High defense system expression broadens protection range at the cost of increased autoimmunity

The evolutionary arms race between bacteria and their phage viruses has given rise to elaborate anti-phage defense mechanisms. Major advances have been made in revealing the molecular details underlying diverse defense systems, but general principles and constraints are largely unkown. Defense systems are often tested against a diverse set of phages, revealing widely varying protection ranges. While these disparities are usually attributed to differences in mechanism, here we show that increasing expression of defense systems can greatly enhance their protection range. This holds true for disparate mechanisms, and is achieved by circumventing phage strategies for overcoming bacterial defense. However, increased defense system expression comes with a heavy cost of autoimmunity. Therefore, the expression level of defense systems controls a tradeoff between protection range on the one hand and autoimmunity on the other. We discuss how this tradeoff may drive the regulation of defense systems expression and the acquisition of multiple systems within the same genome.