Chromosome-specific and noisy IFNB1 transcription in individual virus-infected human primary dendritic cells

Abstract

The induction of interferon beta (IFNB1) is a key event in the antiviral immune response. We studied the role of transcriptional noise in the regulation of the IFNB1 locus in primary cultures of human dendritic cells (DCs), which are important ‘first responders’ to viral infection. In single cell assays, IFNB1 mRNA expression in virus-infected DCs showed much greater cell-to-cell variation than that of a housekeeping gene, another induced transcript and viral RNA. We determined the contribution of intrinsic noise by measuring the allelic origin of transcripts in each cell and found that intrinsic noise is a very significant part of total noise. We developed a stochastic model to investigate the underlying mechanisms. We propose that the surprisingly high levels of IFNB1 transcript noise originate from the complexity of IFNB1 enhanceosome formation, which leads to a range up to many minutes in the differences within each cell in the time of activation of each allele.

Loss of Sendai virus C protein leads to accumulation of RIG-I immunostimulatory defective interfering RNA

“…Therefore, it is possible that in the absence of DIs or other aberrant RNA generation, the RIG-I pathway may only be poorly activated. This phenomenon would fit well with the observation that only a very small portion of infected cells activate their IFN responses, which may represent those cells in which DIs or other abnormal virus replication products are generated [38][39][40][41].…”

Mouse Dendritic Cell (DC) Influenza Virus Infectivity Is Much Lower than That for Human DCs and Is Hemagglutinin Subtype Dependent

“…That mouse BMDCs show a striking lack of infectivity is consonant with recent results using PR8 reporting only 30 to 40% infectivity at an MOI as high as 30 (7). We confirmed these surprising results by two other sensitive techniques, multiprobe single-molecule fluorescence in situ hybridization (FISH) (8) and single-cell PCR assays (9) (Fig. 1D).…”

Human Dendritic Cell Response Signatures Distinguish 1918, Pandemic, and Seasonal H1N1 Influenza Viruses

“…5B). infb1 is upregulated after infection by all strains by 2 h. Single-cell studies of infb1 induction and its response in conjunction with mathematical modeling suggest that very low levels of ifnb1 generated by a few activated cells, which may not be detected in biochemical assays, may nevertheless be adequate to initiate an ISG response (62,63). A similar mechanism may underlie the apparent lack of correspondence of ifnb1 levels and timing with the levels and timing of ISG in 1918 infections, unlike in infections with the other viruses.…”