The defensome of prokaryotes in aquifers. - Related Documents




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840801.0000The defensome of prokaryotes in aquifers. Groundwater harbors a pristine biosphere where microbes co-evolve with less human interference, yet the ancient and ongoing arms race between prokaryotes and viruses remains largely unknown in such ecosystems. Based on our recent nationwide groundwater monitoring campaign across China, we construct a metagenomic groundwater prokaryotic defensome catalogue (GPDC), encompassing 190,810 defense genes, 90,824 defense systems, 139 defense families, and 669 defense islands from 141 prokaryotic phyla. Over 94% of the defense genes in GPDC are novel and contribute vast microbial immune resources in groundwater. We find that candidate phyla radiation (CPR) bacteria possess higher defense system density and diversity against intense phage infection, while microbes as a whole exhibit an inverse relationship between defense systems and adaptive traits like resistance genes in groundwater. We further identify five first-line defense families covering 69.2% of the total defense systems, and high-turnover accessory immune genes are mostly conveyed to defense islands by mobile genetic elements. Our study also reveals viral resistance to microbial defense through co-localized anti-defense genes and interactions between CRISPR-Cas9 and anti-CRISPR protein. These findings expand our understanding of microbial immunity in pristine ecosystems and offer valuable immune resources for potential biotechnological applications.202540659683
840910.9997Comparative genomics reveals key adaptive mechanisms in pathogen host-niche specialization. INTRODUCTION: Understanding the key factors that enable bacterial pathogens to adapt to new hosts is crucial, as host-microbe interactions not only influence host health but also drive bacterial genome diversification, thereby enhancing pathogen survival in various ecological niches. METHODS: We conducted a comparative genomic analysis of 4,366 high-quality bacterial genomes isolated from various hosts and environments. Bioinformatics databases and machine learning approaches were used to identify genomic differences in functional categories, virulence factors, and antibiotic resistance genes across different ecological niches. RESULTS: Significant variability in bacterial adaptive strategies was observed. Human-associated bacteria, particularly from the phylum Pseudomonadota, exhibited higher detection rates of carbohydrate-active enzyme genes and virulence factors related to immune modulation and adhesion, indicating co-evolution with the human host. In contrast, bacteria from environmental sources, particularly those from the phyla Bacillota and Actinomycetota, showed greater enrichment in genes related to metabolism and transcriptional regulation, highlighting their high adaptability to diverse environments. Bacteria from clinical settings had higher detection rates of antibiotic resistance genes, particularly those related to fluoroquinolone resistance. Animal hosts were identified as important reservoirs of resistance genes. Key host-specific bacterial genes, such as hypB, were found to potentially play crucial roles in regulating metabolism and immune adaptation in human-associated bacteria. DISCUSSION: These findings highlight niche-specific genomic features and adaptive mechanisms of bacterial pathogens. This study provides valuable insights into the genetic basis of host-pathogen interactions and offers evidence to inform pathogen transmission control, infection management, and antibiotic stewardship.202540547794
966420.9997Distribution of Genetic Determinants Associated with CRISPR-Cas Systems and Resistance to Antibiotics in the Genomes of Archaea and Bacteria. The CRISPR-Cas system represents an adaptive immune mechanism found across diverse Archaea and Bacteria, allowing them to defend against invading genetic elements such as viruses and plasmids. Despite its broad distribution, the prevalence and complexity of CRISPR-Cas systems differ significantly between these domains. This study aimed to characterize and compare the genomic distribution, structural features, and functional implications of CRISPR-Cas systems and associated antibiotic resistance genes in 30 archaeal and 30 bacterial genomes. Through bioinformatic analyses of CRISPR arrays, cas gene architectures, direct repeats (DRs), and thermodynamic properties, we observed that Archaea exhibit a higher number and greater complexity of CRISPR loci, with more diverse cas gene subtypes exclusively of Class 1. Bacteria, in contrast, showed fewer CRISPR loci, comprising a mix of Class 1 and Class 2 systems, with Class 1 representing the majority (~75%) of the detected systems. Notably, Bacteria lacking CRISPR-Cas systems displayed a higher prevalence of antibiotic resistance genes, suggesting a possible inverse correlation between the presence of these immune systems and the acquisition of such genes. Phylogenetic and thermodynamic analyses further highlighted domain-specific adaptations and conservation patterns. These findings support the hypothesis that CRISPR-Cas systems play a dual role: first, as a defense mechanism preventing the integration of foreign genetic material-reflected in the higher complexity and diversity of CRISPR loci in Archaea-and second, as a regulator of horizontal gene transfer, evidenced by the lower frequency of antibiotic resistance genes in organisms with active CRISPR-Cas systems. Together, these results underscore the evolutionary and functional diversification of CRISPR-Cas systems in response to environmental and selective pressures.202540572209
