The Zika genome and insights in the era of emerging outbreaks

The dengue virus and its equally infamous cousin, the Zika virus, together infect up to around 400 million people every year. The Zika virus and genomic studies of it have opened fascinating windows into our knowledge of the infectious disease and its relevance in the context of emerging outbreaks.

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The Zika virus is a mosquito-borne flavivirus. Most infections in humans are asymptomatic or with mild symptoms, including fever, rash, and joint pain. The Zika virus became notorious during the 2015-2018 outbreak that swept through the Americas. The outbreak was characterised by an alarming increase in the number of microcephaly cases in newborns, prompting the World Health Organisation to declare it a public health emergency of international concern in early 2016.

From Africa, the Zika virus has spread to Asia, Pacific islands, to the Americas, and beyond. The disease has of late been in the headlines with multiple outbreaks in the last few years in multiple Indian states, including, more recently, Kerala and Karnataka.

Researchers isolated the virus in 1947 from monkeys from the Zika forest in Uganda. The first human cases were detected in 1952 in Uganda and Tanzania. There have since been multiple outbreaks around the world, but largely confined to the tropics.

A significant number of insights have come from the Zika virus’s genome. Researchers sequenced the complete genome first in 2007. It has more than 10,000 bases of single-stranded RNA. The genome is also peculiar: it encodes for a large polyprotein, which is further cleaved into capsid, membrane precursor (prM), envelope, and seven non-structural proteins.

The diagnosis of a Zika virus infection is mostly through genetic testing. An antibody-based test would be complicated because antibodies produced by the infection can cross-react with those of the dengue (DENV), yellow fever, and West Nile viruses.

Epidemiology and surveillance

The Zika virus has an RNA genome, and thus a very high potential to accumulate mutations. The tools, techniques, and modalities we’ve developed to track the evolution, genetic epidemiology, and molecular underpinnings of transmission and pathogenesis could be extended to Zika virus outbreaks as well.

Genomic studies have suggested that the Zika virus has two lineages: African and Asian. (The lineage that wreaked havoc in the Americas is a sub-lineage with genomes similar to those of isolates from an outbreak in French Polynesia in 2013-2014.)

In a significant example of the usefulness of genetic surveillance plus sequencing, researchers in the U.S. used active surveillance of travellers to uncover a hidden outbreak in Cuba, and also established its time characteristics. The work was published in Cell in August 2019.

Zika and microcephaly

The small heads of children born to infected mothers has been one of the more alarming complications of a Zika virus infection.

Earlier, based on studies with mice, researchers had suggested that a mutation in one of the precursor membrane proteins, called prM, of the Zika virus was associated with microcephaly. Researchers also suspected that this mutation originated during the outbreak in French Polynesia in 2013 before breaking out in South America, causing microcephaly.

However, while the large outbreak in South America was caused by lineages of the virus with the specific mutation, only a subset of the relevant pregnancies resulted in microcephaly. Scientists have since been trying to understand the molecular mechanism that causes microcephaly only in some cases.

The Zika-microcephaly hypothesis also suffered when researchers recorded microcephaly in Thailand following infections of the Asian lineage of the Zika virus that lacked the mutation. Differences in the prevalence of microcephaly across geographical areas in Brazil also suggested that scientists’ picture is incomplete.

This said, a study published recently in Science Translational Medicine, and conducted with primates, suggested that the foetal Zika virus infections were associated with heavy viral loads during pregnancy, and the viral load strongly influenced foetal growth. In another recent study in the same journal, researchers again used primate models to suggest that preexisting antibodies against DENV could worsen the severity of congenital Zika.

Taken together, the findings underscore the importance of the viral load and DENV infections for the occurrence of microcephaly.

Making it attractive

Zika virus and DENV infections are interesting in their own right. In a beautiful demonstration of the interplay between organisms with significant public health consequences, researchers in Tsinghua University, suggested in a recent study in Cell that infections of two viruses in primates encourage specific microbes to grow on the skin by suppressing an antimicrobial peptide, RELMα, on the skin. These microbes produce acetophenones, which are volatile molecules that could provide a chemical cue to mosquitoes, attracting them towards the individual and supporting forward transmission of the viruses.

The researchers also reported that administering isotretinoin could upregulate RELMα and reverse this phenomenon.

Zika virus and DENV interactions have also been an interesting area of research. A significant body of evidence suggests that a Zika virus infection can significantly increase the risk for severe dengue. Researchers exposed a large cohort of people in Nicaragua to both Zika and DENV one after the other, and found that while high levels of anti-DENV antibodies were protective, intermediate levels due to a prior Zika or DENV infection could significantly enhance the severity of dengue infections. This observation is of great public health significance because Zika and dengue circulate around the planet, and could inform the design of Zika vaccines.

As climate change helps drive the spread of vector borne diseases, and global warming brings environmental conditions that favour them to new places, our genomic technologies and such deep insights into the molecular pathogenesis of these viruses will be an important guiding light.

The authors are senior consultants at the Vishwanath Cancer Care Foundation. All opinions expressed here are personal.

  • The dengue virus and its equally infamous cousin, the Zika virus, together infect up to around 400 million people every year. The Zika virus and genomic studies of it have opened fascinating windows into our knowledge of the infectious disease and its relevance in the context of emerging outbreaks.
  • The Zika virus is a mosquito-borne flavivirus. Most infections in humans are asymptomatic or with mild symptoms, including fever, rash, and joint pain. Genomic studies have suggested that the Zika virus has two lineages: African and Asian.
  • Zika virus and DENV interactions have also been an interesting area of research. A significant body of evidence suggests that a Zika virus infection can significantly increase the risk for severe dengue. 

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