Why Put-Up with Immunity when there is Resistance: An Excursion into the Population and Evolutionary Dynamics of Restriction-Modification and CRISPR-Cas

Abstract

Bacteria can readily generate mutations that prevent bacteriophage (phage) adsorption and thus make bacteria resistant to infections with these viruses. Nevertheless, the majority of bacteria carry complex innate and/or adaptive immune systems: restriction-modification (RM) and CRISPR-Cas, respectively. Both RM and CRISPR-Cas are commonly assumed to have evolved and be maintained to protect bacteria from succumbing to infections with lytic phage. Using mathematical models and computer simulations, we explore the conditions, under which selection mediated by lytic phage will favor such complex innate and adaptive immune systems, as opposed to simple envelope resistance. The results of our analysis suggest that when populations of bacteria are confronted with lytic phage: (i) In the absence of immunity, resistance to even multiple bacteriophage species with independent receptors can evolve readily. (ii) RM immunity can benefit bacteria by preventing phage from invading established bacterial populations and particularly so when there are multiple bacteriophage species adsorbing to different receptors. (iii) Whether CRISPR-Cas immunity will prevail over envelope resistance depends critically on the length of the co-evolutionary arms race between the bacteria acquiring spacers and the phage generating CRISPR-escape mutants. We discuss the implications of these results in the context of the evolution and maintenance of RM and CRISPR-Cas and highlight fundamental questions that remain unanswered.\n\nSummaryThe two most widely used tools for manipulating and editing DNA restriction and Cas9 endonucleases both originate from studies of mechanisms that provide bacteria with immunity to infections with lytic bacteriophage (phage): restriction modification and CRISPR-Cas. Using mathematical and computer simulations, we explore the a priori conditions under which selection mediated by lytic phage will favor the evolution and maintenance of restriction-modification and CRISPR-Cas immunity in bacteria that, by mutation, can generate envelope resistance to these phage. The results of our analysis make predictions and raise testable-hypotheses about the genetic and ecological conditions under which these immune systems, rather than envelope resistance, will evolve and be maintained as the dominant mechanism of protecting bacteria from succumbing to infections with these viruses.