Biology subjects

Levin, B. R.

Publications and source records attributed to Levin, B. R..

At least 19 recordsLinked to original sources

bioRxiv2026

Bacteriophage Heteroresistance as a Cause of Treatment Failure in Urinary Tract Infections

With the rise of antimicrobial resistance, urinary tract infections (UTIs) have become increasingly more difficult to treat, prompting renewed interest in bacteriophage (phage) therapy as an alternative or adjunct to antibiotics. UTIs are an attractive target for phage therapy because they generate a high density of actively replicating bacteria that supports phage propagation, and because the urinary tract is readily accessible for administration and monitoring. Yet studies of phage therapy for UTIs report mixed outcomes, including failures to meet clinical and microbiological endpoints. Here we follow the population dynamics of a clinical Escherichia coli UTI strain and two phages, HP3 and ES19, to which the strain appears susceptible by standard testing. Despite this apparent susceptibilty, both phages fail to suppress the strain, with resistance emerging almost immediately. Using the measured mutation rate, our mathematical model shows that traditional resistance cannot account for these dynamics. We instead demonstrate, including by a phage-specific population analysis profile assay we developed, that heteroresistance drives this rapid failure, offering a plausible explanation for treatment failures in UTI phage therapy.

evolutionary biology↗

bioRxiv2026

The role of the innate immune system in shaping the dynamics of antimicrobial treatment

Contemporary antibiotic treatment almost solely considers the Minimum Inhibitory Concentration (MIC) when deciding to employ an antibiotic, often overlooking the critical role of host immunity. Using Galleria mellonella and a virulent strain of Staphylococcus aureus, we investigate the infection dynamics and treatment outcomes of antibiotics of different classes--including antibiotics to which the bacteria are resistant--and a lytic bacteriophage. Surprisingly, we find that the hosts ability to control bacterial density and survive infection does not depend on the specific type of antimicrobial agent nor the bacterias susceptibility to it. Our results demonstrate that the innate immune system is the primary factor in therapeutic success, capable of clearing even highly resistant infections, such as those involving beta-lactamase-producing or ribosomal mutant-resistant strains. These findings challenge the traditional antibiotic-centric view of infection outcomes and emphasize the need to account for host-pathogen-drug interactions beyond simple MIC measurements when designing clinical treatment regimens.

microbiology↗

bioRxiv2025

The joint action of antibiotics, bacteriophage, and the innate immune response in the treatment of bacterial infections

Studies of antimicrobial therapeutics have traditionally neglected the contribution of the host in determining the course of treatment and its outcome. One critical host element, which shapes the dynamics of treatment is the innate immune system. Studies of chemotherapeutics and complementary therapies such as bacteriophage (phage), are commonly performed with mice that purposely have an ablated innate immune system. Here, we generate a mathematical and computer-simulation model of the joint action of antibiotics, phage, and phagocytes. Our analysis of this model highlights the need for future studies to consider the role of the hosts innate immune system in determining treatment outcomes. Critically, our model predicts that the conditions under which resistance to the treatment agent(s) will emerge are much narrower than commonly anticipate. We also generate a second model to predict the dynamics of treatment when multiple phages are used. This model provides support for the application of cocktails to treat infections rather than individual phages. Overall, this study provides hypotheses that can readily be tested experimentally with both in vitro and in vivo experiments.

microbiology↗

bioRxiv2025

A theoretical exploration of protocols for treating prosthetic joint infections with combinations of antibiotics and bacteriophage (phage)

With the increase in the placement of prosthetic joints and other hardware in the body has come an increase in associated infections. These infections are particularly difficult to treat due to the underlying bacteria generating matrices which resist clearance by immune system effectors or antibiotics. These matrices, biofilms, have two primary ways of being eradicated, either by physical removal by debridement or by killing the underlying bacteria. The viruses which kill bacteria, bacteriophage, are readily capable of entering into biofilms and eradicating the bacteria therein. Therefore, bacteriophage have therapeutic potential as a supplement to antibiotics for the treatment of prosthetic joint infections. In this investigation, we generate a mathematical-computer simulation model to explore the contributions of the innate immune system with antibiotics, bacteriophage, and the joint action thereof in the control of biofilm-associated infections. Our results question the proposition that bacteriophage are an effective addition in the treatment of prosthetic joint infections.

