Tag Archives: Genome

Experts find remnants of ancient RNA viruses embedded inside reef-building corals

An international team of marine biologists has discovered the remnants of ancient RNA viruses embedded in the DNA of symbiotic organisms living inside reef-building corals.

The RNA fragments are from viruses that infected the symbionts as long ago as 160 million years. The discovery is described in an open-access study published this week in the Nature journal Communications Biology, and it could help scientists understand how corals and their partners fight off viral infections today. But it was a surprising find because most RNA viruses are not known for embedding themselves in the DNA of organisms they infect.

The research showed that endogenous viral elements, or EVEs, appear widely in the genomes of coral symbionts. Known as dinoflagellates, the single-celled algae live inside corals and provide them with their dramatic colors. The EVE discovery underscores recent observations that viruses other than retroviruses can integrate fragments of their genetic code into their hosts’ genomes.

So why did it get in there? It could just be an accident, but people are starting to find that these ‘accidents’ are more frequent than scientists had previously believed, and they’ve been found across all kinds of hosts, from bats to ants to plants to algae.”

Adrienne Correa, Study Co-Author, Rice University

That an RNA virus appears at all in coral symbionts was also a surprise.

“This is what made this project so interesting to me,” said study lead author Alex Veglia, a graduate student in Correa’s research group. “There’s really no reason, based on what we know, for this virus to be in the symbionts’ genome.”

The study was supported by the Tara Ocean Foundation and the National Science Foundation and led by Correa, Veglia and two scientists from Oregon State University, postdoctoral scholar Kalia Bistolas and marine ecologist Rebecca Vega Thurber. The research provides clues that can help scientists better understand the ecological and economic impact of viruses on reef health.

The researchers did not find EVEs from RNA viruses in samples of filtered seawater or in the genomes of dinoflagellate-free stony corals, hydrocorals or jellyfish. But EVEs were pervasive in coral symbionts that were collected from dozens of coral reef sites, meaning the pathogenic viruses were -; and probably remain -; picky about their target hosts.

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“There’s a huge diversity of viruses on the planet,” said Correa, an assistant professor of biosciences. “Some we know a lot about, but most viruses haven’t been characterized. We might be able to detect them, but we don’t know who serves as their hosts.”

She said viruses, including retroviruses, have many ways to replicate by infecting hosts. “One reason our study is cool is because this RNA virus is not a retrovirus,” Correa said. “Given that, you wouldn’t expect it to integrate into host DNA.

“For quite a few years, we’ve seen a ton of viruses in coral colonies, but it’s been hard to tell for sure what they were infecting,” Correa said. “So this is likely the best, most concrete information we have for the actual host of a coral colony-associated virus. Now we can start asking why the symbiont keeps that DNA, or part of the genome. Why wasn’t it lost a long time ago?”

The discovery that the EVEs have been conserved for millions of years suggests they may somehow be beneficial to the coral symbionts and that there is some kind of mechanism that drives the genomic integration of the EVEs.

“There are a lot of avenues we can pursue next, like whether these elements are being used for antiviral mechanisms within dinoflagellates, and how they are likely to affect reef health, especially as oceans warm,” Veglia said.

“If we’re dealing with an increase in the temperature of seawater, is it more likely that Symbiodiniaceae species will contain this endogenous viral element? Does having EVEs in their genomes improve their odds of fighting off infections from contemporary RNA viruses?” he said.

“In another paper, we showed there was an increase in RNA viral infections when corals underwent thermal stress. So there are a lot of moving parts. And this is another good piece of that puzzle.”

Correa said, “We can’t assume that this virus has a negative effect. But at the same time, it does look like it’s becoming more productive under these temperature stress conditions.”

Thurber is the Emile F. Pernot Distinguished Professor in Oregon State’s Department of Microbiology.

Source:
Journal reference:

Veglia, A. J., et al. (2023). Endogenous viral elements reveal associations between a non-retroviral RNA virus and symbiotic dinoflagellate genomes. Communications Biology. doi.org/10.1038/s42003-023-04917-9.

Identifying what makes some gut bacteria strains life-threatening in pre-term babies

Researchers from the Quadram Institute and University of East Anglia have identified what makes some strains of gut bacteria life-threatening in pre-term babies.

The findings will help identify and track dangerous strains and protect vulnerable neonatal babies.

A major threat to neonatal babies with extremely low birth weight is necrotizing enterocolitis (NEC).

Rare in full-term babies, this microbial infection exploits vulnerabilities destroying gut tissue leading to severe complications. Two out of five cases are fatal.

One bacterial species that causes especially sudden and severe disease is Clostridium perfringens. These are common in the environment and non-disease-causing strains live in healthy human guts.

So what makes certain strains so dangerous in preterm babies?

Prof Lindsay Hall and Dr Raymond Kiu from the Quadram Institute and UEA led the first major study on C. perfringens genomes from preterm babies, including some babies with necrotizing enterocolitis.

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The research team analyzed C. perfringens genomes from the faecal samples of 70 babies admitted to five UK Neonatal Intensive Care Units (NICUs).

Based on genomic similarities, they found one set had a lower capacity to cause disease. This allowed a comparison with the more virulent strains.

The less virulent group lacked genes responsible for production of a toxin called PFO and other factors needed for colonization and survival.

This study has begun to construct genomic signatures for C. perfringens associated with healthy preterm babies and those with necrotizing enterocolitis.

Exploring genomic signatures from hundreds of Clostridium perfringens genomes has allowed us potentially to discriminate between ‘good’ bacterial strains that live harmlessly in the preterm gut, and ‘bad’ ones associated with the devastating and deadly disease necrotizing enterocolitis.

We hope the findings will help with ‘tracking’ deadly C. perfringens strains in a very vulnerable group of patients – preterm babies.”

Prof Lindsay Hall, UEA’s Norwich Medical School and the Quadram Institute

Larger studies, across more sites and with more samples may be needed but this research could help identify better ways to control necrotizing enterocolitis.

