The innate immune response to Streptococcus pneumoniae in the lungs: Influence of serotype and host factors
Seyoum Alemu, Beza
MetadataShow full item record
Despite the use of pneumococcal vaccines, Streptococcus pneumoniae (pneumococcus) remains the leading cause of community acquired pneumonia causing high mortality and morbidity. Some pneumococcal serotypes, such as serotype 3 (ST3), are associated with a high risk of mortality in patients with pneumonia, whereas the risk of others, such as serotype 8 (ST8), is low. To provide a molecular framework for understanding the pathogenesis of ST3 and ST8 pneumonia in mice, we performed pulmonary gene expression analyses using oligo cDNA microarrays with total RNA derived from the lungs of Balb/c mice infected with ST3 (strain A66.1) or ST8 and analyzed and compared their gene expression profiles to those of uninfected control mice. Compared to uninfected controls, infection with either ST3 or ST8 led to increased expression of interferon-gamma inducible chemokines among other pro-inflammatory genes. Since CXCR3 is the common receptor for the interferon-gamma inducible chemokines, we used CXCR3-/- mice to examine the role of interferon-gamma inducible chemokines and their receptor in the pathogenesis of ST3 and ST8 pneumonia. Compared to WT mice, the lethality of ST3 but not ST8 was reduced in CXCR3-/- mice. ST3-infected CXCR3-/- mice survived significantly longer than WT mice and had fewer lung neutrophils and more alveolar macrophages 48 hrs post-infection. Although the lung bacterial burden was similar between the two strains of mice, CXCR3 -/- mice had significantly fewer blood CFU than WT mice at 72 hrs post-infection. These finds correlated with histopathological studies that revealed ST3-infected CXCR3-/- mice had reduced inflammation in the lungs compared to WT mice. Microarray analysis of the gene expression of WT Balb/c mice infected with either ST3 or ST8 pneumococcus revealed that ST3 induced a markedly more robust inflammatory response than ST8 in an inoculum dependent manner. Histopathological studies of lung sections mirrored these findings in that ST3-infected mice exhibited a more extensive inflammatory response than ST8-infected mice. These studies provide a possible molecular explanation for the relative differences in the pathogenesis of ST3 and ST8 and hold promise for the development of novel approaches to treatment and prevention of pneumococcal pneumonia.
- Theses and Dissertations