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��«����Ƶ scientists review the evidence for the bacterial origin of eukaryotic immune pathways

Scientists generally agree that eukaryotes, the domain of life whose cells contain nuclei and that includes almost all multicellular organisms, originated from a process involving the symbiotic union of two prokaryotes: an archaeon and a bacterium. It is unsurprising, then, that prokaryotes (single-celled organisms lacking nuclei and organelles) share many basic features—such as DNA genomes, cell membranes and cytoplasm—with eukaryotes; they developed these traits first and passed them down.

However, if the situation is this (relatively) simple, then the different kingdoms of eukaryotic life—animals, plants and fungi—should all have some variation of the same essential traits.

 

CU ��«����Ƶ researchers Hannah Ledvina (left) and Aaron Whiteley reviewed research that suggested a phenomenon known as horizontal gene transfer in eukaryotes.

By reviewing the research on this subject, two ��«����Ƶ scientists have demonstrated that this is not the case with respect to elements of the innate immune system that come from bacteria. Rather, some of the eukaryotic kingdoms have these elements while others do not. This is suggestive of a more obscure phenomenon known as horizontal gene transfer.

As authors of a , Aaron Whiteley, the principal investigator of the Aaron Whiteley Lab and an assistant professor of biochemistry, and postdoctoral fellow Hannah Ledvina were not involved in most of the research used to draw this conclusion, and were not the first to come to it, but write to summarize the state of the field and provide clarity by aggregating sources.

Categories of immune system

There are two categories of immune systems: innate and adaptive. Both exist within an individual because they serve distinct purposes. The adaptive immune system is more effective at eliminating viruses than the innate immune system, Whiteley says, but the innate immune system also plays an important role.

“We all know that you start feeling sick maybe one or two days after you were exposed to most viruses,” he says. “In the beginning, part of the reason you feel sick is because your first line of defense, the innate immune system, is trying to buy as much time as possible for the adaptive immune system.”

It is hard to successfully fight a virus without the antibodies and other virus-specific cells created by the adaptive immune system, Whiteley explains, but the generalized response of the innate immune system is necessary to slow the progression of disease during the time it takes for the adaptive immune system to respond.

By studying the innate immune system, scientists have found connections between the immune systems of bacteria and those of humans.

“We only started sequencing large numbers of genomes about 20 years ago,” Whiteley says, “and before we sequenced any genome, it was very hard to compare two organisms.” When some genomes became available, rudimentary comparisons were possible, “but as of maybe 10 years ago, our detection techniques for similarities of genes have skyrocketed,” and this has made comparisons like the ones in Whiteley and Ledvina’s review possible in combination with the sequencing of many more genomes.

Conserved immune pathways

“What we’ve been finding is the way that bacteria stop phages is very similar to the ways that humans fight off their pathogens,” Ledvina says. “The same proteins, as well as the same types of signaling pathways, are being used.”

Ledvina and Whiteley highlight four such types of signaling pathways of the innate immune system that are conserved between bacteria and either humans or humans and plants: cGAS-STING, NACHT and STAND NTPases, viperins and TIR.

A signaling pathway is a series of chemical reactions between a group of molecules in a cell that collectively control a cell function. The two basic elements of a signaling pathway are sensor and effector proteins: sensors detect the presence of a virus or phage and start the signaling cascade that ends with the activation of an effector, which is responsible for some form of immune response.

In the first type of signaling pathway, bacteria use the same sensor and effector proteins, cGAS and STING, to respond to phages as humans use to respond to DNA viruses (e.g., smallpox-like viruses).

In the second type of signaling pathway, Whiteley says, bacteria sometimes use the exact same protein domain, NACHT, as humans. NACHT is a subtype of STAND NTPase, a class of protein. In other cases, bacteria use different STAND NTPase subtypes, and plants use this protein class too.

A third type of signaling pathway found in eukaryotes and bacteria uses an effector protein called viperin. Similarly, in the fourth type of signaling pathway, the signaling domain TIR is used by plants, humans and bacteria.