The team previously worked alongside Prof Paul Clarke and clinical colleagues at the Norfolk and Norwich University Hospital NICU. And they demonstrated the benefits of providing neonatal babies with probiotic supplements.

The enterocolitis gut microbiome of neonatal infants is significantly disrupted, making it susceptible to C. perfringens overgrowth.

Prof Hall said: “Our genomic study gives us more data that we can use in the fight against bacteria that cause disease in babies – where we are harnessing the benefits of another microbial resident, Bifidobacterium, to provide at-risk babies with the best possible start in life.”

Dr Raymond Kiu, from the Quadram Institute, said: “Importantly, this study highlights Whole Genome Sequencing as a powerful tool for identifying new bacterial lineages and determining bacterial virulence factors at strain level which enables us to better understand disease.”

This research was supported by the Biotechnology and Biological Sciences Research Council, part of UKRI, and the Wellcome Trust.

The study was led by researchers at Quadram Institute and the University of East Anglia, in collaboration with colleagues at Imperial College, London, the University of Glasgow, the University of Cambridge, Newcastle University and Northumbria University.

‘Particular genomic and virulence traits associated with preterm infant-derived toxigenic Clostridium perfringens strains’ is published in Nature Microbiology.

Source:
Journal reference:

Kiu, R., et al. (2023). Particular genomic and virulence traits associated with preterm infant-derived toxigenic Clostridium perfringens strains. Nature Microbiology. doi.org/10.1038/s41564-023-01385-z.

A novel approach to quantify personal information contained within gut metagenome data

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In a recent study published in Nature Microbiology, researchers used shotgun sequencing to extract human reads from deoxyribonucleic acid (DNA) in fecal samples of 343 Japanese individuals comprising the main dataset of this study.

They used this gut metagenome data to reconstruct personal information. Some study participants also provided whole genome sequencing (WGS) data for ultra-deep metagenome shotgun sequencing analysis.

Study: Reconstruction of the personal information from human genome reads in gut metagenome sequencing data. Image Credit: KaterynaKon/Shutterstock.comStudy: Reconstruction of the personal information from human genome reads in gut metagenome sequencing data. Image Credit: KaterynaKon/Shutterstock.com

Background

The knowledge regarding the human microbiome, microorganisms inhabiting the human body, has expanded considerably in the last ten years, thanks to rapid advancements in technologies like metagenome shotgun sequencing.

This technology allows the sequencing of the non-bacterial component of the microbiome samples, including host DNA. For instance, in fecal samples, the amount of host DNA is less than 10% but is removed to protect the privacy of donors.

Human germline genotype in metagenome data is substantial to enable the re-identification of individuals. However, researchers and donors should recognize that it is highly confidential, so sharing it with the community requires careful consideration.

Apart from ethical concerns related to sharing this data, it is necessary to understand that if human reads in metagenome data are not removed before deposition, what kind of personal information (e.g., sex and ancestry) could this data help recover?

In addition, human reads in gut metagenome data could be a good resource for stool-based forensics, robust variant calling, and polygenic risk scores based estimates of disease risks (e.g., type 2 diabetes).

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Since this data could help quantitatively and precisely reconstruct genotype information, it could complement human WGS data.

About the study

In the present study, researchers applied a few humans reads in the gut metagenome data of the main study dataset to reconstruct personal information, including genetic sex and ancestry. For predicting genetic sex and the ancestries of these 343 individuals, they used sequencing depth of the sex chromosomes and modified likelihood score-based method, respectively.

In addition, the researchers developed methods to re-identify a person from a genotype dataset. Furthermore, they combined two harmonized genotype-calling approaches, the direct calling of rare variants and the two-step imputation of common variants, to reconstruct genotypes.

The main dataset of the study included 343 Japanese participants, whereas the validation dataset for the genetic sex prediction analysis comprised 113 Japanese individuals.

The multi-ancestry dataset, which helped the researchers validate ancestry prediction analysis, comprised 73 individuals of various nationalities, including samples from individuals in New Delhi, India.

The female and male participants in each dataset were 196 & 147, 65 & 48, and 25 & 48, respectively. Likewise, the age range for these three datasets was 20 to 88, 20 to 81, and 20 to 61 years, respectively.

Results and conclusion

Given that human reads in the gut metagenome data were derived consistently from all chromosomes, the read depth of the X chromosome was nearly double in females and that of the Y chromosome in males.

So, in a logistic regression analysis, when the researchers applied a 0.43 Y:X chromosome read-depth ratio to the validation dataset, which correctly predicted the genetic sex of 97.3% of the study samples.

In human microbiome and genetic research, the feasibility of sex prediction using human gut metagenome data could help remove mislabelled samples.

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The study analysis also helped researchers remarkably predict ancestry in 98.3% of individuals using 1,000 Genomes Project (1KG) data as a reference.

However, the likelihood score-based method often misclassified South Asian (SAS) samples as American (AMR) and European (EUR), especially when the number of human reads was small. It is understandable because the genetic diversity of the SAS population is complex.

The likelihood score-based method also efficiently utilized the data from genomic areas with low coverage demonstrating the quantitative power of gut metagenome data to re-identify individuals and successfully re-identified 93.3% of individuals.

Despite ethical concerns, the re-identification method used in this study could help in the quality control of multi-omics datasets comprising gut metagenome and human germline genotype data.

In addition, the authors successfully reconstructed genome-wide common variants using genomic approaches. Historically researchers used stool samples as a source of germline genomes for wild and domestic animals but not humans.

Thus, further development of suitable methodologies could help efficiently utilize the human genome in gut metagenome data and benefit animal research.

Nonetheless, the study remarkably demonstrated that optimized methods could help reconstruct personal information from the human reads in gut metagenome data.

Moreover, the findings of this study could serve as a guiding resource to devise best practices for using the already accumulated gut metagenome data of humans.