microbiology↗

bioRxiv2024

The dynamics of Staphylococcal infection and their treatment with antibiotics and bacteriophage in the Galleria mellonella model system

Critical to our understanding of infections and their treatment is the role the innate immune system plays in controlling bacterial pathogens. Nevertheless, many in vivo systems are made or modified such that they do not have an innate immune response. Use of these systems denies the opportunity to examine the synergy between the immune system and antimicrobial agents. In this study we demonstrate that the larva of Galleria mellonella is an effective in vivo model for the study of the population and evolutionary biology of bacterial infections and their treatment. To do this we test three hypotheses concerning the role of the innate immune system during infection. We show: i) sufficiently high densities of bacteria are capable of saturating the innate immune system, ii) bacteriostatic drugs and bacteriophages are as effective as bactericidal antibiotics in preventing mortality and controlling bacterial densities, and iii) minority populations of bacteria resistant to a treating antibiotic will not ascend. Using a highly virulent strain of Staphylococcus aureus and a mathematical computer-simulation model, we further explore how the dynamics of the infection within the short term determine the ultimate infection outcome. We find that immune activation in response to high densities of bacteria leads to a strong but short-lived immune response which ultimately results in a high degree of mortality. Overall, our findings illustrate the utility of the G. mellonella model system in conjunction with established in vivo models in studying infectious disease progression and treatment. Significance statementCentral to our understanding of the course of bacterial infections and their treatment is the contribution of the innate immune system. We use the larvae of Galleria mellonella to test hypothesis about the role of the innate immune system on Staphylococcus aureus infections. We demonstrate that the innate immune system of these larvae can control the infection and be saturated by high bacterial densities. As a consequence of this innate immune system, bacteriostatic drugs and phages are as effective as bactericidal drugs, and minority populations of bacteria resistant to antibiotics do not ascend. Our findings illustrate the utility of G. mellonella as a model for studying infections dynamics and therapeutic strategies.

microbiology↗

bioRxiv2024

The Tradeoffs Between Persistence and Mutation Rates at Sub-Inhibitory Antibiotic Concentrations in Staphylococcus aureus

The rational design of the antibiotic treatment of bacterial infections employs these drugs to reach concentrations that exceed the minimum needed to prevent the replication of the target bacteria. However, within a treated patient, spatial and physiological heterogeneity promotes antibiotic gradients such that the concentration of antibiotics at specific sites is below the minimum needed to inhibit bacterial growth. Here, we investigate the effects of sub-inhibitory antibiotic concentrations on three parameters central to bacterial infection and the success of antibiotic treatment, using in vitro experiments with Staphylococcus aureus and mathematical-computer simulation models. Our results, using drugs of six different classes, demonstrate that exposure to sub-inhibitory antibiotic concentrations not only alters the dynamics of bacterial growth but also increases the mutation rate to antibiotic resistance and decreases the rate of production of persister cells thereby reducing the persistence level. Understanding this trade-off between mutation rates and persistence levels resulting from sub-inhibitory antibiotic exposure is crucial for optimizing, and mitigating the failure of, antibiotic therapy.

microbiology↗

bioRxiv2023

Enteric Populations of Escherichia coli are Likely to be Resistant to Phages Due to O Antigen Production

