Micobial Pathogenesis and Immunity Group

Lab head: A/Prof James Triccas
Location: Blackburn Building The University of Sydney, Camperdown Campus

The research programme of the laboratory is divided into three main areas:

New vaccines to combat tuberculosis: Our focus in recent years has been to develop and assess live vaccines engineered to augment components of the immune response required for optimal anti-tuberculosis protective immunity. This has included the use of BCG strains engineered to secrete cytokines or chemokines that influence the number and activation state of dendritic cells (DCs) in order to enhance T cell immunity and pathogen elimination. Some of these vaccines have shown promise in our pre-clinical models of tuberculosis infection, and are undergoing further appraisal as candidates to control M. tuberculosis infection in humans. In parallel, attenuated strains of M. tuberculosis are being developed and tested for their vaccine potential.

Defining immunity induced by infection with Mycobacterium tuberculosis and new tuberculosis vaccine candidates: By the use of recombinant mycobacterial strains expressing reporter proteins and transgenic T cell systems, we are defining in detail the parameters associated with optimal protective immunity against tuberculosis. We are also using confocal microscopy and live-cell imaging to examine the relationship between mycobacteria and host cells. The information derived from the studies will aid selection of suitable mycobacterial strains for future development as anti-tuberculosis vaccines.


 

Identifying and developing new antibiotics to treat drug-resistant bacteria. 

We are using high throughput screening of natural product libraries and medicinal chemistry approaches to find and develop new antibiotics against pathogenic mycobacteria, drug resistant Pseudomonas and MRSA. We undertake initial compound identification and validation together with analysis of drug safety and efficacy using in vitro and in vivo model of bacterial infection. 

Defining the interaction of Pseudomonas aeruginosa with components of the host immune response

Primary supervisor: James Triccas

 

Infection with Pseudomonas aeruginosa is the major cause of mortality in people living with the genetic disorder cystic fibrosis (CF). CF occurs in 1 out of 2500 Caucasians, and is characterised by the production of thick, static lung mucus. Unlike other bacterial pathogens that can be easily cleared from the CF lung by antibiotic therapy, P. aeruginosa persists in the mucus and is likely to exacerbate lung inflammation during chronic infection. Further, P. aeruginosa is a major cause of hospital-acquired infection, in particular burns and wounds.

Despite the importance of his pathogen in CF and other infections, the immune response against clinical PP. aeruginosa isolates has been poorly studied. We have access to clinical strains of P. aeruginosa isolated from patients with CF, including ‘persistent’ strains that chronically infect patients. How these strains interact with the host immune response and potentially modify immunity to promote persistence is unknown.

In this project we will examine in detail the immunity generated by P. aeruginosa in a mouse model of infection. By using both persistent and non-persistent P. aeruginosa clones we will determine which immune parameters are associated with chronic infection. To do this, recombinant P. aeruginosa strains will be developed that express fluorescent markers (e.g. mCherry) as well as the model ovalbumin protein (OVA) and a well characterized CD4 T cell antigen (Ag85B). Both CD4+ and CD8+ transgenic T cell receptor mice that recognise either the OVA or Ag85B proteins are available in the laboratory. By using multi-parameter flow cytometry and adoptive T cell transfer systems, we will examine the kinetics of T cell activation, migratory patterns of activated T cells and generation of T cell memory after P. aeruginosa infection. We will also determine the influence of infection on the expansion and activation of innate cells (e.g. macrophages, dendritic cells, neutrophils) as well as the release of inflammatory cytokines. We will be particularly interested in comparing responses after infection with persistent and non-persistent strains, to determine if certain immune parameters correlate with strain persistence and virulence. In parallel will also use advanced miscopy techniques to examine the early interaction of the strains with host cells. This will allow us to determine how the interaction of P. aeruginosa with host cells impacts on the subsequent generation of T cell immunity.

This project will give the student experience in molecular biology techniques, animal handling, infection strategies and various immunological techniques (tissue culture, assays of T cell activation including ELISPOT, multi-parameter flow cytometry).


Discipline: Infectious diseases and Immunology
Co-supervisors: Jim Manos
Keywords: Cystic fibrosis, Pseudomonas aeruginosa, Infection and immunity
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