Pulmonary infection caused by nontypeable Haemophilus influenzae (NTHi) is a
significant cause of morbidity and mortality in both industrialised and developing
countries. Previous work from this group resulted in the development of a respiratory
model in rodents which has precipitated studies into the pathogenesis of infection by
NTHi and investigation of the humoral and cellular mechanisms by which the bacteria
are cleared from the lung. Comparison of mucosally immunised with non-immunised
animals has demonstrated that not only are bacteria cleared more rapidly from the lungs,
but there is a more rapid response and resolution of inflammatory factors in the
mucosally immunised animals following challenge with NTHi.
This inflammatory response is partially regulated by the ability of the mucosally
immunised animals to rapidly produce, then control the production of tumour necrosis
factor (TNF)-a. The TNF-a is produced by both macrophages and type I pneumocytes
in the alveoli and also by the endothelial cells lining the blood vessels in the lungs.
Immunocytochemical studies have identified cellular subsets accumulating in the lung
at various time points following infection. Marked differences in cellular infiltration
into the lung tissue were noted between immunised and non-immunised animals after
challenge with NTHi. Immunised animals demonstrated an early influx of
macrophages, CD8+ T cells and Y8+ T cells, followed by enhanced expression of the
MHC-II marker, cellular infiltration by polymorphonuclear leukocytes and finally an
increased number of both B cells and CD4+ T cells. In contrast, non-immunised
animals did not demonstrate any proliferation nor extravasation of lymphocytes or
increased expression of MHC-II before total bacterial clearance had occurred.
Polymorphonuclear leukocyte infiltration occurred in the non-immunised animals,
however at a later time than that seen in immunised animals.
Challenging rodents to establish persistent infection highlighted the inappropriately
aggressive white blood cell response to an initial challenge when bacteria may be
masked by other substances, followed by the inability to amplify the
polymorphonuclear leukocyte response on repeated challenge with NTHi. This
hyporesponsiveness in the macrophage population, shown by lack of detectable TNF-a
production, concomitant with low numbers of NTHi resulted in a continuously high
number of macrophages in the alveoli and the possibility of increased damage to the
lung tissue.
The requirement for cell surface TNF-a and CD8+ T cells to enhance the clearance of
NTHi from the lungs further strengthens previous in vitro and in vivo findings of the
possible significance of cellular invasion as a mechanism of pathogenicity for NTHi.
This thesis has contributed to the understanding of both the immune response to and the
pathogenicity mechanisms of pulmonary infection with NTHi. Kinetic studies
identifying cellular responses and cytokine levels have emphasised the ability of
mucosal immunisation to increase the rate of immune response and resolution of
inflammation to NTHi infection in the lung. Observations demonstrating a requirement
for macrophages and CD8+ T cells in mechanisms associated with enhancing NTHi
clearance from the lung will lead to further investigations.
| Identifer | oai:union.ndltd.org:ADTP/219600 |
| Date | January 1998 |
| Creators | Foxwell, Alice Ruth, n/a |
| Publisher | University of Canberra. Applied Science |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | ), Copyright Alice Ruth Foxwell |
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