Why You Might Have to Doubly Beware Zika if You've Already Had Dengue

With grave repercussions for India, a recent study suggests that the Zika virus can be even more infectious to people who have been exposed to dengue in their past.

With grave repercussions for India, a recent study suggests that the Zika virus can be even more infectious to people who have been exposed to dengue in their past. Due to their similarity, when Zika infects a person who has previously had dengue, the immune system recognises the Zika virus as the same dengue virus it encountered earlier. What results is a weak battle that instead of combating Zika works to the virus’s advantage, giving it a greater opportunity to infect.

At a time when Zika is on the rise globally, these findings bring out pressing concerns for India, where the dengue virus claims many lives each year. Since Zika’s outbreak in Brazil since December, authorities have reported a monumental 1.5 million cases already. In Singapore, cases have soared to an alarming 242 since last week and authorities expect the number to rise further. Zika may be spreading fast in Southeast Asia where, apart from Singapore, Malaysia has registered two cases – one infection in a woman returning from Singapore and one locally infected patient. Hong Kong has also registered one case of Zika infection. According to a new study in Lancet Infectious Diseases, published on September 1, 2016, India is among eight countries in Asia and Africa that are at great risk of Zika transmission because of weather conditions coupled with their high population densities.

The hot and humid tropical weather is perfect for the carrier of the disease, the Aedes aegypti mosquito. Along with Zika, this insect also spreads diseases like dengue, yellow fever and Chikungunya. Zika, which was first identified in 1947 in Uganda’s Zika forest, had until recently been considered to be quite harmless, rarely showing any symptoms in infected individuals. And in individuals where it did show symptoms, they included mild dengue-like fever, muscle and joint pain, conjunctivitis and rashes. During the outbreak in Brazil, however, a shocking link was discovered between the infection and a rare neurological disorder, the Guillain-Barré syndrome. The virus is also considered to be particularly dangerous for newborns after many pregnant women infected with Zika gave birth to babies with microcephaly, a developmental birth defect resulting in undersized heads and brains.

The dengue virus, belonging to the same flavivirus family as Zika, shows similar symptoms as Zika but with greater severity. Symptoms include fever, rashes, muscle and joint pain and conjunctivitis; however, neurological disorders have not been reported. Although similar, Zika symptoms are rarely fatal and last for only a few days whereas dengue fever can last for weeks, sometimes resulting in a dengue hemorrhagic fever known to be fatal.

There are four different subtypes, or serotypes, of dengue. Even though all of these subtypes result in a similar sort of infection, there are differences in the viral proteins among these serotypes. This results in the body treating every serotype differently.

Upon infection by a virus or any other foreign pathogen, special proteins called antibodies are produced by our defence system. The job of these antibodies is to stand guard by neutralising pathogenic proteins (antigens) and hence prevent the pathogen from causing havoc. The antibodies latch onto specific proteins – viral proteins in this case. Signals are then sent to the immune cells to destroy this antibody-antigen complex and neutralise the threat. The binding is so specific that a particular type of antibody can bind to only a particular type of viral protein, just like a key can only fit in one lock.

So upon infection with a specific dengue subtype, antibodies are produced to neutralise proteins of that specific subtype. These antibodies tightly bind to the proteins on the virus, so that they can be destroyed by the system and the infection be contained. Because proteins from one serotype of dengue are very similar to the other serotype (approximately 65-70% similarity), the antibodies against one serotype can bind to the other serotype but can not neutralise the virus. This is similar to having a key which somehow fits into a lock but doesn’t unlock it. Here comes the catch.

Because the binding isn’t strong enough, the virus isn’t completely incapacitated. Signals are still sent to the defence mechanism, which deploys fighter cells to engulf the pathogen and kill it. Finding itself surrounded by the fighter cells, the virus finds the perfect opportunity to infect those cells themselves and proliferate. So the very guardians protecting our body lose the battle against this different strain, worsening the situation and wreaking yet more havoc. In immunological terms, such a phenomenon is called antibody-dependent enhancement (ADE).

ADE can happen whenever antibodies to one specific protein cross-react with other similar proteins. A protein that sits on the outer cover of the Zika virus, called the Zika envelope protein, is about 55% similar to the dengue envelope protein. It is this similarity which Zika exploits to become even more infectious in the body. Dengue antibodies can now weakly bind to the Zika virus and lead to ADE, as was shown in a study led by scientists at Imperial College, London, and published in the journal Nature Immunology in June 2016. The study was conducted using blood collected from dengue-infected children in Thailand. The antibodies against dengue proteins which were present in their blood could bind to the Zika virus but not neutralise it.

Next, the scientists tested whether these antibodies could promote ADE in model cells of the myeloid lineage in the laboratory. These cell lines are generally not very prone to Zika infection. However, when the Zika virus was mixed with the plasma that contained antibodies from dengue patients, the virus was able to infect these cells with ease, clearly showing that the antibodies against dengue helped Zika invade more cells.

The widespread occurrence of dengue in Brazil could be assisting the explosive spread of the Zika virus through ADE. A study carried out in the 1950s in the Indian population showed the presence of antibodies against Zika in healthy individuals. Because Zika has never been reported in India, the presence of these antibodies could only be explained due to the population’s exposure to a similar virus, like the endemic dengue virus. Earlier, these reports might have led people to heave a sigh of relief at the passive immunity conferred by these antibodies. But with the recent findings that show that the antibodies might in fact worsen the infection, it is important to reconsider our strategies for monitoring and controlling the virus.

These strategies include controlling the mosquito, which lays eggs in stagnant water. WHO stresses that fogging with insecticide should be adopted only as an emergency measure, and more importance should be given to completely eliminating the breeding grounds of mosquitoes. These include stagnant water in tyres, buckets, waste storage containers and puddle water. With fogging, there is the chance that mosquitoes resistant to the pesticides will emerge over time, rendering all efforts futile.

Although authorities have been active in frequently fogging high risk areas, the urgent need to eradicate mosquito breeding sites by clearing garbage dumps and sewages has been ignored in India’s major cities. Moreover, disease monitoring should be done with special attention in areas prone to dengue, taking care that new Zika cases, if any, are distinguished and correctly diagnosed from similar dengue cases.

A cure for these contagious viral infections hasn’t yet been found. To make things worse, the similarity between Zika and dengue raises new complications as well. ADE now stands as a major obstacle ahead of ongoing vaccine development efforts. Getting vaccinated against a disease makes the body produce a small amount of antibodies against the infection in advance, ready to take on the infection before it strikes. A vaccine against dengue is tricky because antibodies against one subtype will actually enhance an infection by another.

The most advanced vaccine against dengue, Dengvaxia, has already raised safety issues after dengue was found to recur in previously vaccinated children. The Nature Immunology study suggests that dengue in these children could as well be a result of ADE, which means that there is now an added threat of a Zika infection.

These efforts will take time – but it seems unavoidable in the meantime that Zika spread across countries at an alarming rate. Despite the efforts of health officials, it could just be a matter of time before it comes to India. There is still a chance that some of the antibodies that the Indian population has against dengue will be able to neutralise Zika. In the wake of this epidemic and the neurological complications associated with it, a close watch on the health situation, especially across political borders, efforts to prevent Aedes aegypti from proliferating, careful monitoring and preparedness is of paramount importance to prevent matters from getting any worse.

Neelakshi Varma is a masters student in molecular biology at the Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru.

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