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1.
bioRxiv ; 2024 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-38352502

RESUMO

Infections caused by multi-drug resistant (MDR) pathogenic bacteria are a global health threat. Phage therapy, which uses phage to kill bacterial pathogens, is increasingly used to treat patients infected by MDR bacteria. However, the therapeutic outcome of phage therapy may be limited by the emergence of phage resistance during treatment and/or by physical constraints that impede phage-bacteria interactions in vivo. In this work, we evaluate the role of lung spatial structure on the efficacy of phage therapy for Pseudomonas aeruginosa infection. To do so, we developed a spatially structured metapopulation network model based on the geometry of the bronchial tree, and included the emergence of phage-resistant bacterial mutants and host innate immune responses. We model the ecological interactions between bacteria, phage, and the host innate immune system at the airway (node) level. The model predicts the synergistic elimination of a P. aeruginosa infection due to the combined effects of phage and neutrophils given sufficiently active immune states and suitable phage life history traits. Moreover, the metapopulation model simulations predict that local MDR pathogens are cleared faster at distal nodes of the bronchial tree. Notably, image analysis of lung tissue time series from wild-type and lymphocyte-depleted mice (n=13) revealed a concordant, statistically significant pattern: infection intensity cleared in the bottom before the top of the lungs. Overall, the combined use of simulations and image analysis of in vivo experiments further supports the use of phage therapy for treating acute lung infections caused by P. aeruginosa while highlighting potential limits to therapy given a spatially structured environment, such as impaired innate immune responses and low phage efficacy.

2.
bioRxiv ; 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38293203

RESUMO

The rise of antimicrobial resistance has led to renewed interest in evaluating phage therapy. In murine models highly effective treatment of acute pneumonia caused by Pseudomonas aeruginosa relies on the synergistic antibacterial activity of bacteriophages with neutrophils. Here, we show that depletion of alveolar macrophages (AM) shortens the survival of mice without boosting the P. aeruginosa load in the lungs. Unexpectedly, upon bacteriophage treatment, pulmonary levels of P. aeruginosa were significantly lower in AM-depleted than in immunocompetent mice. To explore potential mechanisms underlying the benefit of AM-depletion in treated mice, we developed a mathematical model of phage, bacteria, and innate immune system dynamics. Simulations from the model fitted to data suggest that AM reduce bacteriophage density in the lungs. We experimentally confirmed that the in vivo decay of bacteriophage is faster in immunocompetent compared to AM-depleted animals. These findings demonstrate the involvement of feedback between bacteriophage, bacteria, and the immune system in shaping the outcomes of phage therapy in clinical settings.

3.
iScience ; 26(2): 106004, 2023 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-36818291

RESUMO

For decades, biomedically centered studies of bacteria have focused on mechanistic drivers of disease in their mammalian hosts. Likewise, molecular studies of bacteriophage have centered on understanding mechanisms by which bacteriophage exploit the intracellular environment of their bacterial hosts. These binary interactions - bacteriophage infect bacteria and bacteria infect eukaryotic hosts - have remained largely separate lines of inquiry. However, recent evidence demonstrates how tripartite interactions between bacteriophage, bacteria and the eukaryotic host shape the dynamics and fate of each component. In this perspective, we provide an overview of different ways in which bacteriophage ecology modulates bacterial infections along a spectrum of positive to negative impacts on a mammalian host. We also examine how coevolutionary processes over longer timescales may change the valence of these interactions. We argue that anticipating both ecological and evolutionary dynamics is key to understand and control tripartite interactions and ultimately to the success or failure of phage therapy.

4.
Proc Natl Acad Sci U S A ; 119(31): e2204131119, 2022 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-35905321

RESUMO

Repeat proteins are made with tandem copies of similar amino acid stretches that fold into elongated architectures. These proteins constitute excellent model systems to investigate how evolution relates to structure, folding, and function. Here, we propose a scheme to map evolutionary information at the sequence level to a coarse-grained model for repeat-protein folding and use it to investigate the folding of thousands of repeat proteins. We model the energetics by a combination of an inverse Potts-model scheme with an explicit mechanistic model of duplications and deletions of repeats to calculate the evolutionary parameters of the system at the single-residue level. These parameters are used to inform an Ising-like model that allows for the generation of folding curves, apparent domain emergence, and occupation of intermediate states that are highly compatible with experimental data in specific case studies. We analyzed the folding of thousands of natural Ankyrin repeat proteins and found that a multiplicity of folding mechanisms are possible. Fully cooperative all-or-none transitions are obtained for arrays with enough sequence-similar elements and strong interactions between them, while noncooperative element-by-element intermittent folding arose if the elements are dissimilar and the interactions between them are energetically weak. Additionally, we characterized nucleation-propagation and multidomain folding mechanisms. We show that the global stability and cooperativity of the repeating arrays can be predicted from simple sequence scores.


