scholarly journals Bacterial evolution during human infection: Adapt and live or adapt and die

2021 ◽  
Vol 17 (9) ◽  
pp. e1009872 ◽  
Author(s):  
Matthew J. Culyba ◽  
Daria Van Tyne
Keyword(s):  
Bacterial Infections ◽  
Evolutionary Dynamics ◽  
De Novo ◽  
Human Infection ◽  
Bacterial Evolution ◽  
Block Transmission ◽  
Adaptive Mutations ◽  
Rich Information ◽  
Human Infections

Microbes are constantly evolving. Laboratory studies of bacterial evolution increase our understanding of evolutionary dynamics, identify adaptive changes, and answer important questions that impact human health. During bacterial infections in humans, however, the evolutionary parameters acting on infecting populations are likely to be much more complex than those that can be tested in the laboratory. Nonetheless, human infections can be thought of as naturally occurring in vivo bacterial evolution experiments, which can teach us about antibiotic resistance, pathogenesis, and transmission. Here, we review recent advances in the study of within-host bacterial evolution during human infection and discuss practical considerations for conducting such studies. We focus on 2 possible outcomes for de novo adaptive mutations, which we have termed “adapt-and-live” and “adapt-and-die.” In the adapt-and-live scenario, a mutation is long lived, enabling its transmission on to other individuals, or the establishment of chronic infection. In the adapt-and-die scenario, a mutation is rapidly extinguished, either because it carries a substantial fitness cost, it arises within tissues that block transmission to new hosts, it is outcompeted by more fit clones, or the infection resolves. Adapt-and-die mutations can provide rich information about selection pressures in vivo, yet they can easily elude detection because they are short lived, may be more difficult to sample, or could be maladaptive in the long term. Understanding how bacteria adapt under each of these scenarios can reveal new insights about the basic biology of pathogenic microbes and could aid in the design of new translational approaches to combat bacterial infections.

scholarly journals Genetically and Antigenically Divergent Influenza A(H9N2) Viruses Exhibit Differential Replication and Transmission Phenotypes in Mammalian Models

2020 ◽  
Vol 94 (17) ◽  
Author(s):  
Jessica A. Belser ◽  
Xiangjie Sun ◽  
Nicole Brock ◽  
Claudia Pappas ◽  
Joanna A. Pulit-Penaloza ◽  
...  
Keyword(s):  
Influenza A ◽  
Human Infection ◽  
Influenza Viruses ◽  
Human Populations ◽  
Human Respiratory Tract ◽  
Live Bird Markets ◽  
Human Infections ◽  
Live Bird

ABSTRACT Low-pathogenicity avian influenza A(H9N2) viruses, enzootic in poultry populations in Asia, are associated with fewer confirmed human infections but higher rates of seropositivity compared to A(H5) or A(H7) subtype viruses. Cocirculation of A(H5) and A(H7) viruses leads to the generation of reassortant viruses bearing A(H9N2) internal genes with markers of mammalian adaptation, warranting continued surveillance in both avian and human populations. Here, we describe active surveillance efforts in live poultry markets in Vietnam in 2018 and compare representative viruses to G1 and Y280 lineage viruses that have infected humans. Receptor binding properties, pH thresholds for HA activation, in vitro replication in human respiratory tract cells, and in vivo mammalian pathogenicity and transmissibility were investigated. While A(H9N2) viruses from both poultry and humans exhibited features associated with mammalian adaptation, one human isolate from 2018, A/Anhui-Lujiang/39/2018, exhibited increased capacity for replication and transmission, demonstrating the pandemic potential of A(H9N2) viruses. IMPORTANCE A(H9N2) influenza viruses are widespread in poultry in many parts of the world and for over 20 years have sporadically jumped species barriers to cause human infection. As these viruses continue to diversify genetically and antigenically, it is critical to closely monitor viruses responsible for human infections, to ascertain if A(H9N2) viruses are acquiring properties that make them better suited to infect and spread among humans. In this study, we describe an active poultry surveillance system established in Vietnam to identify the scope of influenza viruses present in live bird markets and the threat they pose to human health. Assessment of a recent A(H9N2) virus isolated from an individual in China in 2018 is also reported, and it was found to exhibit properties of adaptation to humans and, importantly, it shows similarities to strains isolated from the live bird markets of Vietnam.

