2016 Theses Doctoral
Determinants of Human Rhinovirus Cellular Tropism in Monocyte-Lineage Cells
Human rhinovirus (HRV) is responsible for the majority of common cold infections and asthma exacerbations. HRV predominantly replicates in the epithelial cells of the upper airway, where common cold symptoms are produced. However, HRV also enters the lower airway, encountering the epithelial cells and alveolar macrophages thought to produce inflammatory responses during HRV-induced asthma exacerbations. Notably, alveolar macrophages release inflammatory mediators such as MCP1/CCL2 and RANTES/CCL5 in response to HRV despite the fact that limited if any HRV replication occurs in these cells. The present study seeks to address the mechanism by which alveolar macrophages are susceptible but not permissive to HRV replication and to identify the step in the HRV replication cycle that restricts HRV to abortive replication in macrophages. Evidence presented herein demonstrates that major-group (ICAM-1 tropic) HRV replicate with limited success in cell line-derived macrophages, whereas minor-group (LDLR tropic) HRV do not replicate in these monocyte-lineage cells. In contrast, neither major- nor minor-group HRV replicate in primary human PBMC-derived macrophages. Capsid swap experiments demonstrated that difference in replicative capacity between major- and minor-group HRV is mediated at the level of permissiveness rather than susceptibility. RNA- Seq gene expression studies identified candidate host genes that may act to regulate HRV replication. These RNA-Seq studies also revealed positive- and negative-sense HRV RNA genomes in monocyte-lineage cells, suggesting that abortive HRV replication takes place within them. Overexpressing interferon-stimulated genes (ISGs) implicated in restricting the replication of poliovirus did not affect the accumulation of HRV RNA. Further study will continue to investigate the differences between major- and minor-group HRV responsible for differential replication success in cell-line derived macrophages and characterize the point(s) in the HRV replication cycle at which replication is blocked in primary macrophages. The ultimate goals of these studies are to reveal vulnerabilities in the HRV replication cycle and to identify host factors whose expression might be pharmacologically altered to attenuate HRV infection, thereby providing novel treatment options for controlling the common cold and HRV-induced asthma exacerbations.
- Schreiber_columbia_0054D_13134.pdf binary/octet-stream 6.09 MB Download File
More About This Work
- Academic Units
- Microbiology, Immunology, and Infection
- Thesis Advisors
- Racaniello, Vincent R.
- Ph.D., Columbia University
- Published Here
- February 4, 2016