Assuntos
Repetição de Anquirina , Dobramento de Proteína , Modelos Químicos
5.
Proc Natl Acad Sci U S A ; 118(27)2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34183397

RESUMO

The evolution of many microbes and pathogens, including circulating viruses such as seasonal influenza, is driven by immune pressure from the host population. In turn, the immune systems of infected populations get updated, chasing viruses even farther away. Quantitatively understanding how these dynamics result in observed patterns of rapid pathogen and immune adaptation is instrumental to epidemiological and evolutionary forecasting. Here we present a mathematical theory of coevolution between immune systems and viruses in a finite-dimensional antigenic space, which describes the cross-reactivity of viral strains and immune systems primed by previous infections. We show the emergence of an antigenic wave that is pushed forward and canalized by cross-reactivity. We obtain analytical results for shape, speed, and angular diffusion of the wave. In particular, we show that viral-immune coevolution generates an emergent timescale, the persistence time of the wave's direction in antigenic space, which can be much longer than the coalescence time of the viral population. We compare these dynamics to the observed antigenic turnover of influenza strains, and we discuss how the dimensionality of antigenic space impacts the predictability of the evolutionary dynamics. Our results provide a concrete and tractable framework to describe pathogen-host coevolution.


Assuntos
Antígenos Virais/imunologia , Evolução Molecular , Imunidade , Difusão , Modelos Biológicos , Simulação de Dinâmica Molecular , Processos Estocásticos
6.
Pathogens ; 8(3)2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31362404

RESUMO

Viruses evolve in the background of host immune systems that exert selective pressure and drive viral evolutionary trajectories. This interaction leads to different evolutionary patterns in antigenic space. Examples observed in nature include the effectively one-dimensional escape characteristic of influenza A and the prolonged coexistence of lineages in influenza B. Here, we use an evolutionary model for viruses in the presence of immune host systems with finite memory to obtain a phase diagram of evolutionary patterns in a two-dimensional antigenic space. We find that, for small effective mutation rates and mutation jump ranges, a single lineage is the only stable solution. Large effective mutation rates combined with large mutational jumps in antigenic space lead to multiple stably co-existing lineages over prolonged evolutionary periods. These results combined with observations from data constrain the parameter regimes for the adaptation of viruses, including influenza.

7.
PLoS Comput Biol ; 15(8): e1007282, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31415557

RESUMO

The coding space of protein sequences is shaped by evolutionary constraints set by requirements of function and stability. We show that the coding space of a given protein family-the total number of sequences in that family-can be estimated using models of maximum entropy trained on multiple sequence alignments of naturally occuring amino acid sequences. We analyzed and calculated the size of three abundant repeat proteins families, whose members are large proteins made of many repetitions of conserved portions of ∼30 amino acids. While amino acid conservation at each position of the alignment explains most of the reduction of diversity relative to completely random sequences, we found that correlations between amino acid usage at different positions significantly impact that diversity. We quantified the impact of different types of correlations, functional and evolutionary, on sequence diversity. Analysis of the detailed structure of the coding space of the families revealed a rugged landscape, with many local energy minima of varying sizes with a hierarchical structure, reminiscent of fustrated energy landscapes of spin glass in physics. This clustered structure indicates a multiplicity of subtypes within each family, and suggests new strategies for protein design.


Assuntos
Proteínas/química , Proteínas/genética , Sequências Repetitivas de Aminoácidos/genética , Algoritmos , Sequência de Aminoácidos , Biologia Computacional , Sequência Conservada , Entropia , Evolução Molecular , Modelos Moleculares , Conformação Proteica , Dobramento de Proteína , Alinhamento de Sequência/estatística & dados numéricos , Homologia de Sequência de Aminoácidos , Termodinâmica
8.
Cell Rep ; 25(3): 761-771.e4, 2018 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-30332654

RESUMO

Understanding the classic problem of how single E. coli cells coordinate cell division with genome replication would open the way to addressing cell-cycle progression at the single-cell level. Recent studies produced new data, but the contrast in their conclusions and proposed mechanisms makes the emerging picture fragmented and unclear. Here, we re-evaluate available data and models, including generalizations based on the same assumptions. We show that although they provide useful insights, none of the proposed models captures all correlation patterns observed in data. We conclude that the assumption that replication is the bottleneck process for cell division is too restrictive. Instead, we propose that two concurrent cycles responsible for division and initiation of DNA replication set the time of cell division. This framework allows us to select a nearly constant added size per origin between subsequent initiations as the most likely mechanism setting initiation of replication.


Assuntos
Divisão Celular , Cromossomos Bacterianos/genética , Replicação do DNA , DNA Bacteriano/genética , Proteínas de Escherichia coli/metabolismo , Escherichia coli/crescimento & desenvolvimento , Escherichia coli/genética , Ciclo Celular , Proteínas de Escherichia coli/genética , Modelos Estatísticos , Análise de Célula Única
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