Abstract
Human rhinovirus (HRV) infections are associated with the common cold, occasionally with more serious lower respiratory tract illnesses, and frequently with asthma exacerbations. The clinical features of HRV infection and its association with asthma exacerbation suggest that some HRV disease results from virus-induced host immune responses to infection. To study the HRV-infection-induced host responses and the contribution of these responses to disease, we have developed an in vitro model of HRV infection of human airway epithelial cells (Calu-3 cells) and subsequent exposure of human peripheral blood mononuclear cells (PBMCs) to these infected cells in a two-chamber trans-well tissue culture system. Using this model, we studied HRV 14 (species B) and HRV 16 (species A) induced cytokine and chemokine responses with PBMCs from four healthy adults. Infection of Calu-3 cells with either virus induced HRV-associated increases in FGF-Basic, IL-15, IL-6, IL-28A, ENA-78 and IP-10. The addition of PBMCs to HRV 14-infected cells gave significant increases in MIP-1β, IL-28A, MCP-2, and IFN-α as compared with mock-infected cells. Interestingly, ENA-78 levels were reduced in HRV 14 infected cells that were exposed to PBMCs. Addition of PBMCs to HRV 16-infected cells did not induce MIP-1β, IL-28A and IFN-α efficiently nor did it decrease ENA-78 levels. Our results demonstrate a clear difference between HRV 14 and HRV 16 and the source of PBMCs, in up or down regulation of several cytokines including those that are linked to airway inflammation. Such differences might be one of the reasons for variation in disease associated with different HRV species including variation in their link to asthma exacerbations as suggested by other studies. Further study of immune responses associated with different HRVs and PBMCs from different patient groups, and the mechanisms leading to these differences, should help characterize pathogenesis of HRV disease and generate novel approaches to its treatment.
Highlights
Human rhinoviruses (HRVs) belong to the genus Enterovirus in the family Picornaviridae
HRV-associated change in the levels, i.e. difference between HRV-infected compared to mock infected cells at 3-5 days p.i was noted for IL-6, IL-15, MIP1b, IL-28A, interferon gamma-induced protein 10 (IP-10 or CXCL10), epithelial neutrophil activation protein-78 (ENA-78), and basic fibroblast growth factor (FGF-Basic) without peripheral blood mononuclear cells (PBMCs) (Table 1)
Differences in responses induced by HRV 14 compared to HRV 16 infected cells were evident for ENA-78, Figure 1
Summary
Human rhinoviruses (HRVs) belong to the genus Enterovirus in the family Picornaviridae They are small, non-enveloped, positive strand RNA viruses with a diameter of about 30 nm. HRV infection causes lower respiratory tract disease including bronchitis, bronchiolitis and pneumonia [4], and is associated with wheezing and asthma exacerbations in children and adults [5,6,7]. These studies demonstrate that HRV infection is commonly associated with asthma exacerbations, i.e. detected in 50% to 80% of patients with exacerbations, and it is likely that the HRV-induced host response to infection is important to these exacerbations. Studying this response should provide insight into pathogenesis of HRV disease including exacerbations of asthma
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