Microbes that “eat together” can benefit from co-immunology

Viruses are the most abundant and diverse biological entities on Earth, living in every type of habitat. In the oceans alone, viruses are ten times more numerous than microbes.

Viruses replicate by infecting living organisms, from humans and animals to insects, and even microbes. While environmental viruses infecting microbes are not a new finding, their prevalence was, however, not known before. Researchers are only now beginning to understand the diversity of viruses and their impact and function in ecosystems.

A new study published in Natural Microbiology studied viruses that infect microbes in the deep sea and found evidence that viruses interact with a much more diverse host pool than previously thought. The findings of this study may aid in a better understanding of viruses and engineered viral therapies.

PhD candidate lead author Yunha Hwang and senior author Professor Peter Girguis, both in the Department of Organisms and Evolutionary Biology, collected samples from microbial mats of deep-sea hydrothermal vents during a 2021 expedition in Mexico’s Guaymas Basin. This microbial mat consists of a large number of bacteria and archaea, the microbes that dominate this ecosystem. Both are microbes, but bacteria and archaea are very different taxa; differ from one another in the same way that bacteria are from humans.

Although worlds apart, many archaea and bacteria survive through symbiotic relationships. In the hydrothermal vents, bacteria and archaea formed masses that could harness energy from the methane found in these environments. While this relationship is necessary for survival, it doesn’t change the fact that the two lineages are biologically very different. What made it even more surprising for Hwang and Girguis to find that bacteria and archaea carry immunity to the same viruses.

“We were confused when we saw the results,” said Hwang, “because whether it is symbiosis or not, the infection engine is thought to be very complicated and host-specific. If archaea and bacteria are so different, how can one virus infect both?” That question led researchers to think about the different ways in which viruses might interact with microbes that go beyond infection.

Most of the work on viruses is done in a laboratory with one culture and one virus. Studies have only recently begun to expand into the natural environment, which requires the use of different tools because microbes are not easy to culture in the laboratory.

“About ninety-nine percent or more of the microbes that we know exist in nature that we can’t culture in the lab,” Hwang says, “now we can sequence the DNA of microbes without culturing what’s in the ocean or on the ground. And with that, we can ask, ‘what viruses are there and how do they interact?’”

Prior to joining the Girguis lab, Hwang studied viruses in a desert environment and observed that the host-virus interactions in nature were much more nuanced than in a laboratory environment. Deep-sea vents – in contrast to desert lands – harbor huge microbial mats with billions of microbes involved in symbiotic relationships. In observing this unique environment, the researchers asked, if microbes lived in such high density, would any virus have a wider “host range”? In other words, are they capable of infecting a wide variety of microbes?

They sequenced the DNA from the samples and recovered the metagenome-assembled microbial and viral genomes. They used the CRISPR spacer (which encodes the microbial immunological memory) to infer which viruses in the sample were microbially resistant.

To confirm their findings, they used a newer technique called Hi-C sequencing (high throughput chromosome conformation capture). If viral DNA is found in cells, the Hi-C technique can sequence the cross-linked host and viral DNA. Finding statistically significant contacts between viral DNA and microbial DNA, the researchers were able to confirm their findings that viral DNA is present not only in one cell type, but also in phylogenetically distant cells.

“CRISPR spacer analysis and Hi-C data show a striking pattern in that viruses interact genomically with very distant microbial assemblages, especially those that are symbiotic with each other,” said Hwang, “this interaction generates a very interesting phenomenon in which symbiotic microbes carry memory. immunologically against the same virus, meaning there is an advantage in the cooperation of the existing symbiotic partners in their immunity. We’ve seen this in bacterial populations, but we haven’t seen it in distantly related species. This is quite a touching finding because it reveals how interconnected the natural environment is.”

“Yunha is very good at designing experiments that utilize vent microbial mats to better understand the role of viruses in habitats where microbial densities are very high,” says Girguis, “he is also very wise at looking for patterns in the genomes of archaea and bacteria. The CRISPR and Hi-C spacer data show us that bacteria interact, in some way, with the same viruses as archaea, which are truly wild.”

This study challenges the conventional wisdom that viruses interact with a narrow host pool. And while researchers are still gathering direct evidence of a single type of virus infecting these two very different hosts, the data clearly show evidence that bacteria and archaea have immunity to the same viruses.

These results led Hwang and Girguis to propose a different virus-host interaction model with ecological and evolutionary implications that extend beyond infection. They suggest that interactions of viruses with microbes that are not the primary host of viruses may in fact be prevalent in nature, especially where the microbes exist in a symbiotic relationship.
It is very unlikely that the same virus could infect bacteria and archaea,” said Hwang. “Instead, we propose that one partner acquires and maintains immunity after a non-infectious encounter with a virus, and/or that immunity is transferred horizontally between symbiotic partners.”

The polyvalent nature of virus-host interactions in the natural environment, and the multiple modes of interaction beyond infection, present important considerations as researchers move to using viruses for biotechnological and medical applications, such as viral therapy in natural environments such as the gut.

“This host-virus interaction in the natural environment suggests that immunity can cross large phylogenetic distances so that populations build greater viral resistance together,” said Hwang.

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