Metagenomic data provide evidence that bacteriophage (phage) abound in the enteric microbiomes of humans. However, the contribution of these viruses in shaping the bacterial composition of the gut microbiome and how these phages are maintained remains unclear. We performed experiments with 751 combinations of 54 Escherichia coli and 9 phage isolates from four fecal microbiota transplantation (FMT) doses and 5 laboratory phages as samples of non-dysbiotic human enteric microbiota. We also developed a mathematical model of the population and evolutionary dynamics of bacteria and phage. Our experiments predict that as a consequence of the production of the O-antigen, most of the E. coli in the human enteric microbiome will be resistant to infections with the array of co-occurring phages. Our modeling suggests that phages are maintained in these enteric communities due to the high rates of transition between the resistant and sensitive states resulting from O-antigen production or spontaneous O-antigen loss, respectively. Based on our observations and predictions from this theory, we postulate that the phage found in the human gut are likely to play little role shaping the strain composition of E. coli of healthy individuals. Although we only investigated E. coli, the mechanism of resistance described here is shared among most of the Gram-negative bacteria. Extended AbstractEvidence is provided that as a consequence of O-antigen-mediated resistance, the genetically diverse array of bacteriophage in the gut microbiome of humans play little or no role in determining the densities and distribution of genetically diverse strain E. coli in this habitat. Our mathematical model predicts, and our experiments support the hypothesis that the phage present in the gut microbiome are maintained by replication on the minority of sensitive bacteria generated by the leakiness of O-antigen-mediated resistance.

microbiology↗

bioRxiv2023

The Evolution of Heteroresistance via Small Colony Variants in Escherichia coli Following Long Term Exposure to Bacteriostatic Antibiotics

Traditionally, bacteriostatic antibiotics are agents able to arrest bacterial growth. Despite being traditionally viewed as unable to kill bacterial cells, when they are used clinically the outcome of these drugs is frequently as effective as when a bactericidal drug is used. We explore the dynamics of Escherichia coli after exposure to two ribosome-targeting bacteriostatic antibiotics, chloramphenicol and azithromycin, for thirty days. The results of our experiments provide evidence that bacteria exposed to these drugs replicate, evolve, and generate a sub-population of small colony variants (SCVs) which are resistant to multiple drugs. These SCVs contribute to the evolution of heteroresistance and rapidly revert to a susceptible state once the antibiotic is removed. Stated another way, exposure to bacteriostatic drugs selects for the evolution of heteroresistance in populations previously lacking this trait. More generally, our results question the definition of bacteriostasis as populations exposed to bacteriostatic drugs are replicating despite the lack of net growth.

microbiology↗

bioRxiv2023

The contribution of abortive infection to preventing populations of Lactococcus lactis from succumbing to infections with bacteriophage

In the dairy industry bacteriophage (phage) contamination significantly impairs the production and quality of products like yogurt and cheese. To combat this issue, the strains of bacteria used as starter cultures possess mechanisms that make them resistant to phage infection, such as envelope resistance, or processes that render them immune to phage infection, such as restriction-modification and CRISPR-Cas. Lactococcus lactis, used to manufacture cheese and other dairy products, can also block the reproduction of infecting phages by abortive infection (Abi), a process in which phage-infected cells die before the phage replicate. We employ mathematical-computer simulation models and experiments with two Lactococcus lactis strains and two lytic phages to investigate the conditions under which Abi can limit the proliferation of phages in L. lactis populations and prevent the extinction of their populations by these viruses. According to our model, if Abi is almost perfect and there are no other populations of bacteria capable of supporting the replication of the L. lactis phages, Abi can protect bacterial populations from succumbing to infections with these viruses. This prediction is supported by the results of our experiment, which indicate that Abi can help protect L. lactis populations from extinction by lytic phage infections. However, our results also predict abortive infection is only one element of L. lactis defenses against phage infection. Mutant phages that can circumvent the Abi systems of these bacteria emerge. The survival of L. lactis populations then depends on the evolution of envelope mutants that are resistant to the evolved host-range phage.

microbiology↗

bioRxiv2022

What's the matter with MICs: The contribution of nutrients and limiting resources to the pharmacodynamics of antibiotics and bacteria