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Journal reference:

Study identifies key genetic mechanism of drug resistance in the deadliest malaria parasites

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An important genetic mechanism of drug resistance in one of the deadliest human malaria parasites has been identified in a new study published in Nature Microbiology.

A second key gene, pfaat1, responsible for encoding a protein that transports amino acids in the membrane of Plasmodium falciparum, is involved in its resistance to the major anti-malaria drug, chloroquine.

The findings may have implications for the ongoing battle against malaria, which infects an estimated 247 million people worldwide and kills more than 619,000 each year, most of which are young children.

Chloroquine is a major antimalaria drug, however in recent years, resistance has emerged in malaria parasites, first spreading through Southeast Asia and then through Africa in the 1970s and 1980s. Although alternative antimalarial drugs have been developed, resistance to chloroquine remains a big challenge.

Since its discovery in 2000, only one gene has been believed to have been responsible for resistance to chloroquine – the resistance transporter pfcrt which helps the malaria parasite transport the drug out of a key region in their cells, subsequently rendering it ineffective.

In this study, researchers from the Medical Research Council (MRC) Unit The Gambia at the London School of Hygiene & Tropical Medicine (LSHTM) analysed more than 600 genomes of P. falciparum that were collected in The Gambia over a period of 30 years. The team found that mutant variants of  a second gene, pfaat1, which encodes an amino acid transporter, increased in frequency from undetectable to very high levels between 1984 and 2014. Importantly, their genome-wide population analyses also indicated long term co-selection on this gene alongside the previously-known resistance gene pfcrt.

In the laboratory, a further team of researchers including from Texas Biomed, University of Notre Dame and Seattle Children’s Research Institute found that replacing these mutations in parasite genomes using CRISPR gene-editing technology impacted drug resistance. A team from Nottingham University also found that these mutations could impact the function of pfaat1 in yeast, resulting in drug resistance.

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Complementary analysis of malaria genome datasets additionally suggested that parasites from Africa and Asia may carry different mutations in pfaat1 which could help explain differences in the evolution of drug resistance across these continents.

Alfred Amambua-Ngwa, Professor of Genetic Epidemiology at MRC Unit The Gambia at LSHTM said: “This is a very clear example of natural selection in action – these mutations were preferred and passed on with extremely high frequency in a very short amount of time, suggesting they provide a significant survival advantage.

“The mutations in pfaat1 very closely mirror the increase of pfcrt mutations. This, and other genetic analyses in the paper demonstrate that the transporter AAT1 has a major role in chloroquine resistance.”

Grappling with drug resistance, for malaria and other pathogens, requires taking a holistic approach to both drug development and pathogen surveillance. We must be aware that different genes and molecules will be working together to survive treatments. That is why looking at whole genomes and whole populations is so critical.”

David Conway, Professor of Biology, LSHTM

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Source:
Journal reference:

Amambua-Ngwa, A., et al. (2023). Chloroquine resistance evolution in Plasmodium falciparum is mediated by the putative amino acid transporter AAT1. Nature Microbiology. doi.org/10.1038/s41564-023-01377-z.

MGI Empowers the Completion of Nearly 60,000 Samples for The Million Microbiome of Humans Project

SHENZHEN, China, 10 May 2023 – MGI Tech Co. Ltd. (MGI), a company committed to building core tools and technology to lead life science, today shared that a total of nearly 60,000 samples have been sequenced among 21 institutes and over 10 participating nations throughout Europe, as part of the Million Microbiome of Humans Project (MMHP) that was officially launched in 2019.

Image Credit: MGI

The project was launched as a joint effort by the Karolinska Institute of Sweden, Shanghai National Clinical Research Center for Metabolic Diseases in China, the University of Copenhagen in Denmark, Technical University of Denmark, MetaGenoPolis at the National Research Institute for Agriculture, Food and Environment (INRAE) in France, and the Latvian Biomedical Research and Study Center. Relying on MGI’s core DNBSEQ™ technology, MMHP aims to sequence and analyze microbial DNA from a million human samples to construct a microbiome map of the human body and build the world’s largest human microbiome database.

“Countless studies have highlighted the importance of the microbiome in human health and disease. Yet, our knowledge of the composition of the microbiome in different parts of the body across countries, ages, sexes, and in relation to human health and disease remains limited,” said Duncan Yu, President of MGI. “Through MMHP, we are pushing forward microbial metagenomic research while empowering researchers within the microbiology community with access to MGI’s innovative sequencing technology. Despite a brief interruption by the COVID-19 pandemic, we are delighted to see such a monumental milestone merely four years into the project.”

The rise of microbial metagenomic sequencing​​​​​​​

Since the first description of human microbiome was published in 2010, the field of human microbiome has moved fast from sampling hundreds of individuals to thousands. Advances in genome sequencing has enabled researchers to better characterize the composition of the microbiome through identification of unculturable microbes. It has also allowed them the opportunity to study how the microbiome influences the development of some cancers and drug responses.

Metagenomics, coupled with high-throughput sequencing technologies, have revolutionized microbial ecology. Today, metagenomic sequencing has become both a powerful and popular tool for identifying and classifying complex microbial communities. It facilitates accelerated discovery of new markers that translate to virulence or antibiotic resistance, as well as de novo discovery and characterization of novel species and assembly of new genomes. Besides human microbiome, it is highly applicable in agricultural microbiome studies, environmental microbiome studies, pathogen surveillance and identification, and monitoring of antimicrobial resistance genes.

Indeed, the global metagenomic sequencing market was estimated to be worth USD 1.86 billion in revenue in 2022 and is poised to reach USD 4.33 billion by 2027, growing at a CAGR of 18.4% during the forecast period. In particular, Europe and Africa account for approximately 29.7% market share from the globe, ranking second after North America at 45.6%. Thanks to continuous technological innovations in high-throughput sequencing platforms, the metagenomic sequencing market within Europe and Africa is projected to grow from USD 551.7 million in 2022 to 1.29 billion by 2027, presenting huge market opportunities and providing local institutions with the impetus to invest and get involved.

