Bacterial origins of human cell-autonomous innate immune mechanisms

The cell-autonomous innate immune system enables animal cells to resist viral infection. This system comprises an array of sensors that, after detecting viral molecules, activate the expression of antiviral proteins and the interferon response. The repertoire of immune sensors and antiviral proteins has long been considered to be derived from extensive evolutionary innovation in vertebrates, but new data challenge this dogma. Recent studies show that central components of the cell-autonomous innate immune system have ancient evolutionary roots in prokaryotic genes that protect bacteria from phages. These include the cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway, Toll/IL-1 receptor (TIR) domain-containing pathogen receptors, the viperin family of antiviral proteins, SAMHD1-like nucleotide-depletion enzymes, gasdermin proteins and key components of the RNA interference pathway. This Perspective details current knowledge of the elements of antiviral immunity that are conserved from bacteria to humans, and presents possible evolutionary scenarios to explain the observed conservation.