Pathogenesis Of Infections With Yersinia Enterocolitica
Funder
National Health and Medical Research Council
Funding Amount
$339,634.00
Summary
Yersinia enterocolitica is a significant cause of food-poisoning, gastroenteritis and abdominal pain which may be mistaken for acute appendicitis. Y. enterocolitica is a heterogenous bacterial species only some strains of which are able to cause disease. Many of the disease-causing strains have readily identifiable virulence determinants which facilitate their detection in clinical microbiological laboratories. By contrast, other types, in particular the biotype 1A strains, lack these determinan ....Yersinia enterocolitica is a significant cause of food-poisoning, gastroenteritis and abdominal pain which may be mistaken for acute appendicitis. Y. enterocolitica is a heterogenous bacterial species only some strains of which are able to cause disease. Many of the disease-causing strains have readily identifiable virulence determinants which facilitate their detection in clinical microbiological laboratories. By contrast, other types, in particular the biotype 1A strains, lack these determinants, although many of them are significantly associated with disease. During the past few years, we have compared biotype 1A strains of Y. enterocolitica obtained from patients with those from non-clinical sources in a number of assays for virulence-associated properties. These studies have shown that clinical isolates differ from non-clinical ones in terms of their ability to (1) invade epithelial cells in vitro and intestinal absorptive cells in vivo, (2) escape from epithelial cells and macrophages they have invaded, (3) resist killing by macrophages, and (4) colonise the intestinal tracts of mice. The aim of the study is to identify the bacterial determinants responsible for these differences between clinical and non-clinical strains of Y. enterocolitica biotype 1A. This will be achieved by using genetic techniques to modify virulent strains of biotype 1A at random and then identify derivatives of these bacteria with altered virulence properties. We shall also use genetic techniques to identify genes that are specifically activated when the bacteria come into contact with animal cells and tissues. The results of this research will provide new insights into the virulence mechanisms of Y. enterocolitica and related bacteria, and will be used to develop diagnostic tests which will allow pathogenic strains to be distinguished from harmless ones.Read moreRead less
Analysis And Regulation Of Leptospiral Virulence Factors.
Funder
National Health and Medical Research Council
Funding Amount
$630,465.00
Summary
Leptospirosis is a globally important infectious disease caused by Leptospira spp. This project aims to identify and characterise factors which play a role in disease development by knocking out genes, then investigating the impact on overall gene-protein expression in the mutant strain and its ability to cause disease. This will allow us to gain insights on mechanisms by which Leptospira spp. cause disease, leading to development of better methods of disease control and prevention.
Molecular Characterization Of E. Coli That Cause Urinary Tract Infection
Funder
National Health and Medical Research Council
Funding Amount
$387,114.00
Summary
The long term goals of the proposed research are to understand the processes by which uropathogenic Escherichia coli (UPEC) cause acute, recurrent and chronic infections and to identify new UPEC targets for therapeutic intervention. Urinary tract infections (UTI) are among the most common infectious diseases of humans and a major cause of morbidity and mortality. In the USA, UTI accounts for more than 1 million hospitalizations and $1.6 billion in medical expenditures each year. It is estimated ....The long term goals of the proposed research are to understand the processes by which uropathogenic Escherichia coli (UPEC) cause acute, recurrent and chronic infections and to identify new UPEC targets for therapeutic intervention. Urinary tract infections (UTI) are among the most common infectious diseases of humans and a major cause of morbidity and mortality. In the USA, UTI accounts for more than 1 million hospitalizations and $1.6 billion in medical expenditures each year. It is estimated that one in four women and one in twenty men will develop a UTI in their lifetime. The recurrence rate is high and no treatment other than antibiotics (often inefficient) is currently available. UPEC are the primary cause of UTI. In the last grant period, we focused on the molecular interplay that exists between different surface adhesins of UPEC. We succeeded in demonstrating functional interference between adhesins, motility organelles, aggregation factors and the capsule. We also discovered and partially characterized several novel UPEC adhesins that may play a role in pathogenesis. We established two novel technology sets: a mouse model of ascending UTI and the flow chamber biofilm model. In the next grant period, we will build on these concepts and experimental systems to gain a deeper understanding of the molecular mechanisms underlying UPEC virulence. We will characterize the role of several novel UPEC surface proteins in cell adhesin, aggregation, biofilm formation and colonization of the mouse urinary tract. We will employ an integrated approach that combines a powerful bacterial genetic system, a biofilm model, a mouse UTI model, microscopy and tissue culture systems to reveal the cellular, molecular, and structural basis for the pathogenesis of UTI. The work will facilitate the development of new vaccine approaches to prevent UTI, such as novel mechanisms for strain attenuation and vaccine design. The burden of UTI disease demands such research endeavours.Read moreRead less
Role Of Autotransporter Proteins In Uropathogenic E. Coli Infections
Funder
National Health and Medical Research Council
Funding Amount
$611,149.00
Summary
Urinary tract infections (UTI) are among the most common infectious diseases of humans. Uropathogenic E. coli (UPEC), the primary cause of UTI, utilize a range of adherence mechanisms to colonize the urinary tract. In this project we will characterise the function and mode of secretion for one important class of UPEC adherence factors – autotransporter proteins. This work may inform new approaches to prevent UTI, an urgent need given the rapid increase in resistance to antibiotics among UPEC.
