In a new study published in the journal Cell, scientists have found that koala DNA is protected against attack by retroviruses by a special type of immune response, which distinguishes foreign DNA from the host genome and destroys it before it can proliferate. This finding could help us understand both how koalas survive these infections, and the mechanics of adaptive gene change.
Australian Koala with joey in Eucalyptus tree. Image Credit: Worldswildlifewonders / Shutterstock
It is already known that all animals and human cells contain sequences of DNA that are shared by retroviruses, possibly reflecting infections that occurred long ago. A retrovirus is able to insert the genome into the infected cell’s DNA and thereafter the host cell operates on the basis of commands from the altered DNA. The incorporation of viral nucleic acid has kept the process of change alive in both humans and animals over the course of time, allowing new properties and characteristics to be acquired by the host. While evolutionists hitherto considered that these viral elements were regulated by natural selection pressures, the immune response within the koala’s germline cells show the existence of a unique pathway capable of blocking the retroviral invader.
If the germline cells – the cell line that gives rise to the reproductive cells (sperms and eggs) – are involved in this retroviral transcription, the viral DNA enters the germline and remains there permanently, which serves as a potential conduit for the persistence of the virus in generations to come. However, germline infiltration is rare because of an immune response that prevents the viral sequences from replicating or expressing themselves. Human beings share about 8% of their DNA with viruses.
Koalas teach us about germline immunity
Koalas are unique in that they show evidence of recent viral infection of their germline cells. A koala retrovirus A (KoRV-A) has been attacking koalas in Australia, spreading across the country from north to south. It passes from one animal to another, by horizontal transmission, and its presence indicates increased risk of chlamydial infection and cancer.
The most noteworthy feature of this virus, as far as the study of viral-host interactions is involved, is the way it is starting to make its way into the germline DNA as well. This is seen by the presence of the viral DNA in newborn koalas – which means the viral DNA had already managed to successfully incorporate into the genome inside the germline cells themselves. This is called vertical transmission.
The presence of this type of active infiltration is valuable for scientists who want to see what actually happens during the process of transition of a virus from being outside the host (exogenous) to an accepted part of the genome (endogenous). They also want to observe how the host cell resists this process, by using various immune processes. Normally, this is a rare event. As a result, says researcher William Theurkauf, “So basically, it’s never been directly studied, certainly not in a mammal. And that’s where the koala comes in.” The observation of this transition process in the koala is being treated as a once-in-a-lifetime opportunity to actually see how humans picked up certain permanent viral-like sequences in their DNA.
In most cases, the viral DNA which is embedded permanently into a host genome loses its infectious properties by repeated mutations over time. The detection of these mutations allows the sequences to be dated with a reasonable degree of accuracy. However, in some cases, these viral sequences remain functional and continue to make proteins. And in rare instances, the viral proteins are beneficial to the host. Some scientists hypothesize that the mammalian placenta is partly due to the influence of retroviral contributions to the human germline.
The study looks at samples from the testis, liver and brain from two koalas in the wild that had KoRV. It describes not a secondary immune response – adaptive immunity – that specifically targets some harmful genes after the viral sequence is inserted into the host cell genome, but a primary wide-ranging immune response that prevents this initial incorporation itself. This is called innate immunity and is hugely helpful in gaining time for the body to organize its defenses, identify the virus strain and recruit more powerful and specific immune forces. The secondary response is what occurs when pathogenic viruses infect the body, stimulating the production of specific antibodies against that particular strain of the virus. According to Theurkauf, “The genome basically has the same two-phase system.” Some viruses do beat this barrier and get their DNA into the host genome.
The current study identified some details of this initial immune response. It begins with a mechanism whereby the cell recognizes the foreign nature of the inserted KoRV-A, and tries to prevent the proliferation of the viruses by initiating an immune response rather than accepting it as one of its own genes. Theurkauf says, “We think we’ve stumbled on this innate recognition response.”
Splicing and innate immunity
The nature of this recognition pivots on the occurrence of a phenomenon called splicing in viral protein transcription. When mammals produce a gene product, the first step is to produce a piece of RNA bearing the exact nucleotide sequence as the gene within the DNA does – a process called transcription. However, this RNA contains some unnecessary bits from the perspective of protein encoding. These bits are cut out following transcription, and the remaining relevant parts are spliced together to make a sequence ready to be translated into a gene. This splicing process is absent in viral transcription – and this alerts the germline cell to the fact that this is a foreign sequence. The response is to block viral replication pathways.
Theurkauf says, “Just like the human body launches an immune response to invading viral and bacterial infections, our findings suggest that germline cells mount an attack to chop up the viral sequences.”
However, a few mammalian genes are also prone to remain unspliced, or use other splicing pathways. Thus other mechanisms must also be at work to explain the nature of the germline immunity to retroviral infiltration. This needs ongoing research to explain the full process.
Theurkauf, W.E. et al. (2019) The piRNA Response to Retroviral Invasion of the Koala Genome. Cell. doi.org/10.1016/j.cell.2019.09.002. https://www.cell.com/cell/fulltext/S0092-8674(19)31008-6