A catalog of tens of thousands of viruses from human metagenomes reveals hidden associations with chronic diseases, 2021, Tisza and Buck

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A catalog of tens of thousands of viruses from human metagenomes reveals hidden associations with chronic diseases

Michael J. Tisza and Christopher B. Buck

PNAS June 8, 2021 118 (23) e2023202118;

https://doi.org/10.1073/pnas.2023202118

 

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Despite remarkable strides in microbiome research, the viral component of the microbiome has generally presented a more challenging target than the bacteriome. This gap persists, even though many thousands of shotgun sequencing runs from human metagenomic samples exist in public databases, and all of them encompass large amounts of viral sequence data. The lack of a comprehensive database for human-associated viruses has historically stymied efforts to interrogate the impact of the virome on human health. This study probes thousands of datasets to uncover sequences from over 45,000 unique virus taxa, with historically high per-genome completeness. Large publicly available case-control studies are reanalyzed, and over 2,200 strong virus–disease associations are found.

 

[Hutan]

Interesting paper from a couple of researchers from the Laboratory of Cellular Oncology, National Cancer Institute, NIH, Bethesda.

I've copied the bits I found most interesting and understandable (which was not the methodology). It sounds like substantial advances are being made in techniques to find bits of virus genome, and to identify them against databases of known viruses.

Phages can materially change how bacteria interact with the human body

To this effect, prophages often encode genes that can dramatically alter the phenotype of the bacteria, such as toxins (17), virulence factors (18), antibiotic resistance genes (19), photosystem components (20), other auxiliary metabolic genes (21), and CRISPR-Cas systems (22), along with countless genes of unknown function.

There have been a few documented cases in which phages have been shown to be mechanistically involved in human health and disease, sometimes through direct interactions with human cells. This includes roles in increased bacterial virulence (17), response to cancer immunotherapy (23), clearance of bacterial infection (24), and resistance to antibiotics (25). Furthermore, phage therapy, the targeted killing of specific bacteria using live phage particles, has shown increasing promise for treatment of antibiotic-resistant bacterial infections (26). Considering the progress already made, phages represent attractive targets of and tools for microbiome restructuring in the interest of improving health outcomes.

Techniques are still developing. The technique used really affects what is found, often more than what disease the human host has.

Virus enrichment methods can be highly variable, however (Fig. 1C), and can inadvertently remove some viral taxa while failing to significantly select against host sequences (10, 32). Indeed, Gregory et al. (13) report that studies employing different virus enrichment protocols to investigate the same disease state (e.g., inflammatory bowel disease) rarely contain the same virus populations in their data. Instead, studies using similar enrichment protocols (regardless of disease state of patients) shared more virus populations. Furthermore, sequences encapsidated within virions may not be the best reflection of the total viral population, especially in human digestive tracts, where many phages are believed to exist primarily in lysogenic (nonlytic) states (73), and some have been “grounded,” losing their ability to independently excise from the host genome (74). It is possible that the most important phages for human physiology are those that express accessory genes from an integrated provirus state, as opposed to phages that are producing abundant virions. It is thus ideal to examine total DNA (also known as WGS) sequencing, which can detect all DNA virus genomes.

You need a large sample (150 patients) and/or time series data to control for noise

A limitation of the case-control studies analyzed here is that they only consisted of a single timepoint for each subject. Virome composition can be noisy, and longitudinal data on individual patients might be more effective for discerning stable viral populations (11). This problem may have been partly offset by use of large cohort sizes (mostly over 150 total patients).

They see the potential applications of investigation of the virome to chronic human disease. Me too, it would be great to have studies of ME/CFS viromes.

the current study shows that, using random Forest Classifiers, the virome may well be more diagnostic than the bacteriome for a variety of chronic diseases. The strong associations of specific virus OTUs in chronic diseases, along with medium-to-large–effect sizes for many OTUs, cries out for more mechanistic investigation of possible causal roles for viruses in chronic human disease.

There's so much more to be known.

Even with the relatively inclusive criteria used by Cenote-Taker 2 (discernable amino acid similarity of a viral hallmark gene to a protein the RefSeq virus database), thousands of viruses that live on humans from this dataset could not be taxonomically classified, suggesting that additional families of as-yet-unidentified viruses await formal discovery and categorization.

edited to remove my spellchecker's preference for the virile rather than the virome

 

[InfiniteRubix]

Thanks for the great success and dice