841030.9996Unveiling the role of phages in shaping the periodontal microbial ecosystem. The oral microbiome comprises various species and plays a crucial role in maintaining the oral ecosystem and host health. Phages are an important component of the periodontal microbiome, yet our understanding of periodontal phages remains limited. Here, we investigated oral periodontal phages using various advanced bioinformatics tools based on genomes of key periodontitis pathogens. Prophages were found to encode various auxiliary genes that potentially enhance host survival and pathogenicity, including genes involved in carbohydrate metabolism, antibiotic resistance, and immune modulation. We observed cross-species transmission among prophages with a complex network of phage-bacteria interactions. Our findings suggest that prophages play a crucial role in shaping the periodontal microbial ecosystem, influencing microbial community dynamics and the progression of periodontitis.IMPORTANCEIn the context of periodontitis, the ecological dynamics of the microbiome are largely driven by interactions between bacteria and their phages. While the impact of prophages on regulating oral pathogens has been increasingly recognized, their role in modulating periodontal disease remains underexplored. This study reveals that prophages within key periodontitis pathogens contribute significantly to virulence factor dissemination, antibiotic resistance, and host metabolism. By influencing the metabolic capabilities and survival strategies of their bacterial hosts, prophages may act as critical regulators of microbial communities in the oral cavity. Understanding these prophage-mediated interactions is essential not only for unraveling the mechanisms of periodontal disease progression but also for developing innovative therapeutic approaches that target the microbial ecosystem at the genetic level. These insights emphasize the need for more comprehensive studies on the ecological risks posed by prophages in shaping microbial pathogenicity and resistance.202540152610
966540.9996Time-calibrated genomic evolution of a monomorphic bacterium during its establishment as an endemic crop pathogen. Horizontal gene transfer is of major evolutionary importance as it allows for the redistribution of phenotypically important genes among lineages. Such genes with essential functions include those involved in resistance to antimicrobial compounds and virulence factors in pathogenic bacteria. Understanding gene turnover at microevolutionary scales is critical to assess the pace of this evolutionary process. Here, we characterized and quantified gene turnover for the epidemic lineage of a bacterial plant pathogen of major agricultural importance worldwide. Relying on a dense geographic sampling spanning 39 years of evolution, we estimated both the dynamics of single nucleotide polymorphism accumulation and gene content turnover. We identified extensive gene content variation among lineages even at the smallest phylogenetic and geographic scales. Gene turnover rate exceeded nucleotide substitution rate by three orders of magnitude. Accessory genes were found preferentially located on plasmids, but we identified a highly plastic chromosomal region hosting ecologically important genes such as transcription activator-like effectors. Whereas most changes in the gene content are probably transient, the rapid spread of a mobile element conferring resistance to copper compounds widely used for the management of plant bacterial pathogens illustrates how some accessory genes can become ubiquitous within a population over short timeframes.202133305421
962150.9996Bacterial biodiversity drives the evolution of CRISPR-based phage resistance. About half of all bacteria carry genes for CRISPR-Cas adaptive immune systems(1), which provide immunological memory by inserting short DNA sequences from phage and other parasitic DNA elements into CRISPR loci on the host genome(2). Whereas CRISPR loci evolve rapidly in natural environments(3,4), bacterial species typically evolve phage resistance by the mutation or loss of phage receptors under laboratory conditions(5,6). Here we report how this discrepancy may in part be explained by differences in the biotic complexity of in vitro and natural environments(7,8). Specifically, by using the opportunistic pathogen Pseudomonas aeruginosa and its phage DMS3vir, we show that coexistence with other human pathogens amplifies the fitness trade-offs associated with the mutation of phage receptors, and therefore tips the balance in favour of the evolution of CRISPR-based resistance. We also demonstrate that this has important knock-on effects for the virulence of P. aeruginosa, which became attenuated only if the bacteria evolved surface-based resistance. Our data reveal that the biotic complexity of microbial communities in natural environments is an important driver of the evolution of CRISPR-Cas adaptive immunity, with key implications for bacterial fitness and virulence.201931645729