scholarly journals Evolutionary dynamics and structural consequences of de novo beneficial mutations and mutant lineages arising in a constant environment

BMC Biology ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Margie Kinnersley ◽  
Katja Schwartz ◽  
Dong-Dong Yang ◽  
Gavin Sherlock ◽  
Frank Rosenzweig
Keyword(s):  
High Frequency ◽  
High Throughput Sequencing ◽  
Evolutionary Dynamics ◽  
De Novo ◽  
Allelic Diversity ◽  
Microbial Evolution ◽  
De Novo Mutations ◽  
Beneficial Mutations ◽  
Adaptive Mutations ◽  
The Impact

Abstract Background Microbial evolution experiments can be used to study the tempo and dynamics of evolutionary change in asexual populations, founded from single clones and growing into large populations with multiple clonal lineages. High-throughput sequencing can be used to catalog de novo mutations as potential targets of selection, determine in which lineages they arise, and track the fates of those lineages. Here, we describe a long-term experimental evolution study to identify targets of selection and to determine when, where, and how often those targets are hit. Results We experimentally evolved replicate Escherichia coli populations that originated from a mutator/nonsense suppressor ancestor under glucose limitation for between 300 and 500 generations. Whole-genome, whole-population sequencing enabled us to catalog 3346 de novo mutations that reached > 1% frequency. We sequenced the genomes of 96 clones from each population when allelic diversity was greatest in order to establish whether mutations were in the same or different lineages and to depict lineage dynamics. Operon-specific mutations that enhance glucose uptake were the first to rise to high frequency, followed by global regulatory mutations. Mutations related to energy conservation, membrane biogenesis, and mitigating the impact of nonsense mutations, both ancestral and derived, arose later. New alleles were confined to relatively few loci, with many instances of identical mutations arising independently in multiple lineages, among and within replicate populations. However, most never exceeded 10% in frequency and were at a lower frequency at the end of the experiment than at their maxima, indicating clonal interference. Many alleles mapped to key structures within the proteins that they mutated, providing insight into their functional consequences. Conclusions Overall, we find that when mutational input is increased by an ancestral defect in DNA repair, the spectrum of high-frequency beneficial mutations in a simple, constant resource-limited environment is narrow, resulting in extreme parallelism where many adaptive mutations arise but few ever go to fixation.

scholarly journals AtypicalSalmonella entericaserovars in murine and human infection models: Is it time to reassess our approach to the study of salmonellosis?

2016 ◽  
Author(s):  
Daniel Hurley ◽  
Maria Hoffmann ◽  
Tim Muruvanda ◽  
Marc W. Allard ◽  
Eric W. Brown ◽  
...  
Keyword(s):  
United States ◽  
Cell Lines ◽  
The United States ◽  
Human Infection ◽  
Raw 264.7 ◽  
Murine Models ◽  
Infection Models ◽  
Foodborne Outbreaks ◽  
Human Infections

AbstractNontyphoidalSalmonellaspecies are globally disseminated pathogens and the predominant cause of gastroenteritis. The pathogenesis of salmonellosis has been extensively studied usingin vivomurine models and cell lines typically challenged withSalmonellaTyphimurium. Although serovars Enteritidis and Typhimurium are responsible for the most of human infections reported to the CDC, several other serovars also contribute to clinical cases of salmonellosis. Despite their epidemiological importance, little is known about their infection phenotypes. Here, we report the virulence characteristics and genomes of 10 atypicalS. entericaserovars linked to multistate foodborne outbreaks in the United States. We show that the murine RAW 264.7 macrophage model of infection is unsuitable for inferring human relevant differences in nontyphoidalSalmonellainfections whereas differentiated human THP-1 macrophages allowed these isolates to be further characterised in a more relevant, human context.