​​​​​​​

Image Credit: MGI

An optimized workflow with MGI’s cutting-edge technology

Equipped with MGI’s innovative lab systems, the MMHP Consortium guarantees high-throughput processes, extreme precision, and high quality data output. The dedicated, one-stop workflow begins with sample transfer on MGISTP-7000* high-throughput automated sample transfer processing system. It then goes through nucleic acid extraction and library preparation on MGISP-960 high-throughput automated sample preparation system, a flexible and fully automated workstation capable of processing 96 samples per run. MGISP-960’s fully automatic operation design allows DNA extraction of 50,000 samples per year and library preparation of 25,000 samples per year. MGISP-Smart 8, the professional automated pipetting robot, equipped with an independent 8 pipetting channel can be used for the pooling, normalization and DNB making. Lastly, DNBSEQ-T7* ultra-high throughput sequencer and DNBSEQ-G400* versatile benchtop sequencer enables an efficient, productive, and streamlined sequencing experience.

“We are very focused on data quality, cost and time. After contrasting DNBSEQ™ technology by MGI with other sequencing technologies, we are convinced that MGI’s products have met high industry standards and provide a very good user experience,” commented Professor Lars Engstrand, Research Director of Center for Microbial Translational Research (CMTR) at Karolinska Institutet. “MGI’s platforms have enabled our team to upgrade our original microbiological research from 16SrRNA gene amplicon sequencing to shotgun metagenomic sequencing. I look forward to introducing more equipment and super-large projects as human microbiome emerges as a crucial diagnostic and treatment method in precision medicine.”

The next chapter in microbiomics

“Microbiomics will be part of precision medicine in the future, and data from the microbiome biobank that will result from MMHP will be leveraged for therapeutic R&D,” said Professor Stanislav Dusko Ehrlich of University College London, UK. “With 21 public and private institutions and 10+ countries currently involved in MMHP, we are actively looking for more research groups to take part in this landmark international microbiological research partnership and help generate the world’s biggest free-access human microbiome database.”

Since the inception of MMHP, MGI has played an important role in providing the program with state-of-the-art research platforms and technologies. Now entering its second phase towards sequencing and analyzing a final total of one million samples, the project welcomes further exchange and participation from relevant organizations to jointly promote research and applications of cutting-edge translational medicine in the field of microbiome. Those interested can fill the application form on www.mgi-tech.eu/mmhp.

About MGI

MGI Tech Co. Ltd. (MGI), headquartered in Shenzhen, is committed to building core tools and technology to lead life science through intelligent innovation. Based on its proprietary technology, MGI focuses on research & development, production and sales of sequencing instruments, reagents, and related products to support life science research, agriculture, precision medicine and healthcare. MGI is a leading producer of clinical high-throughput gene sequencers*, and its multi-omics platforms include genetic sequencing*, medical imaging, and laboratory automation. MGI’s mission is to develop and promote advanced life science tools for future healthcare. For more information, please visit the MGI website or connect with us on TwitterLinkedIn or YouTube.

*Unless otherwise informed, StandardMPS and CoolMPS sequencing reagents, and sequencers for use with such reagents are not available in Germany, Spain, UK, Sweden, Italy, Czech Republic, Switzerland and Hong Kong (CoolMPS is available in Hong Kong).

*For Research Use Only. Not for use in diagnostic procedures (except as specifically noted).

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Reconstructing ancient bacterial genomes can revive previously unknown molecules – offering a potential source for new antibiotics

Microorganisms – in particular bacteria – are skillful chemists that can produce an impressive diversity of chemical compounds known as natural products. These metabolites provide the microbes major evolutionary advantages, such as allowing them to interact with one another or their environment and helping defend against different threats. Because of the diverse functions bacterial natural products have, many have been used as medical treatments such as antibiotics and anti-cancer drugs.

The microbial species alive today represent only a tiny fraction of the vast diversity of microbes that have inhabited Earth over the past 3 billion years. Exploring this microbial past presents exciting opportunities to recover some of their lost chemistry.

Directly studying these metabolites in archaeological samples is virtually impossible because of their poor preservation over time. However, reconstructing them using the genetic blueprints of long-dead microbes could provide a path forward.

We are a team of anthropologists, archaeogeneticists and biochemists who study ancient microbes. By generating previously unknown chemical compounds from the reconstructed genomes of ancient bacteria, our newly published research provides a proof of concept for the potential use of fossil microbes as a source of new drugs.

The cellular machinery producing bacterial natural products is encoded in genes that are typically in close proximity to one another, forming what are called biosynthetic gene clusters. Such genes are difficult to detect and reconstruct from ancient DNA because very old genetic material breaks down over time, fragmenting into thousands or even millions of pieces. The end result is numerous tiny DNA fragments less than 50 nucleotides long all mixed together like a jumbled jigsaw puzzle.

We sequenced billions of such ancient DNA fragments, then improved a bioinformatic process called de novo assembly to digitally order the ancient DNA fragments in stretches of up to 100,000 nucleotides long – a 2,000-fold improvement. This process allowed us to identify not only what genes were present, but also their order in the genome and the ways they differ from bacterial genes known today – key information to uncovering their evolutionary history and function.

This method allowed us to take an unprecedented look at the genomes of microbes living up to 100,000 years ago, including species not known to exist today. Our findings push back the previously oldest reconstructed microbial genomes by more than 90,000 years.

In the microbial genomes we reconstructed from DNA extracted from ancient tooth tartar, we found a gene cluster that was shared by a high proportion of Neanderthals and anatomically modern humans living during the Middle and Upper Paleolithic that lasted from 300,000 to 12,000 years ago. This cluster bore the molecular hallmarks of very ancient DNA and belonged to the bacterial genus Chlorobium, a group of green sulfur bacteria capable of photosynthesis.

