Unraveling the Zika Virus Mystery: Lessons Learned from Another Flavivirus

Feb 8, 2016 | Lauren Marsh, Sumiko Mekaru, Maia Majumder, Chris Mantell | Outbreak News

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.

Supplementary Material: Zika virus vs. Bovine viral diarrhea virus, at a glance 

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References

[1]  International Committee on Taxonomy of Viruses. Virus Taxonomy: 2014 Release. EC 46. Montreal, Canada Email ratification 2015 (MSL#29). [Online] Copyright 2016. [Cited: Feb 02, 2016.] Retrieved from http://ictvonline.org/virusTaxonomy.asp

[2] International Committee on Taxonomy of Viruses. Virus Taxonomy: 2014 Release. EC 46. Montreal, Canada Email ratification 2015 (MSL#29). [Online] Copyright 2016. [Cited: Feb 02, 2016.] Retrieved from http://ictvonline.org/virusTaxonomy.asp

[3] International Committee on Taxonomy of Viruses. Copyright 2016.
Virus Taxonomy: 2014 Release.  EC 46. Montreal, Canada Email ratification 2015 (MSL#29).
Retrieved from http://ictvonline.org/virusTaxonomy.asp

[4] Besnard M, Lastère S, Teissier A, Cao-Lormeau VM, Musso D. Evidence of perinatal transmission of Zika virus, French Polynesia, December 2013 and February 2014 . Euro Surveill. 2014;19(13):pii=20751. Article DOI: http://dx.doi.org/10.2807/1560-7917.ES2014.19.13.20751  Accessed Feb 6 2016. http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20751

[5] Maclachlan, N. James;Dubovi, Edward J. 2010., Fenner's Veterinary Virology. [online]. Academic Press. Available from:<http://www.myilibrary.com?ID=295474> 4 February 2016  Chapter 30: Flaviviridae. p 475. 
DOI: 10.1016/B978-0-12-375158-4.00030-4

[6] Agerholm JS, Hewicker-Trautwein M, Peperkamp K, Windsor PA. Virus-induced congenital malformations in cattle. Acta Veterinaria Scandinavica. 2015;57(1):54. doi:10.1186/s13028-015-0145-8.

Hewicker-Trautwein M, Liess B, Trautwein G. Brain lesions in calves following transplacental infection with bovine-virus diarrhea virus. J Vet Med B. 1995;42:65–77. doi: 10.1111/j.1439-0450.1995.tb00684.x.

Badman RT, Mitchell G, Jones RT, Westbury HA. Association of bovine viral diarrhea virus infection to hydranencephaly and other central nervous system lesions in perinatal calves. Aust Vet J. 1981;57:306–307. doi: 10.1111/j.1751-0813.1981.tb05831.x

[7] Ernst Peterhans, Matthias Schweizer, BVDV: A pestivirus inducing tolerance of the innate immune response, Biologicals, Volume 41, Issue 1, January 2013, Pages 39-51, ISSN 1045-1056, http://dx.doi.org/10.1016/j.biologicals.2012.07.006.

[8] Maclachlan, N. James;Dubovi, Edward J. 2010., Fenner's Veterinary Virology. [online]. Academic Press. Available from:<http://www.myilibrary.com?ID=295474> 4 February 2016  Chapter 30: Flaviviridae. p 475. DOI: 10.1016/B978-0-12-375158-4.00030-4

Info Sheet: Bovine Viral Diarrhea Virus. United States Department of Agriculture- Veterinary Services- Centers for Epidemiology and Animal Health.  Fort Collins, CO. December 2007.

Maclachlan, N. James;Dubovi, Edward J. 2010., Fenner's Veterinary Virology. [online]. Academic Press. Available from:<http://www.myilibrary.com?ID=295474> 4 February 2016  Chapter 30: Flaviviridae.  

DOI: 10.1016/B978-0-12-375158-4.00030-4

Merck Veterinary Manual [online] Copyright 2009-2015 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, N.J., U.S.A.   “Overview of Congenital and Inherited Anomalies” Last full review/revision October 2015 by Dana G. Allen, DVM, MSc, DACVIM; Andrew Dart, BVSc, PhD, DACVS, DECVS Accessed Feb 4,

M.R. McGowan, P.D. Kirkland, Early reproductive loss due to bovine pestivirus infection, British Veterinary Journal, Volume 151, Issue 3, May–June 1995, Pages 263-270, ISSN 0007-1935, http://dx.doi.org/10.1016/S0007-1935(95)80176-2016. 

Sasha R. Lanyon, Fraser I. Hill, Michael P. Reichel, Joe Brownlie, Bovine viral diarrhoea: Pathogenesis and diagnosis, The Veterinary Journal, Volume 199, Issue 2, February 2014, Pages 201-209, ISSN 1090-0233, http://dx.doi.org/10.1016/j.tvjl.2013.07.024.

Peterhans, Ernst, and Matthias Schweizer. Pestiviruses: How to Outmaneuver Your Hosts. http://dx.doi.org/10.1016/j.vetmic.2009.09.038

Ernst Peterhans, Matthias Schweizer, BVDV: A pestivirus inducing tolerance of the innate immune response, Biologicals, Volume 41, Issue 1, January 2013, Pages 39-51, ISSN 1045-1056, http://dx.doi.org/10.1016/j.biologicals.2012.07.006.

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