Infection and immunogenetics in unexplained infant deaths in Australia.
Date
2010
Authors
Highet, Amanda Rachel
Editors
Advisors
Goldwater, Paul Nathan
Gibson, Catherine Sue
Berry, Anne M.
Gibson, Catherine Sue
Berry, Anne M.
Journal Title
Journal ISSN
Volume Title
Type:
Thesis
Citation
Statement of Responsibility
Conference Name
Abstract
The pathological, epidemiological and genotypic findings in SIDS infants suggest an infectious aetiology possibly being potentiated by immunoregulatory polymorphisms. The objective of this project was to investigate new infectious and genetic risk factors for SIDS which could explain the typical findings and help identify a marker for susceptibility that could be assayed. We conducted a molecular-based investigation into potential candidate bacterial virulence factors of enteric Escherichia coli, Staphylococcus aureus and Clostridium sordellii from SIDS infants. In the case of E. coli and S. aureus, genes encoding potentially lethal virulence factors were detected in cultures from both SIDS and healthy infants, and C. sordellii lethal toxin detected in none. S. aureus and its enterotoxins were found significantly more often in intestinal contents in SIDS infants than in comparison babies. The curli-producing phenotype observed to be associated with SIDS in a previous investigation was expanded to cover more serotypes, but in this case failed to demonstrate an association. The investigation then moved on to host factors that influence the outcome of infection by such organisms, in particular the following immunoregulatory gene polymorphisms: 1) Interleukin 1 receptor antagonist gene (IL-1RN) 89bp variable number of tandem repeats polymorphism, which influences the circulating levels of IL-1; 2) T cell receptor Vβ 3.1 recombination signal sequence polymorphism (TCRBV3S1), which increases the proportion of T cells responsive to staphylococcal enterotoxin A; 3) CD14 gene promoter C-260T polymorphism which increases monocyte and macrophage responsiveness to endotoxin and 4) Toll-like receptor 2 (TLR-2) R-753Q gene polymorphism where a loss-of-function genotype would compromise pathogen recognition. An association was demonstrated between the homozygous A2 allele of the IL-1RN gene and unexplained sudden unexpected death in infancy (uSUDI) and SIDS infants who died prior to 1994. No association was demonstrated between IL-1RN allele 2 and latter SIDS infants (>1994) or between SIDS and TCRBV3S1, CD14 C-260T or TLR-2 R-753Q polymorphism. We constructed a novel hypothesis whereby risk factors for SIDS promote the translocation of bacteria from mucosal surfaces which might explain the finding of potential pathogens in normally sterile body sites, particularly if pathogen pattern recognition is compromised. No association with SIDS could be demonstrated. Prenatal viral infection as a risk factor for SIDS is introduced and a proof of concept study is discussed. Overall, no unique marker of SIDS susceptibility was found, however the higher prevalence of IL-1RN allele 2, predisposing to poor outcomes from infection, in SIDS infants dying before 1994 suggests that the high incidence during this period could point to an infectious aetiology. In the work presented in this thesis we have demonstrated that the intestinal tract contains potentially pathogenic species of bacteria which could contribute to SIDS in a multi-factorial hypothesis which involves host predisposition and favourable environmental conditions. We have suggested some immunoregulatory genes that could be involved. The role of IL-1RN is particularly interesting. The work published from this thesis will contribute to the field of infectious disease research in SIDS and hopefully will lead to the identification of the cause of these deaths and future prevention.
School/Discipline
School of Paediatrics and Reproductive Health
Dissertation Note
Thesis (Ph.D.) -- University of Adelaide, School of Paediatrics and Reproductive Health, 2010
Provenance
Copyright material removed from digital thesis. See print copy in University of Adelaide Library for full text.