scholarly journals Parallel evolution of phage resistance - virulence trade - offs during in vitro and nasal Pseudomonas aeruginosa phage treatment

2021 ◽  
Author(s):  
Meaghan Castledine ◽  
Daniel Padfield ◽  
Pawel Sierocinski ◽  
Jesica Soria Pascual ◽  
Adam Hughes ◽  
...  
Keyword(s):  
Pathogenic Bacteria ◽  
Evolutionary Dynamics ◽  
Phage Therapy ◽  
De Novo ◽  
Resistant Bacteria ◽  
Phage Resistance ◽  
Lower Growth ◽  
Trade Offs

With rising antibiotic resistance, there has been increasing interest in the treatment of pathogenic bacteria with bacteriophages (phage therapy). One limitation of phage therapy is the ease at which bacteria can evolve resistance. The negative effects of resistance may be partially mitigated when resistance results in reduced bacterial growth and virulence, or when phage coevolve to overcome resistance. Resistance evolution and its consequences are highly contingent on the particular combination of bacteria and phage and the ecological context they interact in, making therapeutic outcomes hard to predict. One solution might be to conduct ″in vitro evolutionary simulations″ using the bacteria-phage combinations specific to the therapeutic context. Here, we investigate parallels between in vitro experiments and in vivo dynamics in a human participant. Evolutionary dynamics were similar in vivo and in vitro, with high levels of de novo resistance evolving quickly with limited evidence of phage evolution. Moreover, resistant bacteria – evolved both in vitro and in vivo – had lower virulence when measured in an insect model. In vivo, this was linked to lower growth rates of resistant isolates, whereas in vitro isolates evolved greater biofilm production with phage resistance. Population sequencing suggests resistance was typically the result of selection on de novo mutations rather than sorting of existing variants in the population. These results highlight the speed at which resistance to phages can evolve in vivo, and that in vitro evolution may give useful insights for evolutionary outcomes in vivo.

scholarly journals The PB2 Polymerase Host Adaptation Substitutions Prime Avian Indonesia Sub Clade 2.1 H5N1 Viruses for Infecting Humans

Viruses ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 292 ◽  
Author(s):  
Pui Wang ◽  
Wenjun Song ◽  
Bobo Mok ◽  
Min Zheng ◽  
Siu-Ying Lau ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
H5n1 Virus ◽  
Human Infection ◽  
Influenza Viruses ◽  
Avian Species ◽  
Adaptive Mutation ◽  
Efficient Replication ◽  
Human Infections

Significantly higher numbers of human infections with H5N1 virus have occurred in Indonesia and Egypt, compared with other affected areas, and it is speculated that there are specific viral factors for human infection with avian H5N1 viruses in these locations. We previously showed PB2-K526R is present in 80% of Indonesian H5N1 human isolates, which lack the more common PB2-E627K substitution. Testing the hypothesis that this mutation may prime avian H5N1 virus for human infection, we showed that: (1) K526R is rarely found in avian influenza viruses but was identified in H5N1 viruses 2–3 years after the virus emerged in Indonesia, coincident with the emergence of H5N1 human infections in Indonesia; (2) K526R is required for efficient replication of Indonesia H5N1 virus in mammalian cells in vitro and in vivo and reverse substitution to 526K in human isolates abolishes this ability; (3) Indonesian H5N1 virus, which contains K526R-PB2, is stable and does not further acquire E627K following replication in infected mice; and (4) virus containing K526R-PB2 shows no fitness deficit in avian species. These findings illustrate an important mechanism in which a host adaptive mutation that predisposes avian H5N1 virus towards infecting humans has arisen with the virus becoming prevalent in avian species prior to human infections occurring. A similar mechanism is observed in the Qinghai-lineage H5N1 viruses that have caused many human cases in Egypt; here, E627K predisposes towards human infections. Surveillance should focus on the detection of adaptation markers in avian strains that prime for human infection.