967160.9996Genome-scale genetic manipulation methods for exploring bacterial molecular biology. Bacteria are diverse and abundant, playing key roles in human health and disease, the environment, and biotechnology. Despite progress in genome sequencing and bioengineering, much remains unknown about the functional organization of prokaryotes. For instance, roughly a third of the protein-coding genes of the best-studied model bacterium, Escherichia coli, currently lack experimental annotations. Systems-level experimental approaches for investigating the functional associations of bacterial genes and genetic structures are essential for defining the fundamental molecular biology of microbes, preventing the spread of antibacterial resistance in the clinic, and driving the development of future biotechnological applications. This review highlights recently introduced large-scale genetic manipulation and screening procedures for the systematic exploration of bacterial gene functions, molecular relationships, and the global organization of bacteria at the gene, pathway, and genome levels.201222517266
900570.9996Insights into the Vibrio Genus: A One Health Perspective from Host Adaptability and Antibiotic Resistance to In Silico Identification of Drug Targets. The genus Vibrio comprises an important group of ubiquitous bacteria of marine systems with a high infectious capacity for humans and fish, which can lead to death or cause economic losses in aquaculture. However, little is known about the evolutionary process that led to the adaptation and colonization of humans and also about the consequences of the uncontrollable use of antibiotics in aquaculture. Here, comparative genomics analysis and functional gene annotation showed that the species more related to humans presented a significantly higher amount of proteins associated with colonization processes, such as transcriptional factors, signal transduction mechanisms, and iron uptake. In comparison, those aquaculture-associated species possess a much higher amount of resistance-associated genes, as with those of the tetracycline class. Finally, through subtractive genomics, we propose seven new drug targets such as: UMP Kinase, required to catalyze the phosphorylation of UMP into UDP, essential for the survival of bacteria of this genus; and, new natural molecules, which have demonstrated high affinity for the active sites of these targets. These data also suggest that the species most adaptable to fish and humans have a distinct natural evolution and probably undergo changes due to anthropogenic action in aquaculture or indiscriminate/irregular use of antibiotics.202236290057
972380.9995Deciphering the genetic network and programmed regulation of antimicrobial resistance in bacterial pathogens. Antimicrobial resistance (AMR) in bacteria is an important global health problem affecting humans, animals, and the environment. AMR is considered as one of the major components in the "global one health". Misuse/overuse of antibiotics in any one of the segments can impact the integrity of the others. In the presence of antibiotic selective pressure, bacteria tend to develop several defense mechanisms, which include structural changes of the bacterial outer membrane, enzymatic processes, gene upregulation, mutations, adaptive resistance, and biofilm formation. Several components of mobile genetic elements (MGEs) play an important role in the dissemination of AMR. Each one of these components has a specific function that lasts long, irrespective of any antibiotic pressure. Integrative and conjugative elements (ICEs), insertion sequence elements (ISs), and transposons carry the antimicrobial resistance genes (ARGs) on different genetic backbones. Successful transfer of ARGs depends on the class of plasmids, regulons, ISs proximity, and type of recombination systems. Additionally, phage-bacterial networks play a major role in the transmission of ARGs, especially in bacteria from the environment and foods of animal origin. Several other functional attributes of bacteria also get successfully modified to acquire ARGs. These include efflux pumps, toxin-antitoxin systems, regulatory small RNAs, guanosine pentaphosphate signaling, quorum sensing, two-component system, and clustered regularly interspaced short palindromic repeats (CRISPR) systems. The metabolic and virulence state of bacteria is also associated with a range of genetic and phenotypic resistance mechanisms. In spite of the availability of a considerable information on AMR, the network associations between selection pressures and several of the components mentioned above are poorly understood. Understanding how a pathogen resists and regulates the ARGs in response to antimicrobials can help in controlling the development of resistance. Here, we provide an overview of the importance of genetic network and regulation of AMR in bacterial pathogens.202236506027
