious diseases. In mammals, the innate
immune system acts as the first line of
defence. Once activated, innate immunity
attempts to trigger direct microbial
destruction, and to contain the invading
pathogen by promoting inflammation.
Innate immune cells such as macrophages
use several families of pattern recognition
receptors (PRRs) to detect specific
structural components on pathogens.
PRRs also respond to endogenous host
ligands that are present in inflammatory
disease settings. Thus, PRRs are essential
for host defence against invading
microbes, but also contribute to the
pathology of many inflammatory diseases.
The most widely studied PRRs are the
Toll-like Receptors (TLRs). We study
TLR-dependent and TLR-independent
mechanisms by which macrophages sense
and respond to invading microorganisms
by focusing on recognition of Gramnegative
bacterial pathogens (e.g.
Salmonella Typhimurium, uropathogenic
E. coli), as well as individual microbial
components (e.g. lipopolysaccharide,
double-stranded DNA).
Our interests cover the actual PRR systems
themselves (e.g. TLRs), the downstream
signalling pathways that are activated
by TLR ligands (including cross-talk with
other signalling pathways e.g. CSF-1
signalling), and the functions of TLR
target genes, which ultimately promote
inflammation and anti-microbial responses.
Research highlights for 2010 include:
(1) the identification of a specific histone
deacetylase (HDAC7) that promotes TLRactivated
inflammatory pathways; (2) the
identification of widespread differences
between humans and mice in TLR target
genes; (3) the identification of macrophages
as an intracellular reservoir for the urinary
tract pathogen, uropathogenic E. coli; and
(4) the mapping of molecular mechanisms
involved in immune cell death triggered by
foreign DNA detected in the cytoplasm.
Our immediate research objectives are to
develop small molecule inhibitors against
HDAC7 for testing as anti-inflammatory
agents, to validate the importance of
species differences in TLR-activated antimicrobial
pathways, and to determine the
mechanisms used by uropathogenic E.
coli to subvert macrophage anti-microbial
responses. Our ultimate goals are to
generate new insights into the mechanisms
used by the host innate immune system to
destroy invading microbes, and to develop
novel approaches to targeting inflammatory
diseases.
RESEARCH PROJECTS
• Characterising the role of specific
histone deacetylases in Toll-like
Receptor-mediated inflammatory
responses
• Human macrophage anti-microbial
responses to Gram-negative bacterial
pathogens such as Salmonella
typhimurium
• Role of macrophages in uropathogenic
E. coli pathogenesis
• Characterisation of the cellular
recognition system for detection of
foreign DNA in the cytoplasm
• Involvement of novel TLR-regulated
genes in inflammatory and antimicrobial
responses
KEY PUBLICATIONS
Halili, M.A., Andrews, M.R., Labzin, L.I.,
Schroder, K., Matthias, G., Cao, C.,
Lovelace, E., Reid, R.C., Le, G.T., Hume,
D.A., Irvine, K.M., Matthias, P., Fairlie,
D.P., and Sweet M.J. (2010). Differential
effects of selective HDAC inhibitors on
macrophage inflammatory responses
to the Toll-like Receptor 4 agonist LPS.
Journal of Leukocyte Biology 87: 1103-
1114.
Irvine, K.M., Andrews, M.R., Fernandez-
Rojo, M.A., Schroder, K., Burns, C.J.,
Su, S., Wilks, A.F., Parton, R.G., Hume,
D.A., and Sweet, M.J. (2009). Colony
Stimulating Factor-1 (CSF-1) delivers
a proatherogenic signal to human
macrophages. Journal of Leukocyte
Biology 85: 278-288.
Roberts, T.L., Idris, A., Dunn, J.A., Kelly,
G.M., Burnton, C.M., Hodgson, S., Hardy,
L., Garceau, V., Sweet, M.J., Ross, I.L.,
Hume, D.A., and Stacey, K.J. (2009). HIN-
200 proteins regulate caspase activation
in response to foreign cytoplasmic DNA.
Science 323: 1057-1060.
Bode, K.A., Schroder, K., Hume, D.A.,
Ravasi, T., Heeg, K., Sweet, M.J., and
Dalpke, A.H. (2007). Histone deacetylase
inhibitors decrease Toll-like receptormediated
activation of pro-inflammatory
gene expression by impairing transcription
factor recruitment. Immunology 122:
596-606.
Schroder, K., Spille, M., Pilz, A., Lattin,
J., Bode, K.A., Burrows, A.D., Ravasi, T.,
Weighardt, H., Stacey, K.J., Decker, T.,
Hume, D.A., Dalpke, A., and Sweet, M.J.
(2007). Differential effects of CpG DNA
on IFNb induction and STAT1 activation
in murine macrophages versus dendritic
cells: alternatively activated STAT1
negatively regulates toll-like receptor
signaling in macrophages. Journal of
Immunology 179: 3495-3503.
LAB MEMBERS
Senior Research Officer: Dr Kate Stacey
Research Officers: Dr Steve Broomfield,
Dr Vitalia Sagulenko
Research Assistants: Greg Kelly, Juliana
Ariffin, Jasmyn Dunn
PhD Students: Melanie Andrews, Dr
Nilesh Bokil, Divya Ramnath, Kylie
Alexander
Honours Student: Nabilah Ahmad Kamal