Utilisation of the human plasminogen activation system by group
A streptococci: contribution to virulence and disease.
Summary:
Streptococcus pyogenes (group A streptococci; GAS) is a bacterium
which causes human skin and throat infections as well as highly invasive diseases
including the "flesh eating disease" necrotising fasciitis. Additionally, serious
sequelae, including rheumatic fever and acute glomeulonephritis, may result
following infection. Such diseases cause high morbidity and mortality in Aboriginal
populations and are a continual significant drain on the national health fund.
An important mode of invasion by GAS may be related to their ability to capture
and activate host plasminogen via surface-associated or secreted plasminogen
binding proteins (receptors). Plasminogen can be activated by host activators
or secreted GAS streptokinase to the potent enzyme plasmin which is responsible
for the degradation of tissue barriers. Thus, GAS may utilise plasmin to destroy
tissue barriers and invade host tissues. The characterisation of the interaction
between GAS and the plasminogen activation system would clarify the role of
this system in invasive disease and provide potential targets for therapeutic
intervention.
Chief Investigator(s):
Dr Suresh Mahalingam
Dr Brett Lidbury
2004 $
2005 $
2006 $
Total $
$110,125
$110,125
$110,125
$330,375
Title:
A novel mouse model to investigate the mechanisms of virus-induced
arthritis.
Summary:
We have developed a novel animal model by which to study arthritic
disease caused by insect-transmitted viruses known as arboviruses. The existence
of this model and novel reagents provides an excellent opportunity to further
explore the basic mechanisms of infectious disease in a complete functioning
animal, rather than specific cultured cells. The study will use modern approaches
in molecular and cellular biology to achieve this goal. The production by our
immune systems of soluble mediators (cytokines/chemokines) and antibodies is
an overwhelming positive aspect of our physiological response to infection by
microbes. Protection from disease by these immune compounds can happen naturally,
or the body's ability to produce these factors can be exploited to our benefit
via the administration of vaccines. However, these factors can also be detrimental
to the host contributing to severe disease. For instance, work performed almost
40 years ago showed for the first time that under particular conditions, antibodies
against viruses can enhance infection, instead of inhibiting infection as normally
seen. In the intervening years work by scientists all over the world has associated
“antibody-dependent enhancement” (ADE) of infection to many types
of viruses; ADE is even thought to be a risk factor to serious disease with
dengue virus, and has been shown in vitro for the AIDS virus and Ebola virus.
We have recently discovered a molecular mechanism which explains how antibody
enhances viral infection in vitro. In studies on immune cells infected with
Ross River Virus (RRV) we found that infection helped by antibody resulted in
the specific disruption to the production of cellular chemicals which are toxic
to viruses. Are these mechanisms of antibody-enhanced infection also found in
animals? Will such mode of infection cause enhanced disease and tissue pathology
(arthritis) in animals?