We inserted a synthetic version of this gene cluster into a “modern” bacterium called Pseudomona protegens so it could produce the chemical compounds encoded in the ancient genes. Using this method, we were able to isolate two previously unknown compounds we named paleofuran A and B and determine their chemical structure. Resynthesizing these molecules in the lab from scratch confirmed their structure and allowed us to produce larger quantities for further analysis.

By reconstructing these ancient compounds, our findings highlight how archaeological samples could serve as new sources of natural products.

Microbes are constantly evolving and adapting to their surrounding environment. Because the environments they inhabit today differ from those of their ancestors, microbes today likely produce different natural products than ancient microbes from tens of thousands of years ago.

As recently as 25,000 to 10,000 years ago, the Earth underwent a major climate shift as it transitioned from the colder and more volatile Pleistocene Epoch to the warmer and more temperate Holocene Epoch. Human lifestyles also dramatically changed over this transition as people began living outside of caves and increasingly experimented with food production. These changes brought them into contact with different microbes through agriculture, animal husbandry and their new built environments. Studying Pleistocene-era bacteria may yield insights into bacterial species and biosynthetic genes no longer associated with humans today, and perhaps even microbes that have gone extinct.

While the amount of data collected by scientists on biological organisms has exponentially increased over the past few decades, the number of new antibiotics has stagnated. This is particularly problematic when bacteria are able to evade existing antibiotic treatments faster than researchers can develop new ones.

By reconstructing microbial genomes from archaeological samples, scientists can tap into the hidden diversity of natural products that would have otherwise been lost over time, increasing the number of potential sources from which they can discover new drugs.

Our study has shown that it is possible to access natural products from the past. To tap into the vast diversity of chemical compounds encoded in ancient DNA, we now need to streamline our methodology to be less labor-intensive.

We are currently optimizing and automating our process to identify biosynthetic genes in ancient DNA more quickly and reliably. We are also implementing robotic liquid handling systems to complete the time-consuming pipetting and bacterial cultivation steps in our methods. Our goal is to scale up the process to be able to translate a vast amount of data on ancient microbes into the discovery of new therapeutic agents.

Although we can recreate ancient molecules, their biological and ecological roles are difficult to decipher. Since the bacteria that originally produced these compounds no longer exist, we cannot culture or genetically manipulate them. Further study will need to rely on similar bacteria that can be found today. Whether or not the functions of these compounds have remained the same in the modern relatives of ancient microbes remains to be tested. Although the original functions of these compounds for ancient microbes may be unknown, they still have the potential to be repurposed to treat modern diseases.

Ultimately, we aim to shed new light on microbial evolution and fight the current antibiotic crisis by providing a new time axis for antibiotic discovery.


Christina Warinner


Alexander Hübner


Pierre Stallforth

The Conversation

How the COVID pandemic has improved genomics

insights from industryDavide CacciharelliMolecular Biology and Genomics ProfessorUniversity of Naples

In this interview, Davide Cacchiarelli, Molecular Biology and Genomics Professor at the University of Naples talks to NewsMed about how the COVID pandemic has highlighted the vital role of genomic surveillance and improved genomics.

Please introduce yourself and what inspired your career in molecular biology and genomics?

My name is Davide Cacchiarelli, and I am a molecular biology and genomics professor at the University of Naples. I was inspired by the fact that genomics is classed as an effective tool to improve human health, dissect the molecular events happening in the cell and nucleus, and better understand how cells and organisms work.

Image Credit: ShutterStock/pinkeyes

In The Telethon Institute of Genetics and Medicine, you combine various disciplines with cell biology, molecular biology, and genomics. Why is having a multidisciplinary approach useful when making discoveries, particularly surrounding infectious diseases such as COVID?

The majority of the time, a single omic, measuring only gene expression by RNA sequencing, measuring only epigenetics, or measuring only phenotype, is insufficient to understand how a cell works.

The best solution is to combine all efforts to understand how these events happen, from the nucleus to the cell’s exterior. COVID, in particular, has been a case where acquiring one single omic or a single view of how the system works is ineffective in understanding how COVID behaviors occur in the population or clinically hospitalized patients.

We, therefore, try to combine the general information and patient outcome to get the best result regarding COVID infection.

Davide Cacciarelli at ICG17 – How the COVID pandemic has improved genomics

On what research areas are you and your team at TIGEM currently focusing?

Our group aims to answer various questions, from basic microbiology to developmental biology. Then we can re-engineer it for real regenerative medicine purposes. We also look at how we can effectively use genomics as a medical instrument that can be used to impact the healthcare of patients in our healthcare system.

You have recently co-authored a paper, “Improved SARS-CoV-2 sequencing surveillance allows the identification of new variants and signatures in infected patients.” Can you expand on that?

One of the significant issues in Italy regarding SARS-CoV-2 genome sequencing was the cost. Sequencing the COVID genome was also a tedious and elaborate procedure.

Image Credit: ShutterStock/Kateryna Kon

The main objective was first to make this approach economically affordable and create a proof of printing pulled by which this approach could become a cost-effective method for anyone and any country.

Our second approach, therefore, included integrating the genome information and the transcriptomic profiling of the patient airway epithelia. This helps us to understand how the genome evolves and allows us to track its evolution, in addition to seeing the response of the host respiratory epithelium. Finally, we implemented new ways to classify viral variants based on different characteristics using this approach.

What are the advantages of better identifying new cells, or two variants, for healthcare centers and patients?

The European Center for Disease Control has issued several requirements for next year focused on tracking respiratory viruses. One of these is tracking emerging variants as soon as possible, which we have done with COVID-19. We now know that new, specific variants can emerge in a short timeframe, so immediate tracking is crucial to help contain or at least delay the spreading of possible pathogenic variants.

MGI offers a variety of tools and technology surrounding genomics. Can you tell us more about some of the products used during your research and your experience with them?

At MGI, we have typically applied the COVID and whole genome solutions. We also have the freedom to test the stereo-seq they have in production this month. MGI can offer alternative solutions for various genome sequencing needs.