The minimum inhibitory concentration (MIC) of an antibiotic required to prevent replication is used both as a measure of the susceptibility/resistance of bacteria to that drug and as the single pharmacodynamic parameter for the rational design of antibiotic treatment regimes. MICs are estimated in vitro under conditions optimal for the action of the antibiotic. However, bacteria rarely grow in these optimal conditions. Using a mathematical model of the pharmacodynamics of antibiotics, we make predictions about the nutrient dependency of bacterial growth in the presence of antibiotics. We test these predictions with experiments in a rich media and a glucose-limited minimal media with Escherichia coli and eight different antibiotics. Our experiments uncover properties that question the sufficiency of using MICs and simple pharmacodynamic functions as measures of the pharmacodynamics of antibiotics under the nutritional conditions of infected tissues. To an extent that varies among drugs: (i) The estimated MICs obtained in rich media are greater than those estimated in minimal media. (ii) Exposure to these drugs increases the time before logarithmic growth starts, their lag. (iii) The stationary phase density of E. coli populations declines with greater sub-MIC antibiotic concentrations. We postulate a mechanism to account for the relationship between the sub-MIC concentration of antibiotics and the stationary phase density of bacteria and provide evidence in support of this hypothesis. We discuss the implications of these results to our understanding of the MIC as the unique pharmacodynamic parameter used to design protocols for antibiotic treatment.

microbiology↗

bioRxiv2022

What the book of Lambda did not tell us about lysogens from natural populations

The most significant difference between bacteriophages functionally and ecologically is whether they are purely lytic (virulent) or temperate. Virulent phages can only be transmitted horizontally by infection, most commonly with the death of their hosts. Temperate phages can also be transmitted horizontally, but upon infection of susceptible bacteria, their genomes can be incorporated into that of their hosts as a prophage and be transmitted vertically in the course of cell division by their lysogenic hosts. From what we know from studies with the temperate phage Lambda and other temperate phages, in laboratory culture, lysogenic bacteria are protected from killing by the phage coded for by their prophage by immunity; where upon infecting lysogens, the free temperate phage coded by their prophage are lost. Why are lysogens not also resistant as well as immune to the phage coded by their prophage since immunity does not confer protection against virulent phages? To address this question, we used a mathematical model and performed experiments with temperate and virulent mutants of the phage Lambda in laboratory culture. Our models predict and experiments confirm that selection would favor the evolution of resistant as well as immune lysogens, particularly if the environment includes virulent phage that share the same receptors as the temperate. To explore the validity and generality of this prediction, we examined ten lysogenic Escherichia coli from natural populations. All ten were capable of forming immune lysogens but their original hosts were resistant to the phage coded by their prophage. Significance StatementThis jointly theoretical and experimental study predicted that lysogenic bacteria, will be resistant as well as immune to the phage coded for by their prophage. All ten naturally occurring lysogenic Escherichia coli tested were resistant to the temperate phage coded for by their prophage.

evolutionary biology↗

bioRxiv2021

An evolutionary perspective of suicide as a way to protect bacteria from being killed by phage

Retron were described in 1984 as DNA sequences that code for a reverse transcriptase and a unique single-stranded DNA/RNA hybrid called multicopy single-stranded DNA (msDNA). It would not be until 2020 that a function was shown for retrons, when compelling evidence was presented that retrons activate an abortive infection pathway in response to bacteriophage (phage) infection. When infected with the virulent mutant of the phage lambda, {lambda}VIR, and to a lesser extent, other phages, a retron designated Ec48 is activated, the Escherichia coli bearing this element dies, and the infecting phage is lost. With the aid of a mathematical model, we explore the a priori conditions under which retrons will protect bacterial populations from predation by phage and the conditions under which retron-bearing bacteria will evolve in populations without this element. Using E. coli with and without Ec48 and lVIR, we estimated the parameters of our model and tested the hypotheses generated from our analysis of its properties. Our models and experiments demonstrate that cells expressing a retron-mediated abortive infection system can protect bacterial populations. Our results demonstrate that retron bearing bacteria only have a competitive advantage under a limited set of conditions.

evolutionary biology↗

bioRxiv2020

Joint antibiotic and phage therapy: addressing the limitations of a seemingly ideal phage for treating Staphylococcus aureus infections