scholarly journals 5-Dodecanolide interferes with biofilm formation and reduces the virulence of Methicillin-resistant Staphylococcus aureus (MRSA) through up regulation of agr system

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Alaguvel Valliammai ◽  
Sivasamy Sethupathy ◽  
Arumugam Priya ◽  
Anthonymuthu Selvaraj ◽  
James Prabhanand Bhaskar ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Biofilm Formation ◽  
Bacterial Infections ◽  
Pcr Analysis ◽  
High Morbidity ◽  
Healthy Human ◽  
Methicillin Resistant ◽  
Gene Expression Studies ◽  
Human Infections

Abstract Methicillin resistant Staphylococcus aureus (MRSA) is a predominant human pathogen with high morbidity that is listed in the WHO high priority pathogen list. Being a primary cause of persistent human infections, biofilm forming ability of S. aureus plays a pivotal role in the development of antibiotic resistance. Hence, targeting biofilm is an alternative strategy to fight bacterial infections. The present study for the first time demonstrates the non-antibacterial biofilm inhibitory efficacy of 5-Dodecanolide (DD) against ATCC strain and clinical isolates of S. aureus. In addition, DD is able to inhibit adherence of MRSA on human plasma coated Titanium surface. Further, treatment with DD significantly reduced the eDNA synthesis, autoaggregation, staphyloxanthin biosynthesis and ring biofilm formation. Reduction in staphyloxanthin in turn increased the susceptibility of MRSA to healthy human blood and H2O2 exposure. Quantitative PCR analysis revealed the induced expression of agrA and agrC upon DD treatment. This resulted down regulation of genes involved in biofilm formation such as fnbA and fnbB and up regulation of RNAIII, hld, psmα and genes involved in biofilm matrix degradation such as aur and nuc. Inefficacy of DD on the biofilm formation of agr mutant further validated the agr mediated antibiofilm potential of DD. Notably, DD was efficient in reducing the in vivo colonization of MRSA in Caenorhabditis elegans. Results of gene expression studies and physiological assays unveiled the agr mediated antibiofilm efficacy of DD.

scholarly journals In vivo Infection Dynamics and Human Adaptive Changes of SIVsm-Derived Viral Siblings SIVmac239, SIVB670, and SIVhu in Humanized Mice as a Paralog of HIV-2 Genesis

2021 ◽  
Vol 1 ◽  
Author(s):  
James Z. Curlin ◽  
Kimberly Schmitt ◽  
Leila Remling-Mulder ◽  
Ryan V. Moriarty ◽  
John J. Baczenas ◽  
...  
Keyword(s):  
T Cell ◽  
Small Animal ◽  
Serial Passage ◽  
Human Infection ◽  
Humanized Mice ◽  
New Host ◽  
Adaptive Changes ◽  
Adaptive Mutations ◽  
Immune Pressure

Simian immunodeficiency virus native to sooty mangabeys (SIVsm) is believed to have given rise to HIV-2 through cross-species transmission and evolution in the human. SIVmac239 and SIVB670, pathogenic to macaques, and SIVhu, isolated from an accidental human infection, also have origins in SIVsm. With their common ancestral lineage as that of HIV-2 from the progenitor SIVsm, but with different passage history in different hosts, they provide a unique opportunity to evaluate cross-species transmission to a new host and their adaptation/evolution both in terms of potential genetic and phenotypic changes. Using humanized mice with a transplanted human system, we evaluated in vivo replication kinetics, CD4+ T cell dynamics and genetic adaptive changes during serial passage with a goal to understand their evolution under human selective immune pressure. All the three viruses readily infected hu-mice causing chronic viremia. While SIVmac and SIVB670 caused CD4+ T cell depletion during sequential passaging, SIVhu with a deletion in nef gene was found to be less pathogenic. Deep sequencing of the genomes of these viruses isolated at different times revealed numerous adaptive mutations of significance that increased in frequency during sequential passages. The ability of these viruses to infect and replicate in humanized mice provides a new small animal model to study SIVs in vivo in addition to more expensive macaques. Since SIVmac and related viruses have been indispensable in many areas of HIV pathogenesis, therapeutics and cure research, availability of this small animal hu-mouse model that is susceptible to both SIV and HIV viruses is likely to open novel avenues of investigation for comparative studies using the same host.

