An Eventful April 2016 So Far for Zika Research

We know a lot more about the origins of the ongoing Zika virus outbreak, the nature of the virus strain and its link with brain disorders today than we did last month.

A mosquito. Credit: edans/Flickr, CC BY 2.0

Credit: edans/Flickr, CC BY 2.0

The Zika Research Projects List, a database of all the scientific studies being done on Zika virus worldwide, was launched last week by the Pan American Health Organisation (PAHO) and World Health Organisation (WHO). A quick scan of the resource reveals the pace at which research is progressing. And it’s not just the sheer number of studies – April 2016 has seen some significant advances in our understanding of the recent outbreak and its causal virus.

The first detailed report of the 2015 Rio de Janeiro outbreak, published on April 12, made a number of observations. Zika RNA was detected in 119 of 364 of the cases studied, removing any ambiguity about the diagnosis. The timing of infection also suggested that the infection did not originate in northeast Brazil as was thought. When the RNA sequence was analysed, it showed similarity to Zika strains from Asia. This is being seen as evidence for the hypothesis that Zika entered the country during the 2014 canoe championship in Rio via participating teams from Pacific Island nations, which had suffered Zika outbreaks shortly before.

The report also noted that only 38% of the patients with confirmed Zika remembered mosquito bites, despite the predominant assumption that Zika is primarily transferred via the Aedes aegypti mosquito (raising an interesting conflict, discussed below). The significant amount of clustering – households with multiple cases – may be an indicator of areas of high mosquito density, or that person-to-person transmission is more common than first imagined.

Another recommendation by the group is to consider including pruritus (itchiness) in the case definition of Zika infection. Fever, they found, was actually present only in about one-third of the patients.

Zika and the brain

Finally, it would appear that the much feared link between Zika and brain disorders like Guillain-Barré Syndrome and microcephaly in newborn babies is all but proven. Published on April 13, a review of research that has been ongoing until now used an existing criteria model to conclude that what we know now is enough to say that “a causal relationship exists between prenatal Zika virus infection and microcephaly and other serious brain anomalies”.

More direct evidence came from Brazilian researchers on April 10, who showed in the lab that Zika virus does indeed target human brain cells by affecting their ability to develop into more advanced forms like neurospheres and brain organoids. A few days later, another study discussed a possible mechanism by which viruses can affect foetal brains. A protein called PPARg seemed to play a role in the virus’s ability to infect neurons. Though they studied a different virus – the human cytomegalovirus (HCMV) – their results could have implications for Zika as well. One of the authors has informed The Wire that studies are ongoing in their lab with Zika virus as well.

Meanwhile, scans of affected babies’ brains shed some light on the extent of brain damage that Zika-associated microcephaly can cause. The majority of babies showed brain damage that was “extremely severe, indicating a poor prognosis for neurological function.” Common features included brain calcification and problems with motor control.

A small study presented the possibility that Zika might be linked to another brain disease, acute disseminated encephalomyelitis (ADEM). The sample study was tiny and the authors stress that much more study is needed to explore this.

Sequence analysis

A primary mode of understanding the more fundamental aspects of Zika virus and infection is via RNA sequence analysis. Significant strides were made this month in this aspect as well.

On April 8, a paper published the results of their study of Zika sequences, which confirmed that two distinct lineages of Zika viruses have been evolving in parallel – the African and the non-African (Asia, Pacific, American) lineages. The differences between the two groups were dramatic, and it was recommended that surveillance responses be designed to be more specific to the type of Zika causing the current outbreak.

Another group of scientists made a more comprehensive study. They traced the genetic evolution of the Zika virus by comparing sequences from 41 different strains of the virus – 30 from humans, 10 from mosquitoes and one from monkeys. This kind of study is what can tell us what made this latest outbreak so widespread and symptomatically unique from the previous outbreaks. All the recent samples from humans were found to be more similar to the Malaysian strain from 1966 than to the 1968 Nigerian strain, suggesting that strains in the recent human outbreak evolved from the Asian lineage.

There was also significant difference between the structures of a specific protein in Asian human and African mosquito strains. The evolution of such differences could be playing a role in the severe nature of the recent outbreaks. The researchers noted that no Zika virus had yet been isolated from a mosquito during the 2015-16 outbreak. “No known ZIKV mosquito isolate possesses the same nucleotide sequence as the human strains,” they say in their paper. In fact, among all the Asian Zika strains only one was isolated from a mosquito – but eight African Zika strains came from mosquitoes. This is surprising considering that the Aedes aegypti mosquito is being treated the primary carrier of Zika virus.

Surprising trends

Have we been too hasty in implicating the Aedes aegypti? Last month, a study showed that Aedes mosquitoes were surprisingly inefficient carriers of Zika virus. A news report in The Globe and Mail pointed out that the Culex mosquito is much more common there. This matters because precautions may vary accordingly. For example, Aedes feeds in the day while Culex feeds at night. Moreover, many resources are being pooled into targeting Aedes, so it’s important to clarify this soon.

Whether or not the culprit turns out to be Aedes, it is starting to look more likely that non-mosquito-mediated modes of transmission are more prevalent than acknowledged. Direct evidence of sexual transmission was published on April 15 when scientists detected a 100% genetic match between Zika samples from a couple, among whom only the man had visited Brazil recently. On the same day, the US’s Centers for Disease Control and Prevention (CDC) reported the first case of transmission between a gay couple; the case was recorded in January but it was only now that an investigation confirmed it.

Pregnant women, due to the changes in their body, are usually excluded from medical trials. On April 14 , it was announced that a research team had received funding from the Wellcome Trust to come up with a set of guidelines that can be followed to make sure that this group of women can benefit from medical opportunities, especially in the light of diseases like Zika where they are particularly vulnerable.

The Zika disease has spread to a couple of more nations since The Wire’s last update. The CDC puts the number of countries/territories actively transmitting the virus at 42 whereas Europe’s ECDC says that 49 countries/territories have locally transmitted in the past nine months. However, there has been no update since last month about Zika by the Indian Council of Medical Research.