Rubella Has a Family at Last

Some viruses, such as the human papillomaviruses (HPVs), have co-evolved with mankind throughout evolutionary history. These ancient human viruses often cause silent infections and may establish persistent infections that last for years to decades. Other viruses, often ones associated with common human acute diseases, entered the human population only within the last few millennia. Typically, these more recent viral invasions came from animal viruses that crossed species and jumped into humans. Infections caused by animal viruses are known as zoonotic diseases. SARS-CoV-2 is a zoonotic disease that likely originated in bats before becoming a human pathogen. Most zoonotic diseases don’t establish themselves permanently in human populations and eventually fade away like the original SARS virus that disappeared and never returned. In contrast, some zoonotic viruses do manage to become endemic infections that circulate continuously in humans and will likely never vanish from the human population. For example, HIV originated in chimpanzees but is now a permanent human pathogen, and similarly, SARS-CoV-2 seems likely to become established as a pervasive human virus.

Most human viruses have related animal viruses that are classified as different species within the same viral genus. These viral relatives share similar genomes, proteins, and properties with their human virus counterparts, somewhat like aunts, uncles, and cousins in an extended human family. By comparing the genome and protein sequences of the human viruses and their closely related animal viruses scientists can construct family trees (phylogenetic trees). The branches on these trees reflect the degree of genetic relatedness between viruses and can be used to predict the likely progenitors for the human viruses. Determining the animal origin of human viruses is important because it can offer insight into the mechanisms of pathogenesis, may identify animal models for experimentation, and can inform us about the potential future risk of crossover of the animal viruses into humans.

One common human virus whose origin remains elusive is the rubella virus (RuV), the causative agent of German measles (not to be confused with the more serious rubeola virus that causes measles). The rubella virus spreads via respiratory transmission and typically causes a mild childhood disease with a low fever and a distinctive rash that starts on the face and spreads downwards to the trunk and limbs. The illness usually runs its course in 3-4 days with patients making a complete recovery that confers life-long immunity. Unfortunately, the primary problem with this disease is not the infection of children or adults, but the infection of fetuses. If a susceptible pregnant woman contracts the virus it will cross the placenta and infect the fetus. Infections occurring in the first trimester can be devasting with a high rate of fetal death and with surviving fetuses usually afflicted with significant physical and/or intellectual birth defects, a condition called congenital rubella syndrome (CRS). It was this tragic effect on unborn children that spurred the development of the rubella vaccine (part of the MMR vaccine-measles, mumps, rubella) that has all but eliminated CRS in the United States.

Since its first description in 1814, RuV has been the only species in the genus Rubivirus. In the absence of any other Rubiviruses, RuV has remained an orphan virus whose ancestral heritage and animal relatives were unknown until recently. As reported in the journal Nature, two new members of the Rubivirus genus have been found, the ruhugu virus and the rustrella virus. The ruhugu virus was found in cyclops leaf-nosed bats in Uganda while the rustrella virus was isolated from the brains of three animals (a donkey, a capybara, and a wallaby) in a zoo in Germany. The three animals all died from an encephalitic infection indicating that this virus can have serious disease consequences in some mammals. Subsequently, the rustrella virus was found in numerous yellow-necked field mice in and around the zoo. The infected mice were all healthy suggesting that the virus had adapted to this species and that these mice were the reservoir from which the virus spread into other species of animals. Similarly, the ruhugu virus was isolated from 50% of the healthy bats tested making bats the likely reservoir for this virus in Africa. Analysis of the RNA genomes and proteins of both the ruhugu and rustrella viruses indicated that they were new species of the Rubivirus genus and were the first identified relatives of the rubella virus. The information is still too limited to make any firm conclusions, but two important points are suggested by these new findings. First, either mice or bats may be the original host animal species from which human rubella arose. Second, the ability of the rustrella virus to spread from mice into three different animal species indicates that this virus has impressive host range capabilities and could be a threat to humans. The discovery of these two new Rubiviruses will likely intensify efforts to find additional members of this genus so that we can better understand the origin of rubella and the potential risk of some unknown Rubivirus becoming a new human pathogen.

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