scholarly journals Evolutionary dynamics ofde novomutations and mutant lineages arising in a simple, constant environment

2019 ◽  
Author(s):  
Margie Kinnersley ◽  
Katja Schwartz ◽  
Jacob Boswell ◽  
Dong-Dong Yang ◽  
Gavin Sherlock ◽  
...  
Keyword(s):  
Dna Repair ◽  
Energy Conservation ◽  
High Frequency ◽  
Evolutionary Dynamics ◽  
De Novo ◽  
Whole Genome ◽  
Clonal Interference ◽  
Adaptive Mutations ◽  
E Coli ◽  
Regulatory Changes

AbstractA large, asexual population founded by a single clone evolves into a population teeming with many, whether or not its environment is structured, and whether or not resource levels are constant or fluctuating. The maintenance of genetic complexity in such populations has been attributed to balancing selection, or to either clonal interference or clonal reinforcement, arising from antagonistic or synergistic interactions, respectively. To distinguish among these possibilities, to identify targets of selection and establish when and how often they are hit, as well as to gain insight into howde novomutations interact, we carried out 300-500 generation glucose-limited chemostat experiments founded by anE. colimutator. To discover allde novomutations reaching ≥1% frequency, we performed whole-genome, whole-population sequencing at ∼1000X-coverage every 50 generations. To establish linkage relationships among these mutations and depict the dynamics of evolving lineages we sequenced the genomes of 96 clones from each population when allelic diversity was greatest. Operon-specific mutations that enhance glucose uptake arose to high frequency first, followed by global regulatory mutations. Late-arising mutations were related to energy conservation as well as to mitigating pleiotropic effects wrought by earlier regulatory changes. We discovered extensive polymorphism at relatively few loci, with identical mutations arising independently in different lineages, both between and within replicate populations. Out of more than 3,000 SNPs detected in nearly 1,800 genes or intergenic regions, only 17 reached a frequency ≥ 98%, indicating that the evolutionary dynamics of adaptive lineages was dominated by clonal interference. Finally, our data show that even when mutational input is increased by an ancestral defect in DNA repair, the spectrum of beneficial mutations that reach high frequency in a simple, constant resource-limited environment is narrow, resulting in extreme parallelism where many adaptive mutations arise but few ever go to fixation.Author SummaryMicrobial evolution experiments open a window on the tempo and dynamics of evolutionary change in asexual populations. High-throughput sequencing can be used to catalogde novomutations, determine in which lineages they arise, and assess allelic interactions by tracking the fate of those lineages. Thisadaptive geneticsapproach makes it possible to discover whether clonal interactions are antagonistic or synergistic, and complements genetic screens of induced deleterious/loss-of-function mutants. We carried out glucose-limited chemostat experiments founded by anE. colimutator and performed whole-genome, whole-population sequencing on 300-500 generation evolutions, cataloging 3,346de novomutations that reached ≥1% frequency. Mutations enhancing glucose uptake rose to high frequency first, followed by global regulatory changes that modulate growth rate and limiting resource assimilation, then by mutations that favor energy conservation or mitigate pleiotropic effects of earlier regulatory changes. We discovered that a few loci were highly polymorphic, with identical mutations arising independently in different lineages, both between and within replicate populations. Thus, when mutational input is increased by an ancestral defect in DNA repair, the spectrum of beneficial mutations that arises under constant resource-limitation is narrow, resulting in extreme parallelism where many adaptive mutations arise but few ever become fixed.

