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Statistical structure of host-phage interactions.

ABSTRACT: Interactions between bacteria and the viruses that infect them (i.e., phages) have profound effects on biological processes, but despite their importance, little is known on the general structure of infection and resistance between most phages and bacteria. For example, are bacteria-phage communities characterized by complex patterns of overlapping exploitation networks, do they conform to a more ordered general pattern across all communities, or are they idiosyncratic and hard to predict from one ecosystem to the next? To answer these questions, we collect and present a detailed metaanalysis of 38 laboratory-verified studies of host-phage interactions representing almost 12,000 distinct experimental infection assays across a broad spectrum of taxa, habitat, and mode of selection. In so doing, we present evidence that currently available host-phage infection networks are statistically different from random networks and that they possess a characteristic nested structure. This nested structure is typified by the finding that hard to infect bacteria are infected by generalist phages (and not specialist phages) and that easy to infect bacteria are infected by generalist and specialist phages. Moreover, we find that currently available host-phage infection networks do not typically possess a modular structure. We explore possible underlying mechanisms and significance of the observed nested host-phage interaction structure. In addition, given that most of the available host-phage infection networks examined here are composed of taxa separated by short phylogenetic distances, we propose that the lack of modularity is a scale-dependent effect, and then, we describe experimental studies to test whether modular patterns exist at macroevolutionary scales.

SUBMITTER: Flores CO

PROVIDER: S-EPMC3136311 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Statistical structure of host-phage interactions.

Flores Cesar O CO Meyer Justin R JR Valverde Sergi S Farr Lauren L Weitz Joshua S JS

Proceedings of the National Academy of Sciences of the United States of America 20110627 28

Interactions between bacteria and the viruses that infect them (i.e., phages) have profound effects on biological processes, but despite their importance, little is known on the general structure of infection and resistance between most phages and bacteria. For example, are bacteria-phage communities characterized by complex patterns of overlapping exploitation networks, do they conform to a more ordered general pattern across all communities, or are they idiosyncratic and hard to predict from o ...[more]

PMID: 21709225

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Project description:Bacteriophages, the viruses infecting bacteria, hold great potential for the treatment of multidrug-resistant bacterial infections and other applications due to their unparalleled diversity and recent breakthroughs in their genetic engineering. However, fundamental knowledge of the molecular mechanisms underlying phage-host interactions is mostly confined to a few traditional model systems and did not keep pace with the recent massive expansion of the field. The true potential of molecular biology encoded by these viruses has therefore remained largely untapped, and phages for therapy or other applications are often still selected empirically. We therefore sought to promote a systematic exploration of phage-host interactions by composing a well-assorted library of 68 newly isolated phages infecting the model organism Escherichia coli that we share with the community as the BASEL (BActeriophage SElection for your Laboratory) collection. This collection is largely representative of natural E. coli phage diversity and was intensively characterized phenotypically and genomically alongside 10 well-studied traditional model phages. We experimentally determined essential host receptors of all phages, quantified their sensitivity to 11 defense systems across different layers of bacterial immunity, and matched these results to the phages' host range across a panel of pathogenic enterobacterial strains. Clear patterns in the distribution of phage phenotypes and genomic features highlighted systematic differences in the potency of different immunity systems and suggested the molecular basis of receptor specificity in several phage groups. Our results also indicate strong trade-offs between fitness traits like broad host recognition and resistance to bacterial immunity that might drive the divergent adaptation of different phage groups to specific ecological niches. We envision that the BASEL collection will inspire future work exploring the biology of bacteriophages and their hosts by facilitating the discovery of underlying molecular mechanisms as the basis for an effective translation into biotechnology or therapeutic applications.

Project description:Phage therapy has shown great promise for the treatment of multidrug-resistant bacterial infections. However, the lack of a thorough and organized understanding of phage-body interactions has limited its clinical application. Here, we administered different purified phages (Salmonella phage SE_SZW1, Acinetobacter phage AB_SZ6, and Pseudomonas phage PA_LZ7) intravenously to healthy animals (rats and monkeys) to evaluate the phage-induced host responses and phage pharmacokinetics with different intravenous (IV) doses in healthy animals. The plasma and the organs were sampled after different IV doses to determine the phage biodistribution, phage-induced cytokines, and antibodies. The potential side effects of phages on animals were assessed. A non-compartment model revealed that the plasma phage titer gradually decreased over time following a single dose. Repeated doses resulted in a 2-3 Log10 decline of the plasma phage titer at 5 min compared to the first dose, regardless of the type of phage administered in rats. Host innate immune responses were activated including splenic enlargement following repeated doses. Phage-specific neutralization antibodies in animals receiving phages were detected. Similar results were obtained from monkeys. In conclusion, the mammalian bodies were well-tolerant to the administered phages. The animal responses to the phages and the phage biodistribution profiles could have a significant impact on the efficacy of phage therapy.IMPORTANCEPhage therapy has demonstrated potential in addressing multidrug-resistant bacterial infections. However, an insufficient understanding of phage-host interactions has impeded its broader clinical application. In our study, specific phages were administered intravenously (IV) to both rats and monkeys to elucidate phage-host interactions and evaluate phage pharmacokinetics (PK). Results revealed that with successive IV administrations, there was a decrease in plasma phage concentrations. Concurrently, these administrations elicited both innate and adaptive immune responses in the subjects. Notably, the observed immune responses and PK profiles exhibited variation contingent upon the phage type and the mammalian host. Despite these variations, the tested mammals exhibited a favorable tolerance to the IV-administered phages. This underscores the significance of comprehending these interactions for the optimization of phage therapy outcomes.

Dataset Information

Statistical structure of host-phage interactions.

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Statistical structure of host-phage interactions.

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