A validated regulatory network for Th17 cell specification.

Th17 cells have critical roles in mucosal defense and are major contributors to inflammatory disease. Their differentiation requires the nuclear hormone receptor RORγt working with multiple other essential transcription factors (TFs). We have used an iterative systems approach, combining genome-wide TF occupancy, expression profiling of TF mutants, and expression time series to delineate the Th17 global transcriptional regulatory network. We find that cooperatively bound BATF and IRF4 contribute to initial chromatin accessibility and, with STAT3, initiate a transcriptional program that is then globally tuned by the lineage-specifying TF RORγt, which plays a focal deterministic role at key loci. Integration of multiple data sets allowed inference of an accurate predictive model that we computationally and experimentally validated, identifying multiple new Th17 regulators, including Fosl2, a key determinant of cellular plasticity. This interconnected network can be used to investigate new therapeutic approaches to manipulate Th17 functions in the setting of inflammatory disease.

Susceptibility of domestic dogs and cats to Australian bat lyssavirus (ABLV).

The susceptibility of cats and dogs to Australian bat lyssavirus (ABLV; genotype VII) was investigated by intramuscular (IM) inoculation of 10(3.7)-10(5) 50% tissue culture infective doses (TCID(50)) of virus followed by observation of experimental animals for up to 3 months post-inoculation (pi). Each experiment also included positive and negative controls, animals inoculated with a bat variant of rabies virus (Eptesicus I, genotype I), or a 10% suspension of uninfected mouse brain, respectively. Each of the ABLV-inoculated cats showed occasional abnormal clinical signs, but none died. Necropsies performed at 3 months pi revealed no lesions, and no viral antigen, in the central nervous system of any cat. ABLV could not be recovered from any cats. However, rabies virus-neutralizing antibodies were detected between 4 and 14 weeks pi in the sera of all three ABLV-inoculated cats. At 2-3 weeks pi, three of the five ABLV-inoculated dogs showed very mild abnormal clinical signs that persisted for 1-2 days, after which the dogs recovered. At 3 months pi, when all dogs were necropsied, neither lesions nor ABLV antigen were detected in, and virus was not isolated from, any dog. No ABLV RNA was detected by polymerase chain reaction (PCR) in clinical or necropsy samples from the three ABLV-affected dogs. However, all ABLV-inoculated dogs seroconverted by 2 weeks pi, and serum antibody titres were higher than those observed in cats. CSF, collected at 3 months pi, was positive for rabies virus-neutralizing antibody in two ABLV-inoculated dogs.