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

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 may be useful to the host and may even provide new traits to an organism. To fully understand how viruses shaped us, we must not only study modern microorganisms, but also explore the viral fossil record inside our own genomes.

Acquisition of genes from viruses

Paleovirology sheds light on viral integration events

Viruses are major contributors to genetic changes, especially when they integrate into a cell’s genome. The domain of “paleovirologyexplores the genomic traces of historical viral integration events in modern animals.

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

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

With genomic methods, it can be difficult to discern modern, active infections from recent integration events, because mutations have not had time to accumulate to show divergence, which, in turn, makes difficult to measure time. Moreover, a genome alone does not show what is going on inside a cell. It is however always useful to inventory the EVEs present in a genome to begin to understand the viral contributions to a species.

Horizontal gene transfer contributes to antimicrobial resistance

Horizontal gene transfer expands a cell’s genetic toolbox. In the microbial world, viruses participate in certain horizontal gene transfer events and are now considered a major reservoir of antibiotic resistance genes (ARGs). Environmental niches that harbor ARG-containing viruses include Waste, organically fertilized soil and hospital settings. Although the majority of ARG transfer occurs by cell-mediated methods, a small but important part appears to be explained by viral transmission. Viral transmission of new genetic elements occurs through errors in genome packaging. When the virus accidentally packs host DNA into the viral capsid, followed by 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 acquire this function.

Lysogenic viral replication cycle. The phage DNA integrates into the host genome and then, after environmental stimulation, reactivates and replicates like a lytic infection.

Source: Elise Phillips – created in Biorender

Viral capsids act as an envelope for DNA, which helps hold ARGs in the environment, allowing them to spread through microbial populations more efficiently than naked DNA. This problem is exacerbated by the high antibiotic load and density of host populations that characterize industrial agriculture, resulting in the relatively large proportion of ARG containing free viruses isolated from porcine sewer metagenomes. Future antibiotic stewardship plans will benefit from including ways to reduce the viral reservoir of antibiotic resistance 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 increasingly resolved, the question of nuclear origin in eukaryotic cells remains unknown. An intriguing, if not controversial, hypothesis of nuclear origin is known as “viral eukaryogenesis”. This idea postulates that the nucleus is derived from viral infection of ancient, probably archaeal, cells.

Early evidence for this idea comes from similarities between eukaryotic nuclear traits and those induced by poxviruses. Poxvirus codes for DNA polymerase which is very similar to eukaryotic DNA polymerase A and replicates in a membrane-bound “mini-nucleus”. A defining feature of the nucleus is the uncoupling of transcription and translation, which occurs simultaneously in bacteria and archaea. Ancient cells with prenuclear structures would have required strategies to allow this uncoupling. Poxvirus performs mRNA capping, the addition of modified guanosine to mRNA transcripts, which enables nuclear export and translation in eukaryotes, and is a solution to the necessary uncoupling described above. Although these similarities do not directly imply that eukaryotes evolved from poxvirus infection, they do indicate a common ancestor for these genes and suggest a viral contribution to nuclear evolution.

Exploring New Limits – Compartmentalisation

Other evidence that supports the 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 extensive remodeling of host cellular architecture (membranes and proteins) to generate new structures. Many modern eukaryotic and prokaryotic viruses create subcellular compartments to replicate within. For instance, Pseudomonas 201 virus produces a protein compartment to separate DNA replication and transcription of the translation.

Meanwhile, the Medusavirus, which infects the eucarotic amoeba, Acanthamoeba, takes over the host nucleus and uses its compartmentalization to separate replication from virion packaging. Compartmentalisation has alternatively been hypothesized as a mode of defense of the replication machinery against viral attack, and vice versa, as a means of protect viral DNA CRISPR machines, which act as bacterial immunity against viral infections. In light of the many possible strategies of viral eukaryogenesis, it seems likely that viruses played a role in nuclear evolution.

Viruses have sculpted our cellular constitution even before the diversification of the 3 domains of life by endowing cells with a new genetic potential. Although there are no true fossils of the first nucleated cell, modern infections implicate the role of viruses in its evolution, and viral integration into host genomes has allowed organisms from all domains of life to acquire new functions and to actively shape the world around us.

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