Abstract
This thesis documents the author's research on the pathogenesis and epidemiology of the
pseudomonads in particular the association of Pseudomonas aeruginosa and Pseudomonas
cepacia with pulmonary colonisation and progressive lung damage in patients with cystic
fibrosis.
One of the key virulence determinants in pulmonary colonisation of cystic fibrosis patients by
P. aeluginosa is biosynthesis of alginate. This unusual bacterial polysaccharide confers a
strikingly mucoid colonial phenotype and in vivo is associated with the formation of microbial
biofilms. During the last two decades, my research has focused on the genetic and molecular
regulation of alginate biosynthesis. The origins of these studies derive from my PhD research
on pyocins which led to the development of an internationally recognised typing system for
P. aeruginosa. In the early 1970s, pyocin typing data suggested that mucoid P. aeruginosa arise
in vivo, by mutation or environmental stimulation following primary asymptomatic colonisation
with a nonmucoid parent strain. My genetic studies of alginate regulation were developed in
the mid 1970s during an MRC Travelling Fellowship at Monash University, Melbourne and
produced the first evidence for chromosomal genes controlling the mucoid phenotype. These
embryonic studies and the muc mutations which were identified were to play an important
part in the subsequent molecular unravelling of the sensory regulation of alginate biosynthesis
in collaboration with colleagues in San Antonio. From 1980, my research on the
microbiology of pulmonary infections in cystic fibrosis patients has included studies of
antibiotic therapy, the epidemiology of pseudomonads and the use of animal models of
chronic respiratory infection. Currently, in collaboration with colleagues at the MRC Human
Genetics Unit in Edinburgh, I am involved in microbiological studies of the newly developed
cystic fibrosis mouse.
The most common microbial pathogens in cystic fibrosis patients are Staphylococcus aureus,
Haemophilus influenzae and P. aeruginosa. From the mid 1980s, however, transmissible and
potentially fatal pulmonary infection by the phytopathogen P. cepacia has caused increasing
concern to patients and those involved in patient care. A major aim of my current research
is to clarify the epidemiology of P. cepacia and to identify the host and bacterial factors
associated with transmission and pathogenesis.
