Mucoidy, a general mechanism for maintaining lytic phage in populations of bacteria

Abstract

We present evidence that phage resistance resulting from overproduction of exopolysaccharides, mucoidy, provides a general answer to the longstanding question of how lytic viruses are maintained in populations dominated by bacteria upon which they cannot replicate. In serial transfer culture, populations of mucoid E. coli MG1655 that are resistant to lytic phages with different receptors, and thereby requiring independent mutations for surface resistance, are capable of maintaining these phages with little effect on their total density. Based on the results of our analysis of a mathematical model, we postulate that the maintenance of phage in populations dominated by mucoid cells can be attributed primarily to high rates of transition from the resistant mucoid states to susceptible non-mucoid states. Our tests with both population dynamic and single cell experiments as well as genomic analysis are consistent with this hypothesis. We discuss reasons for the generalized resistance of these mucoid E. coli, and the genetic and molecular mechanisms responsible for the high rate of transition from mucoid to sensitive states responsible for the maintenance of lytic phage in mucoid populations of E. coli.

High-throughput mapping of the phage resistance landscape in E. coli

“…Recent studies have highlighted that the activation of the Rcs pathway and capsular biosynthesis are essential to survive in diverse environmental contexts, membrane damage, and stress-inducing conditions, including those by antibiotic treatment [106,166]. A number of earlier studies have also highlighted the generation of the mucoid phenotype that probably provides a fitness advantage by blocking phage adsorption [16,[167][168][169][170]. Our results suggest this might be a generalized mechanism that provides cross-resistance to diverse phages.…”

In Vitro Newly Isolated Environmental Phage Activity against Biofilms Preformed by Pseudomonas aeruginosa from Patients with Cystic Fibrosis

“…These new mucoid PA morphotypes that switched from their matched PA wild types seem mostly unrelated to the single phage exposures. Even though no evidence yet proves whether new mucoid PA morphotypes originate from a possible phage-imposed selection in vivo [21], this key finding from our in vitro experiments on CF PA isolates supports ample previous observations on new mucoid CF PA morphotypes emerging in chronic PA lung infections [1,4] possibly directly related to phage selection in vivo. To advance the field on testing phages in future CF PA in vivo, further in vitro experiments should therefore investigate phages against CF PA biofilms from early and long-term infections, rather than testing in vain phages only against laboratory PA.…”

“…To advance the field on testing phages in future CF PA in vivo, further in vitro experiments should therefore investigate phages against CF PA biofilms from early and long-term infections, rather than testing in vain phages only against laboratory PA. Doing so might risk hiding possibly dangerous phage-induced side effects in switching PA wild-types to PA mucoid morphotypes, and counteracting potential in vivo adjunctive therapeutic phage strategies [21,22]. In our experiments, this dangerous event arose 6 h after we exposed Pa_Ph4 to phages Φ4_ZP1 and Φ14_OBG, and exhibited a PA morphotype characterized by a "smaller and rounder" shape than the ancestral type.…”

A New Sugar for an Old Phage: a c-di-GMP-Dependent Polysaccharide Pathway Sensitizes Escherichia coli for Bacteriophage Infection

“…For example, in E. coli K-12 O-antigen expression was shown to eliminate the adsorption of a wide range of bacteriophages that could bind diverse terminal receptors and infect productively in the absence of this barrier ( 3 ). Likewise, overproduction of capsules can effectively protect bacteria from phage adsorption ( 10 , 11 ). This dual role of surface glycans as barrier and receptor is mirrored on the phage side in form of tailspikes.…”