Scientists unravel first neurotropic targets of Zika virus

Progress in understanding the obscure virus infection will open up avenues for treatment

A big outbreak of the mysterious disease mobilized the scientific community to double down on it’s biology. Image credits.

The dramatic global rise of Zika virus infections in 2016 emerged as a major public health risk because of its devastating effect on fetal neurodevelopment.

How did this happen? Originally a tropical disease, Zika was first discovered and isolated from rhesus monkeys in Uganda in 1947. Only 5 years later, the first cases of Zika infection in humans had been reported, albeit in very limited numbers. For the ensuing 5 decades, Zika remained an almost esoteric research field very few scientists would set their foot in. Between the ’60 and ’90s, the known geographical distribution expanded from Central Africa to equatorial Asia, including India and Pakistan. Similar to Africa, sporadic human infections occured but no outbreaks were detected. In general, symptoms of Zika are considered mild, including fever, rash and muscle pains. Before 2007, as little as 14 total cases of Zika infections had been reported.

The first large-scale outbreak of Zika happened in 2007, on the remote Pacific island of Yap, Micronesia. Only 5 years later, several major pacific islands had been plagued by Zika outbreaks, including French Polynesia and the Easter Islands, with thousands of suspected infections.

In March 2015, Zika has made it to the Americas, with Brazil reporting 7000 cases of fever and rash in their northeastern states. While gaining more and more recognition, only in 2016, the real toll of Zika infections became clear: The World Health Organization declares an association of Zika with neurodevelopmental defects in newborns, most prominently microcephaly. The outlook is grim: Zika is not going away anytime soon.

Nothing is more unsettling than opening up the webpage of the CDC and reading the following:

Treatment: There is no specific medicine or vaccine.

For most people in developed countries, this is unheard of. Usually, popular diseases have been under investigation for decades, with a plethora of treatment or prevention recommendations available. In the case of Zika, the best recommendations available from the Brazilian government was for women to not get pregnant. Furthermore, reports started coming in about Zika infections not only by mosquitos, but also potentially by sexual transmission or by blood transfusions.

Thus, Zika became a full-blown public health crisis and long-term challenge with scientists feverishly investigating the mechanisms of the disease.

Recently, only 2 years after Zika made it to the world stage, researchers from the University of Cambridge, UK spearheaded a study published in the journal Science that shed some light into the dubious mechanism of Zika virus pathology.

Starting with in silico analysis of the RNA genome of the Zika virus, Chavali et al., discovered in the 3' UTR (special region at the end of mRNAs) three distinct binding sides for a human RNA-binding protein called MSI1. The 3'UTR is an interesting region of every messenger RNA, as it contains regulatory sequences that determine the fate of the viral transcript.

Canonically, before any messenger RNA can be used, it has to be translated by the ribosome.

Imagine the Zika genome as an instruction manual, or a line of code, and the ribosome as the processor. A piece of code alone does not do anything, somebody has to “run” it first so it can perform its function.

In order to get the message to “run” by the ribosome, special proteins have to first bind to it (mostly to specific sequences in their UTRs) and orchestrate the delivery to the right position of the ribosome. These special, RNA-binding proteins can thus function as “ribosome gatekeepers”, to promote certain VIP transcripts while suppressing others. MSI1 is such a protein.

Chivali et al., discovered that the Zika virus uses fake VIP passes (in the form of MSI1 binding sequences) that allow it to hijack this gatekeeper protein and get a prime treatment towards the ribosome, forcing the ribosome to replicate more and more virus messages. Additionally, the authors could show that if one were to delete the VIP sequences from Zika’s 3'UTR, the gatekeeper protein MSI1 significantly reduce its interaction with the viral RNA.

Next, the researchers showed that when they remove the MSI1 gatekeeper from human cell lines which were infected with Zika, the virus had big troubles replicating.

Depletion of the human RNA-binding protein MSI1 impairs Zika virus replication.
So the Zika-MSI1 interaction is important for the virus to replicate, but could it also be involved in the neurodevelopmental symptoms reported by the WHO?

Zika infections cause microcephaly (MCPH), a condition where the cerebral cortex is considerable reduced in size. It has been known that depletion of MSI1 can cause microcephaly in zebrafish, because it controls the expression of MCPH1, a protein identified to be involved in the disease.

Furthermore, they authors identified a Turkish family, where two siblings suffering from microcephaly had a mutation in MSI1, arguing for the importance of this gatekeeper in controlling MCPH1.

Thus, the authors reasoned that maybe Zika causes microcephaly because it preferentially occupies all MSI1 protein, leaving MCPH1 out in the cold.

To run with our analogy: If the ribosome is a nightclub and MSI1 proteins are the bouncers, Zika virus faked VIP passes to get preferential treatment, while the genuine VIP protein MCPH1 gets blocked at the door with the excuse: “Sorry, too many VIPs today”.

Tough luck, because the more Zika viruses get replicated, the more fake VIP passes are in circulation, until finally MCPH1 cannot even visit the ribosome nightclub on a slow Monday night.

Lastly, when MSI1 ignores its canonical function of facilitating MCPH1, the cell is failing to produce enough MCPH1 protein, which results in long-term developmental defects, causing microcephaly.

MSI1 usually makes sure that MCPH1 gets translated by the ribosome. MSI1 mutations or Zika virus infection impair MCPH1 translation, causing microcephaly.

While there are still many questions unanswered, for example if and what other factors contribute to microcephaly beyond MCPH1, or whether MSI1 is the major contributor regulating MCPH1, Chavali et al., provided an important framework for understanding the molecular mechanism of Zika. Their findings could even have further implications beyond Zika, as the authors have already discovered more MSI1 sequences in other flaviviruses.

The first step of devising a cure for a given disease is in understanding how it operates.

Nobody is more aware that the road ahead is still a long and rocky path than the authors themselves:

Although our study provides new insight into the potential pathogenic mechanisms of ZIKV, further work will be required to determine if the modification or interference of the MSI1-ZIKV interaction results in neuronal attenuation of ZIKV. -Chavali et al., Science, 2017

In any case, we are lucky and thankful that dedicated people are working day and night to tackle this emergent public health risk. After all, this is science at its best. Working towards a brighter, healthier future for our children.



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