Abstract 19582: Deletion of miRNA-146a Alters Host Immune Response to Coxsackievirus B3 with Activation of NK cells
Coxsackievirus B3 (CVB3) is a positive single-stranded RNA virus that causes a range of diseases, including myocarditis, hepatitis, and pancreatitis. Understanding complex interplay between the virus and host immune system will provide insight for development of future therapeutic interventions. miRNA-146a plays a role in immune system through regulation of NF-kB signaling. It is expressed at relatively high levels in hematopoetic cells, and upregulated with various immune stimuli. We hypothesized that miRNA-146a is involved in mediating immune response against CVB3 infection. Genetically modified C57BL/6 mice with global deletion of miRNA-146a, and wild type littermate controls were intraperitoneally injected with 103-104 PFU of CVB3. miRNA-146a null mice had significantly higher mortality rate, reaching 45% by day 4 after infection (n=16), compared to zero mortality observed in wild type mice (n=13, p=0.006). Evans blue dye uptake was higher in the hearts of knock out animals 4 days post-infection, indicating disruption of cardiomyocyte membrane integrity. The degree of hepatocyte damage and disruption of the lobular architecture in liver was more pronounced in the miRNA-146a null mice 4 days post-infection. In normal uninfected state the majority of NK cells are localized in liver and spleen, and they are one of the first to get activated in CVB3 infection. We assessed the degree of NK cell activation 24 hours post infection with FACS analyses of mononuclear cells isolated from liver by Percoll gradient. The total percentage of NK cell population in liver was the same between both groups. On average 10+/-0.8% of total NK population in the livers of knock out mice were represented by the cells with high level of TNF-related apoptosis-inducing ligand (TRAIL) expression, whereas only 4.7+/-2% of the hepatic NK cells in the wild type controls had the same level of TRAIL expression (n=3, p=0.03). Liver mRNA levels of Granzymes A and B, and perforin were 4- to 8-fold higher in miRNA-146a null mice compared to wild type controls (n=6 for wild type, n=5 for knock out, p0.05). Taken together, these data indicate that deletion of miRNA-146a alters host response to CVB3 by increasing NK cell activation.
- © 2012 by American Heart Association, Inc.