All ETDs from UAB

Advisory Committee Chair

David E Briles

Advisory Committee Members

Scott R Barnum

William Benjamin

Mamie T Coats

Jessy Deshane

Suzanne Michalek

Document Type

Dissertation

Date of Award

2013

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

pcpA is under control of the Mn 2-dependent repressor PsaR. In the high manganese environment of mucosal sites pcpA gene expression is repressed and at the low manganese environment of the lung and blood derepression of pcpA gene expressionis observed. Previous data has shown that immunization of mice with rPcpA elicits protection against pneumonia and sepsis but had no effect on nasal colonization. We and others have shown that pcpA expression significantly enhances adherence of pneumococci to lung epithelial cell lines and although it is a virulence factor for pneumonia in mice there is no biologically relevant role for PcpA in initial attachment three hours post infection in vivo. Since PcpA has been shown to be a virulence factor in pneumonia and sepsis, we investigated the kinetics of the PcpA-dependent pneumococcal disease in mice. We utilized two different pneumococcal infection mouse models to fully elucidate PcpA's mechanism of virulence. In a bacteremic pneumonia model, weobserved a PcpA-dependent effect on bacterial burden but it did not affect the numbers of CFU in the lungs, blood, liver, BAL and spleens of mice until 24 hrs post infection. Surprisingly, the PcpA-dependent effect on bacterial burden appeared earlier (within 12hrs) in the focal-pneumonia model, which lacks bacteremia or sepsis. Histological changes show that expression of PcpA was more strongly associated with increased inflammation in both of the lung infection models. We looked at the effects of pcpA expression on recruitment of immune cells, using florescence-activated cell sorting (FACS), in our bacteremic pneumonia model and observed that by 12 hrs, in the absence of pcpA expression, there were significantly more macrophages and PMNs in the lung tissue. At 24 hrs post infection, the differences in PMNs remained significant and the differences in myeloid-derived suppressor cells (MDSCs) appeared. At 6 hrs in the airway, the presence of PcpA contributed to a significant increase in PMN recruitment. However, by 12 hrs post infection, there were significantly fewer macrophages and MDSCs in the presence of PcpA. Taken together, expression of PcpA was strongly associated with increased bacterial burden, inflammation and eventually decreased immune cells recruited to the lung tissue.

Share

COinS