Horizontal gene transfer

The relationships between the immune systems of humans and bacteria are especially interesting, Whiteley says, because these four pathways are likely to have been passed to eukaryotes by horizontal rather than vertical gene transfer.

Eukaryotes have many genetic similarities to bacteria, including in terms of the immune system. This, Whiteley explains, is because “things like the mitochondria, which is a really important organelle within all our cells, look like they came from a bacterium that started living inside the cell and then became a permanent resident.”

In other words, bacteria are ancestors of eukaryotes, and therefore many of the genes from bacteria were passed down to eukaryotes through vertical gene transfer, which is the transfer of genes from ancestors to progeny. However, shared genes can also be transferred horizontally.

 

Bacteria are ancestors of eukaryotes, and therefore many of the genes from bacteria were passed down to eukaryotes through vertical gene transfer, which is the transfer of genes from ancestors to progeny, explains CU ��«����Ƶ researcher Aaron Whiteley. (Illustration: Shutterstock) 

The exact mechanism for this type of transfer is unknown, Whiteley says, but the formation of mitochondria may provide a model: “You can imagine something similar, where a bacterium went into a cell, only rather than taking up residence, it broke open and released its genome. DNA is DNA, so it can be incorporated from exotic sources, albeit rarely.”

It is hard to be certain about this because of how long ago it would have happened, according to Whiteley. Eukaryotes lacking a given immune pathway may have used it at one point but then lost it through an evolutionary process like stabilizing selection, which removes traits that are no longer useful in order to free up resources (the classic example being fish or other animals that lose their eyes because they live in dark places like caves).

There is, however, significant evidence for horizontal gene transfer, Whiteley says. “If you find that a gene is in animals, but it's not in all the cousins of animals like plants or fungi,” as was the case with these immune pathways, “then the simplest explanation is that it was transferred in.”

This is all to say that these pathways evolved in bacteria after the creation of the first eukaryotes and were introduced to some of the eukaryotic kingdoms after the last eukaryotic common ancestor, which was about 2 billion years ago.

That kind of interaction is important because it’s how antibiotic resistance forms, Whiteley explains. “Bacteria in the hospital talk to other bacteria and they swap genes. We think about that all the time between bacteria, but we rarely think about it between different domains of life, like going from bacteria into, in this case, some ancestor of a human cell from a billion years ago, and that has real impacts.”

Immune evasion and drug development

According to Ledvina, there are at least four different ways for viruses to prevent immune systems from sensing and inhibiting them. These include preventing critical enzymes from functioning, destroying the products of such enzymes, blocking protein sensors by mimicking whatever activates them, and physically shielding the features that immune systems look for to identify viruses. This is true of both the viruses that make us sick and the viruses that infect bacteria.

One question that people always ask, Whiteley says, is “if our immune system is so great, why are we still getting sick? And it's because viruses find every way possible to maintain the upper hand.

“The wild thing is, I guess because the immune system of humans and bacteria looks so similar, the viruses of humans and bacteria have come up with shared strategies for that immune evasion. So, we can discover things in bacteria, but then go to human viruses and understand, are they also using this mimic strategy? And if so, that becomes a great antiviral strategy for drug development.”

Bacteria are particularly useful for testing, he explains, because they grow fast and because scientists have already developed genetic and biochemical tools with which to study them. These advantages and the similarities between bacterial and human immune systems mean that bacteria could inspire drugs to treat human viruses.

However, Whiteley says, “we know that the world of the immune system is so much bigger than viruses. Our immune system controls cancer, our immune system is important for wound healing and our immune system also restricts bacterial pathogens.”

This is what makes Hannah Ledvina’s research on ubiquitin-like proteins interesting. As demonstrated in , bacteria have ubiquitin pathways resembling those in eukaryotes, and ubiquitin is broadly important in humans according to , such that its failure is associated with the development of cancer, immune disorders, and neurodegenerative diseases, among other things. As that article points out, this means there may be new therapeutic opportunities within the ubiquitin system.

“I think with Hannah's work,” Whiteley says, “we've shown the sky's the limit in terms of understanding the ways bacteria defend themselves, and then hopefully informing the way that human cells defend themselves.”

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