Viruses Inside Us: Viral Contributions to Life

The influence of viruses on our daily lives is hard to ignore. In addition to the inherent potential of some viruses to cause disease, others (through genome mutation and manipulation of host physiology) may inadvertently mobilize genes that can be useful to the host, and may even provide new traits for an organism. To fully understand how viruses have shaped us, we must not only study modern microorganisms, but also explore the viral fossil record inside our own genomes.

Gene Acquisition from Viruses

Paleovirology Illuminates Viral Integration Events

Viruses are major contributors to genetic changes, especially when they integrate into a cell’s genome. The field of “paleovirology” explores genomic traces of historic viral integration events in modern animals.

For example, viruses are thought to have provided the genetic underpinnings for placental mammals through multiple insertion events. In mammals, including humans, the gene syncytin enables the embryo to fuse to the placenta. It is thought to be derived from the virus HERV-W, which utilizes a related gene to fuse its envelope to the host cell. It is possible to infer how long ago the infection occurred by comparing the sequence of modern viral genes to endogenous viral elements (EVEs) and determining whether there are any premature stop codons. These would indicate that DNA has had time to accumulate mutations, and whether the gene may still be active.

Host genomes often contain abundant and diverse EVEs. It is predicted that human endogenous retroviruses contributed 9% of the genome, an additional 30% works in coordination with the retroviral elements, and an additional 50% has unknown function. In one studied isopod species, 5 viral families were represented as EVEs, and out of 54 identified sites, 30 looked to be from recent acquisitions, or current circulating infection. The others were determined to likely be older because they contained nonsense mutations.

With genomic methods, it can be difficult to discern modern, active infections from recent integration events because there hasn’t been time for mutations to accumulate to show divergence, which, in turn, makes it difficult to gauge time. Additionally, a genome alone doesn’t show what is happening inside a cell. It is, however, still valuable to inventory the EVEs present in a genome as a way to begin understanding viral contributions to a species.

Horizontal Gene Transfer Contributes to Antimicrobial Resistance

Horizontal gene transfer broadens a cell’s genetic toolkit. In the microbial world, viruses participate in some horizontal gene transfer events and are now considered a major reservoir of antibiotic resistant genes (ARGs). Environmental niches that harbor ARG-containing viruses include waste water, organically fertilized soil and hospital settings. Although the majority of ARG transfer occurs through cell-mediated methods, a small, but important, portion seems to be explained by viral transmission. Viral transmission of new genetic elements occurs through errors in genome packaging. When the virus accidentally packages host DNA into the viral capsid, followed by the subsequent lysogenic infection of a new cell, DNA from the previous host can be transferred. If this DNA includes a complete gene, such as an antibiotic resistance gene, the new host can gain this function.

Lysogenic viral replication cycle. Phage DNA integrates into the host genome. Then, after environmental stimulus, reactivates and replicates like a lytic infection.
Lysogenic viral replication cycle. Phage DNA integrates into the host genome then, after environmental stimulus, reactivates and replicates like a lytic infection.

Source: Elise Phillips – created in Biorender

Virus capsids act as a casing for the DNA, which helps maintain ARGs in the environment allowing them to spread through microbial populations more effectively than naked DNA. This problem is exacerbated by the high antibiotic load and dense host populations that characterize industrial farming, which can be seen by the relatively large proportion of ARG containing free-viruses isolated from swine sewage metagenomes. Future antibiotic stewardship plans will benefit from including ways to reduce the viral reservoir of antibiotic-resistant genes.

Viral Contribution to the Nucleus

Manipulation of Host Physiology-DNA Polymerase and mRNA Capping

Prokaryotes are often defined, at least colloquially, by the absence of a nucleus. While the internal organization of bacteria and archaea is becoming more resolved, the question of nuclear origin in eukaryotic cells remains unknown. One intriguing, if not controversial, hypothesis for nuclear origin is known as “viral eukaryogenesis.” This idea posits that the nucleus is derived from a viral infection of ancient, likely archaeal, cells.

Early lines of evidence for this idea come from similarities between eukaryotic nuclear traits and those induced by poxvirus. Poxvirus codes for DNA polymerase that is highly similar to eukaryotic DNA polymerase A and replicates within a membrane bound ‘mini-nucleus.’ A defining feature of the nucleus is the decoupling of transcription and translation, which occur concurrently in bacteria and archaea. Ancient cells with pre-nuclear structures would have required strategies to enable this decoupling. Poxvirus performs mRNA capping, the addition of modified guanosine to mRNA transcripts, which enables nuclear export and translation in eukaryotes, and is one solution to the necessary decoupling described above. Although these similarities don’t directly imply that eukaryotes developed from poxvirus infection, they do point to a common ancestor for these genes and suggest a viral contribution to the evolution of the nucleus.

Exploring New Bounds-Compartmentalization

Further evidence that supports viral contribution to the nucleus are the many viral infections that create new cellular compartments. Viral utilization and manipulation of host machinery for replication is a hallmark of active infection, in some cases causing significant remodeling of host cellular architecture (membranes and proteins) to generate new structures. Many modern eukaryotic and prokaryotic viruses create subcellular compartments for themselves to replicate within. For instance, Pseudomonas virus 201 produces a proteinaceous compartment to separate DNA replication and transcription from translation.

Meanwhile, Medusavirus, which infects the eukarotic amoeba, Acanthamoeba, takes over the host nucleus and utilizes its compartmentalization to separate replication from virion packaging. Compartmentalization has been alternately hypothesized as a mode of defending replication machinery from viral attack, and conversely, as a way to protect viral DNA from CRISPR machinery, which acts as bacterial immunity from viral infection. In light of the many possible strategies of viral eukaryogenesis, it seems likely that viruses had a hand to play in nuclear evolution.

Viruses have sculpted our cellular makeup from before the diversification of the 3 domains of life by providing cells with new genetic potential. While there are no actual fossils of the first nucleated cell, modern infections implicate the role of viruses in its evolution, and viral integration into host genomes has enabled organisms from all domains of life to gain new functions and actively shape the world around us.

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