Unraveling the Zika Virus Mystery: Lessons Learned from Another Flavivirus

Viruses, of course, do not live independently outside of their hosts. Rather, they are uniquely bundled bits of data that use the body of their victim to replicate. We group viruses into families based on similar packaging and properties. Comparative virology examines the differences and similarities among viruses, and sometimes these comparisons can suggest answers for unknowns about a specific virus.

Today, growing concern about birth defects linked to Zika virus is a newsworthy medical mystery. Uncertainty about the risk of exposure has led to widespread warnings for pregnant women and those of child-bearing age.

While Zika’s varied manifestations – ranging from a complete lack of clinical disease to (potential) birth defects – are sensationalized in the media, an outbreak with this constellation of clinical signs is not unprecedented in the animal kingdom.

Zika is a member of the Flaviviridae family. This viral family includes a diverse array of pathogens affecting humans and animals, including hepatitis C, dengue, and many other diseases important to public health. Other members of this family might provide clues in cracking Zika’s pathogenesis.

The Flaviviridae family contains four genuses [1]. Flaviviridae flavivirus is the largest genus and is often insect-borne. Many dozens of species in the flavivirus genus have been identified, including some important zoonotic diseases. West Nile Virus, Japanese Encephalitis Virus, and Yellow Fever join Zika virus is in this genus [2]

The next largest genus of Flaviviridae is the Flaviviridae pestivirus. Pestiviruses are not classically spread by insect vectors, but rather via transfer of bodily fluids. The pestiviruses are a smaller group, with four species described [3]. Though these viruses have important differences from what we know about Zika virus, pestiviruses may still aid in conceptually understanding the behavior of Zika virus in pregnant women. As is suspected in Zika virus, one of the hallmarks of pestiviruses is vertical transmission, which means that the unborn fetus is affected if the mother is infected while pregnant [4].

Bovine viral diarrhea virus (BVDV) is an important pestivirus in the Flaviviridae family. BVDV’s complex effects have fueled scientific discovery since the disease was first recognized in the 1940s [5]. Its clinical signs range from transient infection, with no signs of clinical disease, to severe illness and death in affected livestock. Some of the most interesting effects of BVDV are seen in the reproductive and immune systems.

In the event of vertical transmission, BVDV can cause a variety of problems for the calf. The mother’s stage of pregnancy when exposed to BVDV dramatically impacts fetal outcomes, and the infection can cause pregnancy loss and birth defects.
               
How BVDV affects fetal development depends on the timing of maternal infection during pregnancy. The eyes and central nervous system are targets of the virus, and characteristic deformations of the brain and skull are observed. These deformities include hydranencephaly, hydrocephalus, and microencephaly [6].

BVDV is not transmissible to people but can infect a number of ruminants. Other species in the pestivirus family – siblings to bovine viral diarrhea – include border disease of sheep and classical swine fever in pigs. All of these pestiviruses can cause birth deformities.

Another fascinating aspect of pestiviruses is that they can affect host immunity during infection. BVDV is capable of becoming a “persistent infection” that is never fully cleared from the body. Persistent infection can happen in a number of ways. BVDV can manipulate the mechanisms that identify pathogens in the body. The virus is therefore camouflaged as “self” and avoids targeting by the immune system [7]. Calves may be born persistently infected if the virus reaches the unborn baby during early development, before the immune system has the maturity to respond. The lack of immune resistance in the fetus causes the newborn to be persistently infected with the disease. This condition – namely, immune tolerance to the disease – has lifelong implications for the calf. In the case of BVD, a variety of clinical outcomes can occur in persistently infected neonates, and this diversity is partly explained by existence of multiple genotypes and biotypes of the virus.

Persistently infected animals are important in the spread of BVD and have led to endemic status around the world. Testing can be challenging; animals lacking antibodies might still be infected with the virus.    Proven methods of infection from BVDV range from direct contact to sexual transmission, among others. Because animals show a range of clinical disease—from apparent health, immune suppression, co-infections, ulcerated mucous membranes, decreased lactation, gastro-intestinal disease, fevers, abortion, diarrhea, respiratory disease, to birth defects— BVD may go unidentified until widespread.

Like Zika, BVD was initially identified as a disease with nonspecific clinical signs – particularly, diarrhea [8] – but has since been shown to have a complex web of implications. Many brilliant scientists have contributed to the discovery of BVDV’s properties as a pathogen, largely because of its worldwide ubiquity and its economic impact on the livestock industry.

While Zika virus belongs to a different genus of Flaviviridae than BVDV and will undoubtedly attack its host in unique, undiscovered ways, its cousin in the pestivirus family offers an interesting parallel. Regardless of the pathophysiology of Zika virus that is ultimately discovered, Zika’s range of clinical signs will, like BVDV, certainly fuel investigation and publication for decades to come.