Image Credit: ShutterStock/peterschreiber.media

At present many sequencing genomic companies are coming up with different solutions. At MGI, we understand that the best genomic solution is the one that better fits your needs. With our experience, for example, with COVID, MGI had the right solution at the right moment.

How important is selecting the right sequencing technology for your research? When undertaking new research, what do you look for in a product/sequencer?

When the primary focus is not on identifying genes or mapping gene expression but on identifying or qualifying gene variants, there must be no issues in the sequencing, as the sequencing issue might be an error in the sequencing and misinterpreted data.

The error rate of MGI technology on DNB sequencing is extremely low, which offers significant benefits. Users can confidently rely on the data at the level of leaders in the field, which is what we look for when we start COVID genome sequencing.

You have often collaborated with other researchers throughout your research projects, especially concerning COVID. How vital have these collaborations been in accelerating your research?

Like many scientists who faced the COVID pandemic, I had much to learn. We used our knowledge in medical genetics and variant interpretation, and the crosstalk we had with virologists, MGI scientists, and genomic specialists was a step towards acquiring the best solution and the best effort to try to get those results as soon as possible, which is crucial for COVID sequencing.

Surprisingly, some scientists who had no interest in healthcare possessed knowledge valuable in tackling COVID issues. The circumstances and contingencies around the event forced them to think outside the box.

Do you believe that if we can understand SARS-CoV-2 better, we could better use this knowledge to prepare ourselves for future pandemics better? What advantages would this have for global health?

COVID did not give us any significant advantages for healthcare, but it may have for science. It highlighted how vital advanced genomics is to track diseases which influenced decisions at the governmental level.

Image Credit: ShutterStock/CKA

Today, several diseases require advanced genome sequencing, such as cancer diagnostics and medical genetics. Given that the issues with this problem affect a small population, you do not feel the urgency to improve specific knowledge or tests.

Therefore, the COVID pandemic has highlighted the vital role of genomic surveillance and improved genomics. Today, we have laboratories that, until two years ago, thought they could never afford to set up a genomic workflow; the pandemic forced them to enter the genomics field. Our mission as genomic scientists is to help them implement this solution in their lab because improving genomics in any lab is the best for healthcare in the future.

There is a saying, “omics for all.” As a scientist, what does that mean to you?

‘Omics for all’ has to be understood in two ways. It is critical to give everybody the chance to have access to omics. However, we need to remember that it is still a medical procedure. Thus, the omics flow offers everybody access to high-quality omics profiling of their genome, but under medical supervision.

Finally, what is the future for you in your research?

I will continue my basic research in my lab: studying how pluripotent cells and stem cells can be manipulated and organized for medical purposes. We also want to use the knowledge accumulated in the COVID pandemic to apply fast, cost-effective, and reliable genome sequencing to other types of screening.

Image Credit: ShutterStock/Anusorn Nakdee

With this in mind, we hope to screen for several hereditary cancers, for example, breast cancer inheritance. Therefore, we can effectively use the COVID strategies we set up for COVID sequencing as proof of principle to apply the sequencing to human and human disease-driving genes.

About MGI

MGI Tech Co., Ltd. (referred to as MGI) is committed to building core tools and technology to lead life science through intelligent innovation. MGI focuses on R&D, production, and sales of DNA sequencing instruments, reagents, and related products to support life science research, agriculture, precision medicine, and healthcare. MGI is a leading producer of clinical high-throughput gene sequencers, and its multi-omics platforms include genetic sequencing, mass spectrometry, medical imaging, and laboratory automation.

Founded in 2016, MGI has more than 1000 employees, nearly half of whom are R&D personnel. MGI operates in 39 countries and regions and has established multiple research and production bases around the world. Providing real-time, comprehensive, life-long solutions, its vision is to enable effective and affordable healthcare solutions for all.


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Denmark experienced a surge in invasive Strep A Infections during the 2022-2023 winter season

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During the 2022-2023 winter season Denmark experienced a surge in infections caused by group A streptococci (GAS), including the more dangerous, invasive types of infections (iGAS). Incidence of iGAS is highest among the elderly, but the largest relative increase from previous seasons was seen among children. The study is being presented to the European Congress of Clinical Microbiology & Infectious Diseases (ECCMID 2023, Copenhagen, 15-18 April), by Thor Bech Johannesen and Steen Hoffmann, Statens Serum Institut, Copenhagen, Denmark, and colleagues.

Following the implementation of lockdown measures to prevent spread of COVID-19 in March 2020, the number of invasive infections caused by GAS, including more dangerous invasive types (iGAS), decreased. However, during November 2022, an increasing number of these infections occurred in all regions of Denmark, with incidence rates reaching three times the pre-lockdown levels in January-March 2023. While there is no policy on mandatory reporting of GAS infection in Denmark, clinical microbiology laboratories nationwide submit isolates of iGAS to Statens Serum Institut (SSI) for further characterization on a voluntary basis.

Since 2018 approximately 90% of all iGAS cases in Denmark have been submitted to SSI for whole genome sequencing (WGS). For the period 2018 through March 2023, the authors extracted these WGS data and all records from the Danish Microbiology Database (MiBa) with culture-proven GAS and iGAS (invasive GAS being defined as GAS isolated from an anatomical region that should be sterile). Repeated specimens from the same patient of either GAS or iGAS within a 30-day-period were excluded. Potential date of death was collected from the Danish Civil Registration System.

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Incidence of GAS as well as iGAS decreased notably following the restrictions in March 2020. The incidence of both remained at low levels until October 2022 and then dramatically increased in December 2022, peaking between January and March 2023 (Figure 1). The incidence of iGAS was highest in the age groups 65-84 years (4.0/100,000) and 85+ years (5.2/100,000) (Figure 2). Fatalities from iGAS in absolute numbers have also increased, but the case fatality rates for all age groups were similar to previous seasons (approximately 15% overall, and 30% in those aged 85 years and older – rates in children are low and vary due to low absolute numbers).

