Date of Award

January 2012

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Lloyd Cantley

Subject Area(s)

Medicine

Abstract

Purpose: The purpose of this study was to examine host risk factors and measure innate immune function in order to assess their potential associations with carriage of Staphylococcus aureus (S. aureus). Nearly a third of individuals worldwide are carriers of S. aureus. These bacteria usually exist as harmless commensal organisms of the skin or mucosa, most frequently in the anterior nares. Some people are persistently colonized with S. aureus while other people are intermittently or never colonized. If S. aureus gains access to underlying tissues or to the bloodstream, it can cause serious life-threatening infections, and colonization with S. aureus is a known risk factor for S. aureus infection. Several factors have been associated with carriage such as diabetes, a compromised immune system, obesity, eczema, and smoking tobacco. In addition, microbial genetics and host defense mechanisms play a role in both colonization and infection. In this study, we aimed to identify potential host factors related to S. aureus carriage.

Methods: Using serial nasal swabs over a 3-5 month period, we identified two cohorts within our medical school community: those who were persistently colonized and those who were never colonized with S. aureus. We assessed for risk factors for colonization by administering questionnaires. We collected blood samples from a subset of individuals within each cohort and isolated peripheral blood monocyte cells (PBMCs) in order perform quantitative innate immune function experiments. Toll-like-receptors (TLRs) are an integral part of the innate immune system. They are present on nasal epithelial cells as well as immune cells such as PBMCs. We stimulated host PBMCs with known TLR ligands and measured secretion of cytokines interleukin-8 (IL-8) and tumor necrosis factor alpha (TNF-α) by Enzyme-Linked ImmunoSorbent Assays (ELISAs).

Results: We enrolled 190 volunteer subjects from our medical school community and 25% were carriers of S. aureus after a single swab. Among those who completed all swabs, we identified 33 (33%) who were persistently colonized and 69 (68%) who were persistently not colonized. We did not identify any host risk factors significantly associated with persistent colonization. We noted a decreased secretion of both IL-8 and TNF-α by PBMCs from persistent carriers. IL-8 secretion was significantly diminished after stimulation with FSL-1, LTA, Agr (+) S. aureus, and Agr (–) S. aureus, as shown by non-parametric two-sided t-test analysis (P <0.05). Although there was an observed decrease in TNF-α secretion by PBMCs from persistent carriers, none of the differences reached statistical significance.

Conclusion: One third of subjects who completed all swabs were found to be persistent carriers; and thus persistently at increased risk of S. aureus infection. We found a trend in which persistent carriers had a diminished innate immune response evidenced by less IL-8 and TNF-α secretion following TLR stimulation when compared to non-carriers. In particular, we noted decreased IL-8 secretion after stimulation with ligands known to have lipoprotein properties, suggesting a possible underlying dysfunction in TLR-2. Further investigation into the significance of our findings is warranted.

Share

COinS