972490.9995Characteristics of phage-plasmids and their impact on microbial communities. Bacteria host various foreign genetic elements, most notably plasmids and bacteriophages (or phages). Historically, these two classes were seen as separate, but recent research has shown considerable interplay between them. Phage-plasmids (P-Ps) exhibit characteristics of both phages and plasmids, allowing them to exist extrachromosomally within bacterial hosts as plasmids, but also to infect and lyse bacteria as phages. This dual functionality enables P-Ps to utilize the modes of transmission of both phage and plasmids, facilitating the rapid dissemination of genetic material, including antibiotic resistance and virulence genes, throughout bacterial populations. Additionally, P-Ps have been found to encode toxin-antitoxin and CRISPR-Cas adaptive immune systems, which enhance bacterial survival under stress and provide immunity against other foreign genetic elements. Despite a growing body of literature on P-Ps, large gaps remain in our understanding of their ecological roles and environmental prevalence. This review aims to synthesise existing knowledge and identify research gaps on the impacts of P-Ps on microbial communities.202439611587
9670100.9995An Approach to In Silico Dissection of Bacterial Intelligence Through Selective Genomic Tools. All the genetic potential and the intelligence a bacteria can showcase in a given environment are embedded in its genome. In this study, we have presented systematic guidelines to understand a bacterial genome with the relevant set of in silico tools using a novel bacteria as an example. This study presents a multi-dimensional approach from genome annotation to tracing genes and their network of metabolism operating in an organism. It also shows how the sequence can be used to mine the enzymes and construction of its 3-dimensional structure so that its functional behavior can be predicted and compared. The discriminating algorithm allows analysis of the promoter region and provides the insight in the regulation of genes in spite of the similarity in its sequences. The ecological niche specific bacterial behavior and adapted altered physiology can be understood through the presence of secondary metabolite, antibiotic resistance genes, and viral genes; and it helps in the valorization of genetic information for developing new biological application/processes. This study provides an in silico work plan and necessary steps for genome analysis of novel bacteria without any rigorous wet lab experiments.201830013271
9663110.9995The structure of temperate phage-bacteria infection networks changes with the phylogenetic distance of the host bacteria. With their ability to integrate into the bacterial chromosome and thereby transfer virulence or drug-resistance genes across bacterial species, temperate phage play a key role in bacterial evolution. Thus, it is paramount to understand who infects whom to be able to predict the movement of DNA across the prokaryotic world and ultimately the emergence of novel (drug-resistant) pathogens. We empirically investigated lytic infection patterns among Vibrio spp. from distinct phylogenetic clades and their derived temperate phage. We found that across distantly related clades, infections occur preferentially within modules of the same clade. However, when the genetic distance of the host bacteria decreases, these clade-specific infections disappear. This indicates that the structure of temperate phage-bacteria infection networks changes with the phylogenetic distance of the host bacteria.201830429242
9349120.9995Gene essentiality analysis based on DEG, a database of essential genes. Essential genes are the genes that are indispensable for the survival of an organism. The genome-scale identification of essential genes has been performed in various organisms, and we consequently constructed DEG, a Database that contains currently available essential genes. Here we analyzed functional distributions of essential genes in DEG, and found that some essential-gene functions are even conserved between the prokaryote (bacteria) and the eukaryote (yeast), e.g., genes involved in information storage and processing are overrepresented, whereas those involved in metabolism are underrepresented in essential genes compared with non-essential ones. In bacteria, species specificity in functional distribution of essential genes is mainly due to those involved in cellular processes. Furthermore, within the category of information storage and processing, function of translation, ribosomal structure, and biogenesis are predominant in essential genes. Finally, some potential pitfalls for analyzing gene essentiality based on DEG are discussed.200818392983
9606130.9995Rapid identification of key antibiotic resistance genes in E. coli using high-resolution genome-scale CRISPRi screening. Bacteria possess a vast repertoire of genes to adapt to environmental challenges. Understanding the gene fitness landscape under antibiotic stress is crucial for elucidating bacterial resistance mechanisms and antibiotic action. To explore this, we conducted a genome-scale CRISPRi screen using a high-density sgRNA library in Escherichia coli exposed to various antibiotics. This screen identified essential genes under antibiotic-induced stress and offered insights into the molecular mechanisms underlying bacterial responses. We uncovered previously unrecognized genes involved in antibiotic resistance, including essential membrane proteins. The screen also underscored the importance of transcriptional modulation of essential genes in antibiotic tolerance. Our findings emphasize the utility of genome-wide CRISPRi screening in mapping the genetic landscape of antibiotic resistance. This study provides a valuable resource for identifying potential targets for antibiotics or antimicrobial strategies. Moreover, it offers a framework for exploring transcriptional regulatory networks and resistance mechanisms in E. coli and other bacterial pathogens.202540352728