The strains ST28 emm1 (also known as M1) and ST36 emm12, which have both been virtually absent since April 2020, accounted for 53% and 28%, respectively, of iGAS infections in 2023. A new subvariant of M1 emerged in 2022 and has become the dominant subvariant in 2023, accounting for 30% of all iGAS cases (Figure 3). In addition to a distinct core genome, this variant is characterised by its acquisition of a bacteriophage carrying the virulence factor SpeC, a known key exotoxin. From initial analyses, the novel M1 subvariant does not appear to be significantly more virulent than other M1 variants circulating in Denmark, however, M1 variants in general are more likely to cause invasive disease, and iGAS patients infected with M1 variants are more often in need of intensive care. No significant difference was found in mortality rates for individual variants.

The authors conclude: “Since December 2022, the incidence of iGAS-cases in Denmark has been unusually high, partly driven by the emergence of a new M1 subvariant, which has been responsible for 30% of iGAS cases in 2023. Although a large proportion of the variants currently circulating in Denmark have a high capacity for virulence, we estimate that the current surge is largely due to extensive community spread, possibly combined with a low level of immunity in the general population following two years of extraordinarily low incidence rates.

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Genomic study reveals Babesia duncani’s pathogenicity and virulence

‘Tis the season for hiking now that spring has arrived and temperatures are on the upswing. But with hikes come insect bites and on the increase in North America is babesiosis, a malaria-like disease spread especially between May and October by a tick.

Indeed, recent research suggests an increase in the incidence of diseases transmitted by ticks around the world, not just the United States and Canada, due likely to climate change and other environmental factors. Among the tick-borne pathogens, Babesia parasites, which infect and destroy red blood cells, are considered a serious threat to humans and animals. All cases of human babesiosis reported in the United States have been linked to either Babesia microti, B. duncani, or a B. divergens-like species.

Now a research team led by scientists at the University of California, Riverside, and Yale University reports the first high-quality nuclear genome sequence and assembly of the pathogen B. duncani. The team also determined the 3D genome structure of this pathogen that resembles Plasmodium falciparum, the malaria-causing parasite.

“Our data analysis revealed that the parasite has evolved new classes of multigene families, allowing the parasite to avoid the host immune response,” said Karine Le Roch, a professor of molecular, cell and systems biology at UC Riverside, who co-led the study with Choukri Ben Mamoun, a professor of medicine at Yale University.

According to Le Roch, who directs the UCR Center for Infectious Disease Vector Research, the study, published today in Nature Microbiology, not only identifies the molecular mechanism most likely leading to the parasite’s pathogenicity and virulence, but also provides leads for the development of more effective therapies.

By mining the genome and developing in vitro drug efficacy studies, we identified excellent inhibitors of the development of this parasite -; a pipeline of small molecules, such as pyrimethamine, that could be developed as effective therapies for treating and better managing human babesiosis. Far more scientific and medical attention has been paid to B. microti. The genome structure of B. duncani, a neglected species until now, will provide scientists with important insights into the biology, evolution, and drug susceptibility of the pathogen.”

Karine Le Roch, professor of molecular, cell and systems biology at UC Riverside

Human babesiosis caused by Babesia duncani is an emerging infectious disease in the U.S. and is often undetected because healthy individuals do not usually show symptoms. It has, however, been associated with high parasite burden, severe pathology, and death in multiple cases. Despite the highly virulent properties of B. duncani, little was known about its biology, evolution, and mechanism of virulence, and recommended treatments for human babesiosis against B. duncani are largely ineffective.

A strong immune system is required to fight the pathogen. A compromised immune system could lead to flu-like illness. The tick that spreads babesiosis is mostly found in wooded or grassy areas and is the same tick that transmits bacteria responsible for Lyme disease. As a result, around 20% of patients with babesiosis are co-infected with Lyme disease.

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B. duncani mostly infects deer, which serve as the reservoir host during the pathogen’s asexual development. The parasite’s sexual cycle occurs in the tick after the tick bites the infected deer. When this tick bites humans, infection begins. The full life cycle of Babesia parasites has not yet been determined. The tick that spreads babesiosis, called Dermacentor albipictus, lives longer than mosquitoes and could facilitate a long life cycle for B. duncani.

Even though scientists are discovering more Babesia species, diagnostics are mostly developed for B. microti. Le Roch is already working with Stefano Lonardi, a professor of computer science and engineering at UCR and co-first author of the study, on new Babesia strains that have evolved.

“The Babesia genomes are not very long,” said Lonardi, who assembled the B. duncani strain. “But they are challenging to assemble due to their highly repetitive content and can require years of research. Once the genome is assembled and annotated, it can provide valuable information, such as how the genes are organized, which genes are transcribed during infection, and how the pathogen avoids the host’s immune system.”

In older and immunocompromised people, if B. duncani is left unattended, babesiosis could worsen and lead to death. Once the pathogen enters the body and red blood cells start to get destroyed, fever, headache, and nausea can follow. People who get bitten by the ticks often don’t feel the bite, which complicates diagnosis. Skin manifestations of babesiosis are rare, Lonardi said, and difficult to separate from Lyme disease.

Le Roch and Lonardi urge people to be mindful of ticks when they go hiking.

“Check yourself for tick bites,” Le Roch said. “When you see your physician don’t forget to let them know you go hiking. Most physicians are aware of Lyme disease but not of babesiosis.”

Next the team plans to study how B. duncani survives in the tick and find novel vector control strategies to kill the parasite in the tick.

Le Roch, Mamoun, and Lonardi were joined in the study by colleagues at UCR, Yale School of Medicine, Université de Montpellier (France), Instituto de Salud Carlos III (Spain), Universidad Nacional Autónoma de México, and University of Pennsylvania. Pallavi Singh at Yale and Lonardi contributed equally to the study. The B. duncani genome, epigenome, and transcriptome were sequenced at UCR and Yale.

The study was supported by grants from the National Institutes of Health, Steven and Alexandra Cohen Foundation, Global Lyme Alliance, National Science Foundation, UCR, and Health Institute Carlos III.