In response to increasing frequencies of antibiotic-resistant pathogens, there has been a resurrection of interest in the use of bacteriophage to treat bacterial infections: phage therapy. Here we explore the potential of a seemingly ideal phage, PYOSa, for combination phage and antibiotic treatment of Staphylococcus aureus infections. (i) This K-like phage has a broad host range; all 83 tested clinical isolates of S.aureus tested were susceptible to PYOSa. (ii) Because of the mode of action of PYOSa S. aureus is unlikely to generate classical receptor-site mutants resistant to PYOSa; none were observed in the 13 clinical isolates tested. (iii) PYOSa kills S. aureus at high rates. On the downside, the results of our experiments and tests of the joint action of PYOSa and antibiotics raise issues that must be addressed before PYOSa is employed clinically. Despite the maintenance of the phage, PYOSa does not clear the populations of S. aureus. Due to the ascent of a phenotypically diverse array of small colony variants following an initial demise, the bacterial populations return to densities similar to that of phage-free controls. Using a combination of mathematical modeling and in vitro experiments, we postulate and present evidence for a mechanism to account for the demise-resurrection dynamics of PYOSa and S. aureus. Critically for phage therapy, our experimental results suggest that treatment with PYOSa followed by bactericidal antibiotics can clear populations of S. aureus more effectively than the antibiotics alone. Significance StatementThe increasing frequency of antibiotic-resistant pathogens has fostered a quest for alternative means to treat bacterial infections. Prominent in this quest is a therapy that predates antibiotics: bacteriophage. This study explores the potential of a phage, PYOSa, for treating Staphylococcus aureus infections in combination with antibiotics. On first consideration, this phage, isolated from a commercial therapeutic cocktail, seems ideal for this purpose. The results of this population dynamic and genomic analysis study identify a potential liability of using PYOSa for therapy. Due to the production of potentially pathogenic atypical small colony variants, PYOSa alone cannot eliminate S. aureus populations. However, we demonstrate that by following the administration of PYOSa with bactericidal antibiotics, this limitation and potential liability can be addressed.

microbiology↗

bioRxiv2020

How important is CRISPR-Cas for protecting natural populations of bacteria against infections with badass DNAs?

Articles on CRISPR commonly open with some variant of the phrase these short-palindromic repeats and their associated endonucleases (Cas) are an adaptive immune system that exists to protect bacteria and archaea from viruses and infections with other mobile genetic elements. There is an abundance of genomic data consistent with the hypothesis that CRISPR plays this role in natural populations of bacteria and archaea, and experimental demonstrations with a few species of bacteria and their phage and plasmids show that CRISPR-Cas systems can play this role in vitro. Not at all clear are the ubiquity, magnitude and nature of the contribution of CRISPR-Cas systems to the ecology and evolution of natural populations of microbes, and the strength of selection mediated by different types of phage and plasmids to the evolution and maintenance of CRISPR-Cas systems. In this perspective, with the aid of heuristic mathematical-computer simulation models, we explore the a priori conditions under which exposure to lytic and temperate phage and conjugative plasmids will select for and maintain CRISPR-Cas systems in populations of bacteria and archaea. We review the existing literature addressing these ecological and evolutionary questions and highlight the experimental and other evidence needed to fully understand the conditions responsible for the evolution and maintenance of CRISPR-Cas systems and the contribution of these systems to the ecology and evolution of bacteria, archaea and the mobile genetic elements that infect them. SignificanceThere is no question about the importance and utility of CRISPR-Cas for editing and modifying genomes. On the other hand, the mechanisms responsible for the evolution and maintenance of these systems and the magnitude of their importance to the ecology and evolution of bacteria, archaea and their infectious DNAs, are not at all clear. With the aid of heuristic mathematical - computer simulation models and reviews of the existing literature, we raise questions that have to be answered to elucidate the contribution of selection - mediated by phage and plasmids - to the evolution and maintenance of this adaptive immune system and its consequences for the ecology and evolution of prokaryotes and their viruses and plasmids.

