Detecting and understanding early events in RNA and DNA viral infection at high spatial resolution in intact tissues is important and technically challenging. Overcoming these difficulties requires methods of molecular detection that are highly sensitive and specific for viral and host gene detection as well as determining cell identity in 3D tissues. We developed and published a suite of complementary RNA fluorescence in situ hybridisation (FISH) approaches to visualise individual SARS-CoV-2 viral RNA molecules at absolute sensitivity (>95% of all individual viral RNAs) in human cells, animal or human tissues, from the earliest detectable stages after infection. These methods allow us to distinguish genomic and subgenomic viral RNA species or transcribed DNA viral genomes and to resolve and quantify viral genome replication factories as well as host immune responses, by fluorescence multiplexing in 3D tissues. We have demonstrated effective detection and imaging of a number of different viruses, including influenza. Our published work demonstrated that SARS-CoV-2 infection occurs at low levels in 90% of cells in culture or in animal models, but 10% of cells show much higher infection rates. Our unpublished work in patient samples reveals that PBMC blood cells have a lower infection rate than nasal epithelial biopsies, leading us to hypothesise that blood cells transmit infection to internal organs. We have also been studying the correlation of infection levels with interferon gene response levels.