Investigation of Bacterial Virulence and Host Response in Bloodstream Infections Caused by Methicillin-Resistant Staphylococcus Aureus (MRSA) and Methicillin-Susceptible Staphylococcus Aureus (MSSA)
Staphylococcus aureus (S. aureus) bloodstream infection (BSI) is one of the most severe manifestations of S. aureus infection. The outcome of S. aureus BSI is variable and a number of factors contribute to the clinical course of infection and the outcome. The host innate response, bacterial virulence and patient characteristics were investigated to assess their contribution to the outcome of S. aureus BSI. These investigations were carried out to identify modifiable factors that may be linked to an adverse outcome. The identification of host or bacterial factors that predict a poor prognosis would facilitate the stratification of patients that may benefit from more aggressive treatment or new treatment modalities.
Patient characteristics including age, co-morbidities, presence of prosthetic devices and immunosuppressive treatment were assessed in the study population to determine the impact, if any, on the outcome of S. aureus BSI. S. aureus isolates causing BSI were characterised using a DNA microarray to determine the presence or absence of 185 virulence, antimicrobial resistance and typing genes. Isolates were assigned to sequence types using data from DNA microarray analysis combined with spa typing. Various components of the innate immune response to S. aureus were also investigated to assess their role, if any, in the course of S. aureus BSI. Four cytokines or chemokines were identified that were differentially regulated in pooled plasma from a selection of patients with S. aureus BSI (complicated versus uncomplicated infections and methicillin-resistant S. aureus (MRSA) versus methicillin-susceptible S. aureus (MSSA)) and the levels of these cytokines (IL-6, RANTES, GROγ and leptin) were determined in sequential plasma samples (day 0 and 7 following diagnosis and day 14 for complicated infections) from patients with S. aureus BSI taken over the course of their infection. The data was then analysed to establish the correlation, if any, between the cytokine response and the clinical outcome of S. aureus BSI. The relationship between the bactericidal activity of the host innate defence peptide, LL-37 towards S. aureus isolates and the clinical outcome of infection was also assessed.
A number of patient characteristics were associated with the development of S. aureus BSI (e.g. age over 65 years, presence of a central vascular catheter and haemodialysis). Furthermore, an increased risk of developing a complicated BSI was associated with certain patient characteristics (e.g. persistent fever at 72h (p≤0.05)). The clinical outcome of S. aureus BSI appeared to be independent of the type of infecting isolate (i.e MRSA or MSSA) and virulence gene carriage. IL-6, GROγ, RANTES and leptin levels in the plasma of patients with S. aureus BSI were independent of the molecular type of infecting isolate. RANTES levels rose significantly in all patient groups by day seven of the BSI, suggesting a role for this chemokine in the immune response to S. aureus. IL-6 levels were higher in patients with complicated BSI while leptin levels were significantly lower in patients with complicated BSI compared to patients with uncomplicated BSI on day seven with a similar trend identified in samples taken on the day of diagnosis of the BSI suggesting that an attenuated leptin response may contribute to the development of a complicated BSI. Isolates causing uncomplicated infection appeared to be more susceptible to killing by LL-37 than isolates causing complicated infection.
Our findings strengthen the view that the response to S. aureus BSI is multi-factorial with the clinical outcome dependent on a number of factors, with host factors playing an important role in determining the severity of infection. A number of different components of the innate immune response appear to play a key role in the clinical course of S. aureus BSI, and may represent prognostic indicators for the severity of the BSI or potential targets for new treatment modalities.
First SupervisorDoctor Deirdre Fitzgerald-Hughes
Second SupervisorProfessor Hilary Humphreys
CommentsA thesis submitted for the degree of Doctor of Philosophy from the Royal College of Surgeons in Ireland in 2012.
Published CitationMcNicholas S. Investigation of Bacterial Virulence and Host Response in Bloodstream Infections Caused by Methicillin-Resistant Staphylococcus Aureus (MRSA) and Methicillin-Susceptible Staphylococcus Aureus (MSSA) [PhD Thesis]. Dublin: Royal College of Surgeons in Ireland; 2012.
- Doctor of Philosophy (PhD)