9380140.9995Coevolution between marine Aeromonas and phages reveals temporal trade-off patterns of phage resistance and host population fitness. Coevolution of bacteria and phages is an important host and parasite dynamic in marine ecosystems, contributing to the understanding of bacterial community diversity. On the time scale, questions remain concerning what is the difference between phage resistance patterns in marine bacteria and how advantageous mutations gradually accumulate during coevolution. In this study, marine Aeromonas was co-cultured with its phage for 180 days and their genetic and phenotypic dynamics were measured every 30 days. We identified 11 phage resistance genes and classified them into three categories: lipopolysaccharide (LPS), outer membrane protein (OMP), and two-component system (TCS). LPS shortening and OMP mutations are two distinct modes of complete phage resistance, while TCS mutants mediate incomplete resistance by repressing the transcription of phage genes. The co-mutation of LPS and OMP was a major mode for bacterial resistance at a low cost. The mutations led to significant reductions in the growth and virulence of bacterial populations during the first 60 days of coevolution, with subsequent leveling off. Our findings reveal the marine bacterial community dynamics and evolutionary trade-offs of phage resistance during coevolution, thus granting further understanding of the interaction of marine microbes.202337814126
9709150.9995Role of Plasmids in Plant-Bacteria Interactions. Plants are colonized by diverse microorganisms, which may positively or negatively influence the plant fitness. The positive impact includes nutrient acquisition, enhancement of resistance to biotic and abiotic stresses, both important factors for plant growth and survival, while plant pathogenic bacteria can cause diseases. Plant pathogens are adapted to negate or evade plant defense mechanisms, e.g. by the injection of effector proteins into the host cells or by avoiding the recognition by the host. Plasmids play an important role in the rapid bacterial adaptation to stresses and changing environmental conditions. In the plant environment, plasmids can further provide a selective advantage for the host bacteria, e.g. by carrying genes encoding metabolic pathways, metal and antibiotic resistances, or pathogenicity-related genes. However, we are only beginning to understand the role of mobile genetic elements and horizontal gene transfer for plant-associated bacteria. In this review, we aim to provide a short update on what is known about plasmids and horizontal gene transfer of plant associated bacteria and their role in plant-bacteria interactions. Furthermore, we discuss tools available to study the plant-associated mobilome, its transferability, and its bacterial hosts.201930070649
3783160.9995Ecology drives a global network of gene exchange connecting the human microbiome. Horizontal gene transfer (HGT), the acquisition of genetic material from non-parental lineages, is known to be important in bacterial evolution. In particular, HGT provides rapid access to genetic innovations, allowing traits such as virulence, antibiotic resistance and xenobiotic metabolism to spread through the human microbiome. Recent anecdotal studies providing snapshots of active gene flow on the human body have highlighted the need to determine the frequency of such recent transfers and the forces that govern these events. Here we report the discovery and characterization of a vast, human-associated network of gene exchange, large enough to directly compare the principal forces shaping HGT. We show that this network of 10,770 unique, recently transferred (more than 99% nucleotide identity) genes found in 2,235 full bacterial genomes, is shaped principally by ecology rather than geography or phylogeny, with most gene exchange occurring between isolates from ecologically similar, but geographically separated, environments. For example, we observe 25-fold more HGT between human-associated bacteria than among ecologically diverse non-human isolates (P = 3.0 × 10(-270)). We show that within the human microbiome this ecological architecture continues across multiple spatial scales, functional classes and ecological niches with transfer further enriched among bacteria that inhabit the same body site, have the same oxygen tolerance or have the same ability to cause disease. This structure offers a window into the molecular traits that define ecological niches, insight that we use to uncover sources of antibiotic resistance and identify genes associated with the pathology of meningitis and other diseases.201122037308
