An archaeal CBASS shows protective activity against both chronic and lytic viruses

Many cyclic-oligonucleotide-based anti-phage signalling systems (CBASS) defend against viral infections by depleting cellular NAD+ levels, eventually leading to dormancy or death. This abortive infection strategy is beneficial in stopping fast lytic infections, as cells die before spreading the virus to neighbouring cells. However, in chronic viral infections, which often occur in archaea, abortive infection could be detrimental, as the cost of immunity may outweigh that of infection. Here we study an archaeal CBASS system (H-CBASS2) that was expressed in the model species Haloferax volcanii DS2 and Haloferax gibbonsii LR2-5. We show that the system provides protection to H. gibbonsii against a lytic tailed haloarchaeal virus HFTV1 by depleting NAD+, similar to what has been observed for lytic phages in bacteria. H-CBASS2 is also triggered, though with much slower activity, during infection with the chronic, non-lytic virus HFPV-1, and promotes virus clearance after several passages without killing host cells. Moreover, cells that clear the HFPV-1 infection become substantially more resistant to subsequent infections, due to mutations in envelope-associated proteins. Cell death by NAD+ depletion only occurs after a very long infection with HFPV-1 on solid medium. These findings suggest that the magnitude of H-CBASS2 response is somehow tuned to the infection type can benefit the host during non-lytic infections, potentially explaining why such systems are relatively common in archaea.