scholarly journals De novo design of a pH-triggered self-assembled β-hairpin nanopeptide with the dual biological functions for antibacterial and entrapment

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Qiuke Li ◽  
Jinze Li ◽  
Weikang Yu ◽  
Zhihua Wang ◽  
Jiawei Li ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Bacterial Infections ◽  
De Novo ◽  
Ph Regulation ◽  
Membrane Integrity ◽  
Intestinal Flora ◽  
Building Blocks ◽  
Self Assembled

Abstract Background Acid-tolerant enteric pathogens can evade small intestinal acid barriers, colonize and infect the intestinal tract. However, broad-spectrum antibiotics are not the best therapeutic strategy because of the disruption of intestinal flora caused by its indiscriminate antimicrobial activity against beneficial and harmful bacteria. So that is what inspired us to combine pH regulation with nanotechnology to develop a pH-triggered site-targeted antimicrobial peptide with entrapping function. Results A pH-triggered dual biological functional self-assembled peptide (SAP) was designed according to the features of amino-acid building blocks and the diagonal cation–π interaction principle. The results of characterization experiments showed that changes in pH conditions could trigger microstructural transformation of the nanopeptide from nanospheres to nanofibers. The subsequent antibacterial and toxicity experiments determined that SAP had great antimicrobial activity against Escherichia coli, Salmonella typhimurium, Listeria monocytogenes, and Bacillus cereus above 15.6 μg/mL under acidic conditions by disrupting bacterial membrane integrity, excellent biocompatibility in vitro even at 250 μg/mL and high tolerance in physical environment. Moreover, at peptide concentrations greater than 62.5 μg/mL, SAP showed the entrapment property, which played an important role in phagocytic clearance in infection forces. Meanwhile, the in vivo results revealed that SAP possessed excellent therapeutic effect and good biosafety. Conclusions Our study revealed the antibacterial activity of a short β-hairpin forming self-assembled peptide, and established an innovative design strategy for peptide-based nanomaterials and a new treatment strategy for gastrointestinal bacterial infections. Graphic Abstract

scholarly journals On-person adaptive evolution of Staphylococcus aureus during atopic dermatitis increases disease severity

2021 ◽  
Author(s):  
Felix M. Key ◽  
Veda D. Khadka ◽  
Carolina Romo-González ◽  
Kimbria J. Blake ◽  
Liwen Deng ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Atopic Dermatitis ◽  
Disease Severity ◽  
De Novo ◽  
Mouse Skin ◽  
The Body ◽  
Single Mutation ◽  
Skin Damage ◽  
Adaptive Mutations

Bacteria acquire adaptive mutations during infections and within healthy microbiomes 1-4, but the potential of bacterial mutations to impact disease is not well understood. The inflamed skin of people with atopic dermatitis (AD) is heavily colonized with Staphylococcus aureus, an opportunistic pathogen associated with both asymptomatic colonization of nasal passages and invasive disease5,6. While host genetic risk is critical to AD initiation 7,8, S. aureus worsens disease severity by inducing skin damage9. Here, we longitudinally track S. aureus evolution on 25 children with AD over 9 months —sequencing the genomes of 1,330 colonies— and identify common adaptive de novo mutations that exacerbate skin disease in vivo. Novel S. aureus genotypes replace their ancestors across the body within months, with signatures of adaptive, rather than neutral, forces. Most strikingly, the capsule synthesis gene capD obtained four parallel mutations within one patient and is involved in mutational sweeps in multiple patients. Despite the known role of capsule in phagocytic evasion10, we find that an acapsular ΔcapD strain colonizes better and produces worse disease severity on mouse skin than its encapsulated parental strain. Moreover, re-analysis of publicly available S. aureus genomes from 276 people confirms that CapD truncations are significantly more common among strains isolated from AD patients relative to other contexts. Together, these results suggest that targeting capsule-negative strains may be a potential avenue for decreasing S. aureus skin colonization and highlight the importance of single-mutation resolution for characterizing microbe-disease associations.

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