9214170.9995Enabling genetic analysis of diverse bacteria with Mobile-CRISPRi. The vast majority of bacteria, including human pathogens and microbiome species, lack genetic tools needed to systematically associate genes with phenotypes. This is the major impediment to understanding the fundamental contributions of genes and gene networks to bacterial physiology and human health. Clustered regularly interspaced short palindromic repeats interference (CRISPRi), a versatile method of blocking gene expression using a catalytically inactive Cas9 protein (dCas9) and programmable single guide RNAs, has emerged as a powerful genetic tool to dissect the functions of essential and non-essential genes in species ranging from bacteria to humans(1-6). However, the difficulty of establishing effective CRISPRi systems across bacteria is a major barrier to its widespread use to dissect bacterial gene function. Here, we establish 'Mobile-CRISPRi', a suite of CRISPRi systems that combines modularity, stable genomic integration and ease of transfer to diverse bacteria by conjugation. Focusing predominantly on human pathogens associated with antibiotic resistance, we demonstrate the efficacy of Mobile-CRISPRi in gammaproteobacteria and Bacillales Firmicutes at the individual gene scale, by examining drug-gene synergies, and at the library scale, by systematically phenotyping conditionally essential genes involved in amino acid biosynthesis. Mobile-CRISPRi enables genetic dissection of non-model bacteria, facilitating analyses of microbiome function, antibiotic resistances and sensitivities, and comprehensive screens for host-microorganism interactions.201930617347
8664180.9995Genome-centric metagenomics reveals the host-driven dynamics and ecological role of CPR bacteria in an activated sludge system. BACKGROUND: Candidate phyla radiation (CPR) constitutes highly diverse bacteria with small cell sizes and are likely obligate intracellular symbionts. Given their distribution and complex associations with bacterial hosts, genetic and biological features of CPR bacteria in low-nutrient environments have received increasing attention. However, CPR bacteria in wastewater treatment systems remain poorly understood. We utilized genome-centric metagenomics to answer how CPR communities shift over 11 years and what kind of ecological roles they act in an activated sludge system. RESULTS: We found that approximately 9% (135) of the 1,526 non-redundant bacterial and archaeal metagenome-assembled genomes were affiliated with CPR. CPR bacteria were consistently abundant with a relative abundance of up to 7.5% in the studied activated sludge system. The observed striking fluctuations in CPR community compositions and the limited metabolic and biosynthetic capabilities in CPR bacteria collectively revealed the nature that CPR dynamics may be directly determined by the available hosts. Similarity-based network analysis further confirmed the broad bacterial hosts of CPR lineages. The proteome contents of activated sludge-associated CPR had a higher similarity to those of environmental-associated CPR than to those of human-associated ones. Comparative genomic analysis observed significant enrichment of genes for oxygen stress resistance in activated sludge-associated CPR bacteria. Furthermore, genes for carbon cycling and horizontal gene transfer were extensively identified in activated sludge-associated CPR genomes. CONCLUSIONS: These findings highlight the presence of specific host interactions among CPR lineages in activated sludge systems. Despite the lack of key metabolic pathways, these small, yet abundant bacteria may have significant involvements in biogeochemical cycling and bacterial evolution in activated sludge systems. Video Abstract.202336945052
9205190.9995Resistance induction based on the understanding of molecular interactions between plant viruses and host plants. BACKGROUND: Viral diseases cause significant damage to crop yield and quality. While fungi- and bacteria-induced diseases can be controlled by pesticides, no effective approaches are available to control viruses with chemicals as they use the cellular functions of their host for their infection cycle. The conventional method of viral disease control is to use the inherent resistance of plants through breeding. However, the genetic sources of viral resistance are often limited. Recently, genome editing technology enabled the publication of multiple attempts to artificially induce new resistance types by manipulating host factors necessary for viral infection. MAIN BODY: In this review, we first outline the two major (R gene-mediated and RNA silencing) viral resistance mechanisms in plants. We also explain the phenomenon of mutations of host factors to function as recessive resistance genes, taking the eIF4E genes as examples. We then focus on a new type of virus resistance that has been repeatedly reported recently due to the widespread use of genome editing technology in plants, facilitating the specific knockdown of host factors. Here, we show that (1) an in-frame mutation of host factors necessary to confer viral resistance, sometimes resulting in resistance to different viruses and that (2) certain host factors exhibit antiviral resistance and viral-supporting (proviral) properties. CONCLUSION: A detailed understanding of the host factor functions would enable the development of strategies for the induction of a new type of viral resistance, taking into account the provision of a broad resistance spectrum and the suppression of the appearance of resistance-breaking strains.202134454519