Is SARS-CoV-2 infecting gut bacteria? An unusual finding

And paradigm shifting, if true

A surprising finding

We already know SARS-CoV-2 can infect a variety of animal cells, but recently, a series of studies came out that could be paradigm-shifting in the field of virology. These studies appeared to show SARS-CoV-2 growing in bacteria isolated from feces.

This is very surprising, because bacteria are very different from animals. Here’s a phylogeny tree to give you a sense of how different they are:

There are three main branches that represent all life on earth: the Bacteria, Archaea, and Eukarya (commonly called “eukaryotes”). Eukarya include animals, plants, and fungi, as well as lots of different unicellular organisms.

In the tree, the branch distances roughly correlate to relatedness; the farther apart two things are, the less related they are. As you can see from the tree, we (animals) are more related to trees, mushrooms, and slime molds, than we are to bacteria.

The first study

Here’s the first study: Increase of SARS-CoV-2 RNA load in faecal samples prompts for rethinking of SARS-CoV-2 biology and COVID-19 epidemiology

Here’s what they did:

They took SARS-CoV-2 positive fecal samples from people and separated the samples by size in order to separate the viruses from the cells. They took the lighter portion of the samples, which would include viruses but exclude cells, and used that to inoculate fecal samples that were SARS-CoV-2 negative.

When they did that, they noticed that the levels of SARS-CoV-2 RNA went up in those fecal samples. The figure below shows viral RNA load as a function of time, in fecal samples from three different people:

Figure from here.

They also found that when they added certain antibiotics to the samples it killed off the growth of viral RNA.

They also searched for pieces of SARS-CoV-2 proteins, and saw the levels of those go up with time, though curiously some of them contained mutations in them.

A follow-up study used isolated bacteria

But couldn’t it be that there were other organisms besides bacteria in the human fecal samples? After all, there are eukaryotic organisms that are part of the gut microbiome. Perhaps SARS-CoV-2 was infecting some of those?

That’s a possibility, but the same research group followed up with this study: Evidence of SARS-CoV-2 bacteriophage potential in human gut microbiota

They repeated some of the experiments from the first study, and also showed that they could grow SARS-CoV-2 in isolated bacteria; specifically Faecalibacterium prausnitzii and Dorea formicigeneransm, which are bacterial strains commonly found in human feces.

These strains of bacteria were purchased as pure strains. Of course, it’s possible that their bacterial cultures were contaminated with something else, but it’s fair to at least say that we have evidence of SARS-CoV-2 growing in these bacteria.

The study also took images using electron microscopy and observed virus-like structures interacting with the outside walls of bacterial cells.

The virus-like structures were not visible on bacteria from control samples.

The study also gave bacteria a source of nitrogen that used a heavy isotope of nitrogen, N¹⁵. After several days they observed spike protein which had incorporated the N¹⁵. Since viral particles are made from components synthesized from its hosts, this suggests that the source of the heavy nitrogen in the spike protein was the N¹⁵ that had been taken up by the bacteria.

More follow-ups

We’ve since had more follow-ups:

Could SARS-CoV-2 Have Bacteriophage Behavior or Induce the Activity of Other Bacteriophages?

Analysis of Bacteriophage Behavior of a Human RNA Virus, SARS-CoV-2, through the Integrated Approach of Immunofluorescence Microscopy, Proteomics and D-Amino Acid Quantification

These made observations that corroborated the first two studies.

Overlap in authors

It should be mentioned that these studies all share co-authors.

Both the first and second studies have Mauro Petrillo as the first author and Guy Van den Eede as the last author. All the studies have Carlo Brogna and Simone Cristoni as authors.

That’s not necessarily a bad thing, but it’s fair enough to remain somewhat agnostic about these findings until we have corroboration from independent research groups.

Interpreting the results

Our current understanding of how viruses work suggests that viruses infect cells by first binding to specific receptors on those cells. With SARS-CoV-2, we know that they can get into our cells by binding to ACE2 receptors.

Is it possible that some of the bacteria in our gut have receptors that are ACE-2 like?

The researchers report that a bioinformatics analysis revealed that some bacteria found in the human upper respiratory tract “express proteins that bind the SARS-CoV-2 spike glycoprotein.” These bacteria seem to have ACE2-like proteins.

Could there be bacteria in the gut that also express ACE2-like proteins?

At the very least, it appears that gut bacteria interact with SARS-CoV-2, even if SARS-CoV-2 doesn’t directly infect the bacteria.

One of the studies mentioned:

very recent studies have provided clear evidence that bacteriophages can interact with eukaryotic cells, causing effects on the functions of the immune system, respiratory system, central nervous system, gastrointestinal system, urinary tract, and reproductive system.

More on that can be found here.

Of course it’s also possible that SARS-CoV-2 is not interacting with gut bacteria, but other organisms in the gut; perhaps small eukaryotes. However, that would have to mean that when the researchers showed SARS-CoV-2 growing in gut bacterial cultures, those cultures were actually contaminated.

Why haven’t these studies gotten more attention?

Either way, these findings are interesting. It’s not just that to date, we don’t know of any viruses that can infect such unrelated hosts.

But these findings also have implications for how we treat SARS-CoV-2, as well as how we track infections. For example: can we interpret SARS-CoV-2 RNA in wastewater the same way, if these findings hold up?

It’s somewhat surprising there isn’t more interest in these studies. Perhaps it’s because they weren’t published in the “best” journals.

But that's very much in line with how things sometimes go in research; the “scientific community” is often slow to recognize novel work. The “best journals” sometimes don’t recognize groundbreaking research, even when it falls on their laps.¹

We can be agnostic about how to interpret these findings or how groundbreaking they actually are. But at the very least, the findings need to be explained. They should interest anybody who’s interested in viruses.

1. For more on that, read about how Kary Mullis submitted his work on PCR to both Nature and Science, two of the most “prestigious” scientific journals. They both rejected it. He would later win the Nobel Prize for that work. Or read about how Hans Krebs had submitted his work on the Krebs cycle to the journal Nature. They rejected him because the journal was too backlogged. Krebs would later win the Nobel Prize for his discovery, and the Krebs cycle can be found in every modern biochemistry textbook today.