Source:
Journal reference:

Singh, P., et al. (2023). Babesia duncani multi-omics identifies virulence factors and drug targets. Nature Microbiology. doi.org/10.1038/s41564-023-01360-8.

Pediatric invasive group A Streptococcal infections on the rise during respiratory virus outbreak

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In a recent study published in the journal Open Forum Infectious Diseases, researchers performed an interrupted time-series-type analysis to assess the incidence of invasive Group A streptococcal (iGAS) infections among children, with associated risk factors, molecular and clinical characteristics, before and after the coronavirus disease 2019 (COVID-19) pandemic.

tudy: Unexpected Increase in Invasive Group A Streptococcal Infections in Children Following Respiratory Viruses Outbreak in France: a 15-Year Time-Series Analysis. Image Credit: Prrrettty / Shutterstock.com Study: Unexpected Increase in Invasive Group A Streptococcal Infections in Children Following Respiratory Viruses Outbreak in France: a 15-Year Time-Series Analysis. Image Credit: Prrrettty / Shutterstock.com

Background

Infections by Streptococcus pyogenes, a type of iGAS, can result in diseases such as bacteriemia, osteoarticular or soft tissue infections, toxic shock syndrome (TSS), and pleural empyema. These infections have affected millions of individuals globally, especially young children, with many of these infections severe and resulting in adverse outcomes, including fatality.

Varicella zoster virus (VZV) co-infections and the use of non-steroidal-type of anti-inflammatory drugs (NSAIDs) elevate the risk of pediatric invasive GAS infections. Additionally, recent studies have reported an association between respiratory viral infections and iGAS.

A remarkably high incidence of iGAS infections, particularly among children, has been reported toward the end of 2022. However, the extent of these infections and their bacterial and clinical characteristics relative to the period before COVID-19 are not clear.

About the study

In the present non-randomized, monocentric, and retrospective study, researchers assess changes in the incidence of iGAS infections associated with the COVID-19 pandemic.

The study comprised pediatric individuals below 18 years of age who were hospitalized at the Robert Debré University tertiary care hospital in France due to iGAS infections between January 1, 2008, and December 31, 2022. Infections were detected using polymerase chain reaction (PCR) or culture among streptococcal-TSS (S-TSS) or necrotizing fasciitis patients, according to the United States working group for severe-type infections caused by Streptococci.

Clinical, biological, and demographic data were obtained from the participants. Molecular and microbiological data were obtained from the hospital’s microbiology laboratory.

The team performed Emm (M protein gene) genotyping, assessed the virulence gene profiles for GAS, and determined the rates of invasive GAS infections among every 1,000 hospital-admitted children based on pediatric hospitalizations. In addition, the counts of respiratory pathogenic organisms, which were detected using nasopharyngeal multiplexed PCR among children hospitalized due to acute respiratory symptoms between January 1, 2019, and December 30, 2022, were documented.  

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Respiratory infections included those caused by the respiratory syncytial virus (RSV), adenovirus, influenza virus, parainfluenza, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and metapneumovirus. The study periods included the pre-COVID-19-associated non-pharmaceutical intervention (NPI) period between January 2008 and March 2020, the NPI period between April 2020 and April 2021, and the NPI-relaxation period between May 2021 and December 2022. The team performed quasi-Poisson-type regression modeling and calculated the odds ratios (OR).

Results

In total, 135 pediatric iGAS infection-associated hospitalizations were reported among the study participants, with a mean age of three years. During the pre-NPI period, the quarterly rate of invasive GAS infections among every 1,000 hospitalizations was stable. However, the implementation of NPI during March 2020 significantly reduced the quarterly rate of iGAS infections among every 1,000 hospitalizations with an OR of 0.3.

Post-NPI relaxation, a notable rise in the quarterly rate of iGAS infections among every 1,000 hospitalizations, especially between October and December 2022, was observed (OR 6.8). The peak in iGAS infections between October and December 2022 was observed concomitantly with a rise in the circulation of respiratory viruses, especially influenza.

During the final three months, 60% tested positive for respiratory viruses through nasopharyngeal viral swab-PCR, rising to 100% for pleural cavity empyema. During the pre-NPI period, the main clinical presentations comprised osteoarticular infections (39%), TSS/bacteremia (33%), pleural cavity empyema (15%), and cutaneous infections (6%). A shift was observed in the prime clinical manifestations during the final study period, likely associated with an increased percentage of pleural cavity empyema from 15% to 33%.

The inflammatory syndrome intensity and adverse outcomes, which included pediatric intensive care unit (PICU) admissions and deaths, were comparable between the three study periods. Post-NPI relaxation, there was no association between iGAS infections and VZV infections.

M protein genotype distribution was comparable between the study periods. M protein genotyping and virulence genes profile indicated that no leading clones emerged during the rise in iGAS infections.

Conclusions

The study findings showed a remarkable rise in iGAS infections since October 2022, mainly involving pleural empyema, co-occurring with a respiratory virus outbreak. Therefore, physicians must be aware of the elevated risk of pediatric iGAS infections, particularly in settings with an intense circulation of respiratory viruses.

The rise in iGAS infections was associated with various M protein gene types, with identical distribution as that in the pre-COVID-19 period. There were no iGAS cases related to preceding or coinciding Varicella zoster virus infections in 2022; however, there is likely an association between iGAS and the rate of iGAS infections and respiratory pathogens, especially the influenza virus.

Further research, including randomized controlled trials, must be conducted, evaluating pediatric susceptibility to iGAS and whole-genome sequencing (WGS) of iGAS strains.

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Journal reference:
  • Lassoued, Y., Assad, Z., Ouldali, N., et al. (2023). Unexpected Increase in Invasive Group A Streptococcal Infections in Children Following Respiratory Viruses Outbreak in France: a 15-Year Time-Series Analysis. Open Forum Infectious Diseases. doi:10.1093/ofid/ofad188