evolutionary biology↗

bioRxiv2019

Human antimicrobial peptide, LL-37, induces non-inheritable reduced susceptibility to vancomycin in Staphylococcus aureus

Antimicrobial peptides (AMPs) are central components of the innate immune system providing protection against pathogens. Yet, serum and tissue concentrations vary between individuals and disease conditions. We demonstrate that the human AMP LL-37 lowers the susceptibility to vancomycin in the community-associated methicillin-resistant S. aureus (CA-MRSA) strain FPR3757 (USA300). Vancomycin is used to treat serious MRSA infections, but treatment failures occur despite MRSA strains being tested susceptible according to standard susceptibility methods. Exposure to physiologically relevant concentrations of LL-37 increased the minimum inhibitory concentration (MIC) of S. aureus towards vancomycin by 75% and resulted in shortened lag-phase and increased colony formation at sub-inhibitory concentrations of vancomycin. Computer simulations using a mathematical antibiotic treatment model indicated that a small increase in MIC might decrease the efficacy of vancomycin in clearing an S. aureus infection. This prediction was supported in a Galleria mellonella infection model, where exposure of S. aureus to LL-37 abolished the antimicrobial effect of vancomycin. Thus, physiologically relevant concentrations of LL-37 reduce susceptibility to vancomycin, indicating that tissue and host-specific variations in LL-37 concentrations may influence vancomycin susceptibility in vivo.

microbiology↗

bioRxiv2019

The population and evolutionary dynamics of bacteriophage: Why be temperate revisited

Bacteriophages are deemed either lytic (virulent) or temperate, respectively depending on whether their genomes are transmitted solely horizontally, or both horizontally and vertically. To elucidate the ecological and evolutionary conditions under which natural selection will favor the evolution and maintenance of lytic or temperate modes of phage replication and transmission, we use a comprehensive mathematical model of the dynamics of temperate and virulent phage in populations of bacteria sensitive and resistant to these viruses. For our numerical analysis of the properties of this model, we use parameters estimated with the temperate bacteriophage Lambda, {lambda}, its clear and virulent mutants, and E. coli sensitive and resistant - refractory to these phages. Using batch and serial transfer population dynamic and reconstruction experiments, we test the hypotheses generated from this theoretical analysis. Based on the results of this jointly theoretical and experimental study, we postulate the conditions under which natural selection will favor the evolution and maintenance of lytic and temperate modes of phage replication and transmission. A compelling and novel prediction this in silico, in vitro, and in plastico study makes is lysogenic bacteria from natural populations will be resistant-refractory to the phage for which they are lysogenic as well as lytic phage sharing the same receptors as these temperate viruses.

evolutionary biology↗

bioRxiv2019

Promises and pitfalls of in vivo evolution to improve phage therapy

(Background) Phage therapy is the use of bacterial viruses (phages) to treat bacterial infections. Phages lack the broad host ranges of antibiotics, so individual phages are often used with no prior history of use in treatment. Therapeutic phages are thus often chosen based on limited criteria, sometimes merely an ability to plate on the pathogenic bacterium. It is possible that better treatment outcomes might be obtained from an informed choice of phages. Here we consider whether phages used to treat the bacterial infection in a patient might specifically evolve to improve treatment. Phages recovered from the patient could then serve as a source of improved phages or cocktails for use on subsequent patients. (Methods) With the aid of mathematical and computational models, we explore this possibility for four phage properties expected to promote therapeutic success: in vivo growth, phage decay rate, overcoming resistant bacteria, and enzyme activity to degrade protective bacterial layers. (Results) Phage evolution only sometimes works in favor of treatment, and even in those cases, intrinsic phage dynamics in the patient are usually not ideal. An informed use of phages is invariably superior to reliance on within-host evolution and dynamics, although the extent of this benefit varies with the application.

microbiology↗

bioRxiv2018

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

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.

evolutionary biology↗