Origins And Relationships Of Shigella And Enteroinvasive Escherichia Coli
Funder
National Health and Medical Research Council
Funding Amount
$377,310.00
Summary
Shigella is a well known highly infectious human pathogen with as few as 10 cells allowing effective spread by infected food or water, and also by person to person contact. Shigellosis is a particularly significant disease for children due to lack of pre-existing immunity and greater chance of transfer by fecal-oral route. One group of E. coli called Enteroinvasive E. coli (EIEC) resembles Shigella in many aspects from disease symptoms to biochemical properties. EIEC is a major cause of diarrhoe ....Shigella is a well known highly infectious human pathogen with as few as 10 cells allowing effective spread by infected food or water, and also by person to person contact. Shigellosis is a particularly significant disease for children due to lack of pre-existing immunity and greater chance of transfer by fecal-oral route. One group of E. coli called Enteroinvasive E. coli (EIEC) resembles Shigella in many aspects from disease symptoms to biochemical properties. EIEC is a major cause of diarrhoea in less developed countries and has also caused large outbreaks in developed countries. It is now clear that Shigella and E. coli are really one species. EIEC and Shigella strains are variants of E. coli with humans as the only host. However separation of the two in all records and most studies means that there is no integrated understanding of the forms. We aim to study the relationships of Shigella and EIEC and expect significant insights into the origins of Shigella-EIEC. This will facilitate diagnosis and understanding of the disease(s) and lead to a far better classification . EIEC-Shigella strains have arisen from other E. coli independently. This has happened seven times in the derivation of Shigella and we expect more such events with EIEC. An interesting phenomenon during this process is that strains tend to lose metabolic functions. In this study we will look at what, why and how functions are lost. O antigens are important in evading the host immune system. Shigella strains obtained many O antigens, the majority apparently from other species. This is quite likely the key to its success. We will look at how Shigella obtained new O antigens. This project will be significant in the understanding of Shigell-EIEC, a very significant human pathogen, and in general for understanding emergence of new pathogens.Read moreRead less
Mechanism Of Exacerbations In Cystic Fibrosis Lung Disease
Funder
National Health and Medical Research Council
Funding Amount
$254,876.00
Summary
Cystic Fibrosis lung disease is characterised by infeciton with a bug called Pseudomonas aeruginosa. Patients ultimately die in their mid-30's as a result of this infection, but lung decline is accelerated by episodes of exacerbation when patients cough up large volumes of mucky sputum. We are studying the casue of exacerbations by looking at bacterial behaviour and the response of the immune system. We will use this information to try and develop early warning signals and better treatments.
Understanding The Factors Governing Susceptibility And Outcome In Childhood Infection
Funder
National Health and Medical Research Council
Funding Amount
$276,122.00
Summary
This research seeks to understand why a minority of children are prone to severe and often life-threatening infections and inflammation. It focusses on infections both in preterm infants and in later childhood, which may also be relevant to understanding atherosclerosis. I am also interested in improving the health of recently arrived refugees, by conducting research that allows the development of evidence-based health interventions and developing national policy on refugee health.