Toxin/antitoxin systems induce persistence and work in concert with restriction/modification systems to inhibit phage

Author:

Fernández-García Laura12,Song Sooyeon134,Kirigo Joy1,Battisti Michael E.1,Petersen Maiken E.15,Tomás María2,Wood Thomas K.1ORCID

Affiliation:

1. Department of Chemical Engineering, Pennsylvania State University , University Park, Pennsylvania, USA

2. Microbiology Department of Hospital A Coruña (CHUAC), Microbiology Translational and Multidisciplinary (MicroTM)-Research Institute Biomedical A Coruña (INIBIC) and University of A Coruña (UDC) , A Coruña, Spain

3. Department of Animal Science, Jeonbuk National University , Jeonju-Si, Jellabuk-Do, South Korea

4. Agricultural Convergence Technology, Jeonbuk National University , Jeonju-Si, Jellabuk-Do, South Korea

5. Interdisciplinary Nanoscience Center, Aarhus University , Aarhus, Denmark

Abstract

ABSTRACT Myriad bacterial anti-phage systems have been described and often the mechanism of programmed cell death is invoked for phage inhibition. However, there is little evidence of “suicide” under physiological conditions for these systems. Instead of death to stop phage propagation, we show here that persister cells, i.e., transiently-tolerant, dormant, antibiotic-insensitive cells, are formed and survive using the Escherichia coli C496_10 tripartite toxin/antitoxin system MqsR/MqsA/MqsC to inhibit T2 phage. Specifically, MqsR/MqsA/MqsC inhibited T2 phage by 10 5 -fold and reduced T2 titers by 3,000-fold. During T2 phage attack, in the presence of MqsR/MqsA/MqsC, evidence of persistence includes the single-cell physiological change of reduced metabolism (via flow cytometry), increased spherical morphology (via transmission electron microscopy), and heterogeneous resuscitation. Critically, we found restriction-modification systems (primarily EcoK McrBC) work in concert with the toxin/antitoxin system to inactivate phage, likely while the cells are in the persister state. Hence, a phage attack invokes a stress response similar to antibiotics, starvation, and oxidation, which leads to persistence, and this dormant state likely allows restriction/modification systems to clear phage DNA. IMPORTANCE To date, there are no reports of phage infection-inducing persistence. Therefore, our results are important since we show for the first time that a phage-defense system, the MqsRAC toxin/antitoxin system, allows the host to survive infection by forming persister cells, rather than inducing cell suicide. Moreover, we demonstrate that the MqsRAC system works in concert with restriction/modification systems. These results imply that if phage therapy is to be successful, anti-persister compounds need to be administered along with phages.

Funder

Fulbright Scholar Fellowship

Xunta de Galicia Postdoctoral Grant

National Research Foundation of Korea

National Plan for Scientific Research

Publisher

American Society for Microbiology

Subject

Infectious Diseases,Cell Biology,Microbiology (medical),Genetics,General Immunology and Microbiology,Ecology,Physiology

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