Gigantic virus gives researchers a headache

Breaking new ground 7. okt 2019 3 min Professor, Head of Research Group Frank Møller Aarestrup Written by Kristian Sjøgren

Researchers have identified a giant virus that attacks a type of bacteria known to be associated with the development of diabetes and obesity.

A gigantic virus is giving researchers a headache – not because they are being infected with some exotic disease but because they cannot understand how some viruses get to be so large.

The cross-assembly phage (crAssphage) is a phage – a virus that infects bacteria – that is 10 times larger than HIV and is present in the intestines of half the world’s population. CrAssphage does not attack humans but attacks bacteria of the genus Bacteroides.

Bacteroides species are known to be involved in developing diabetes and obesity, so researchers are very clearly interested in understanding these gigantic viruses.

Now researchers have sequenced the entire genome of crAssphage.

“These viruses are so large that researchers are beginning to wonder whether they are viruses or whether they are something else. And then it is interesting that they have the potential to affect our health because they live by infecting bacteria, which are linked to many human diseases,” explains Frank Møller Aarestrup, Professor and Head, Research Group for Genomic Epidemiology, National Food Institute, Technical University of Denmark, Lyngby.

The new study has been published in Nature Microbiology.

Megaphages can be larger than some bacteria

Phages and megaphages are not normally considered to be living organisms. Instead, they are classified as large molecules with a genome in the form of RNA or DNA.

When phages infect bacteria, they can either assume the function of the bacteria or cause the bacteria’s cellular mechanisms to copy the phage's DNA and RNA until the bacteria rupture and new phages flow into the surroundings.

However, megaphages give researchers a headache. Although most phages are much smaller than the bacteria they infect, the Lak megaphage (with Frank Møller Aarestrup also participating in its recent discovery) is larger than the smallest bacteria and thus difficult to classify as anything other than a living organism.

More phages than bacteria

Bacteria of the Prevotella genus are thought to be the hosts of the Lak phage, and Bacteroides for crAssphage. The dominance of Bacteroides in the gut is generally associated with negative health effects among humans, whereas Prevotella is linked to positive effects.

Prevotella helps people digest stubborn plant material and promotes health.

“For example, when we analyse the total DNA in a stool sample from a pig, up to 2% is from the Lak phage. This is a large amount of DNA and almost as much as the amount of Prevotella DNA. This is sort of like having almost as many lions as wildebeest on the savannah, which makes no sense. All this indicates that that we do not yet fully understand these megaphages. Maybe they have other hosts, or their biology differs from what we think it is,” explains Frank Møller Aarestrup.

Phages have coevolved with primates for millions of years

The researchers collected stool samples from around the world and analysed the DNA in them. By studying the relationship between the concentrations of specific parts of the genome in the numerous samples, the researchers can pool the genetic materials into groups that comprise whole genomes.

The researchers used this method to identify the huge crAssphage genome and subsequently prove in the laboratory that it was really just one type of phage.

The researchers found the phage in more than half the samples they analysed. The sequences came from more than one third of the world’s countries and from all continents.

In addition, researchers have also found crAssphage-like sequences among primates, suggesting that the guts of humans and other primates have been home to these phages for millions of years.

The strong association with humans can be an inherent headache for researchers.

“CrAssphage appears to be more associated with people than with Bacteroides. CrAssphage has coevolved closely with humans, similarly to herpesvirus and to bacteria of the Helicobacter genus. However, the phage does not infect us, which makes the association unexplained. It is tempting to think that crAssphage does not infect Bacteroides but infects something else and is transmitted from mother to child, but many unanswered questions remain, and we do not yet understand this,” says Frank Møller Aarestrup.

Using phages to cure diseases and maintain a healthy gut

The researchers have learned, however, that both the Lak phage and crAssphage are megaphages that strongly influence the composition of bacteria in the gut.

The composition of bacteria in the gut is directly linked to numerous diseases: autism, Alzheimer’s, obesity, diabetes and intestinal diseases such as Crohn’s disease and ulcerative colitis.

These huge phages are therefore potentially interesting pharmaceutically if medicine or genetic engineering can get them to behave differently to alter the composition of gut bacteria in one direction or another. This is called phage therapy.

For example, perhaps improving the ability of crAssphage to infect Bacteroides could reduce the bacterial risk of developing obesity or diabetes.

Perhaps crAssphage, Lak phage and other megaphages could create a balance in the composition of gut bacteria that would enable the whole gut environment to better counteract pathogenic bacteria such as Salmonella species.

“We are still in the early stages of this research, trying to discover and identify the megaphages. The next natural step is to study their function and what they do in the real world. For starters, we just need to simply determine whether they really infect the bacteria we think they infect and whether they might also infect other bacteria that may affect people’s health,” says Frank Møller Aarestrup.

“Global phylogeography and ancient evolution of the widespread human gut virus crAssphage” has been published in Nature Microbiology. In 2016, the Novo Nordisk Foundation awarded a Challenge Programme grant of DKK 60 million to Frank Møller Aarestrup for the project Global Surveillance of Antimicrobial Resistance.

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