If you’ve been to Kuala Lumpur, the capital state of Malaysia, then you certainly would’ve caught a glimpse of the Petronas Twin Towers. They’re hard to miss; the two sisters standing tall and proud at 452 metres, with aircraft warning lights easily mistaken for twin stars in the night sky. Beyond skyscrapers and other urban stereotypes, Kuala Lumpur is so much more for young Malaysians. It’s a beacon of hope, an economic harbour that boasts rising income and declining poverty among its residents. Admittedly, these economic feats look impressive on paper but like many metropolitans in low and middle-income countries, pockets of urban poor inhabit selected areas which are often overlooked. Here, scattered between grand, upscale developments are characteristic high-rise, low-cost apartments housing families with income below the national average1 – the People’s Housing Project.
Meet Hanisah, a 5-year-old girl living in Mentari Court, a low-cost apartment situated 10 minutes’ drive away from a luxurious entertainment hub, Sunway. Unfortunately, the odds are not in Hanisah’s favour. The chances are high that she will grow up in a household where malnourishment is many times more common, preschool is inaccessible to half of the children and surrounding environment is both unsafe and unclean.1 These apartments which were initially designed to be a stepping stone for a brighter future have been anything but that, with most residents trapped in a vicious cycle of poverty. Worse still, these poorly-built buildings carry clogged gutters and improper drainage systems2 that become hotbeds for a breed of mosquito most feared in tropical and subtropical regions – Aedes.
One evening, while Hanisah is playing in the living room, an Aedes mosquito, with black-white stripes on its slender legs pierces its long snout into her skin. Typically, female mosquitoes bite their victim to suck blood which is used to mature their eggs. However, some viruses that target humans can hijack this process to travel from one person to another. No one realises this incident until several days later when the poor child develops high fever, tummy pain and continuous vomiting. Rushed to the nearest hospital by her parents, the doctors confirmed that Hanisah had contracted severe dengue, a serious disease that requires urgent hospitalisation. In fact, dengue fever which is caused by a virus that hitch-hikes the Aedes mosquito is notorious for overwhelming healthcare facilities in our region, while carrying a hefty price tag of nine billion US dollars per year.3
Dengue virus is a triple threat; it not only cripples the economy and drains precious healthcare resources but also causes suffering and death. Even worse, this disease has yet another sinister side – its unpredictability. Normally, most people infected with dengue virus will show no symptoms or at most, experience a mild fever that resolves within several days. However, a small group of patients like Hanisah can develop more deadly forms of the disease, collectively known as severe dengue. Decades of scientific inquiry have revealed that this unpredictability in dengue patients is caused by the love-hate relationship between the virus and our own immune system.
The immune system is our friend
From the day we are born, there are microscopic foreign agents like dengue virus all around us waiting for an opportunity to invade. Consequently, our body is a battlefield for war constantly waged between these foreign agents and our protector, the immune system. To shoulder this daunting responsibility, our immune system has undergone over 750 million years of training that perfected an impressive skillset that is both diverse and versatile.
All good things come in pairs and our immune system is no exception. Essentially, it can be compared to a boxer in defence position with two gloved fists that perform the same task, albeit with a different style. One gloved fist called the innate response is spontaneous and instinctive while its counterpart, the adaptive response is more calculated. Both these responses cooperate by assisting and encouraging each other to achieve the common goal of defeating the foreign agent.4
To illustrate the intricacies of our elegant immune system, picture it as the security that protects our home from burglary. Although the innate and adaptive response would have different approaches, both responses would first have to identify the burglar as potentially dangerous. For this, the former would be a crude mechanism that only differentiates burglars from residents without the ability to profile the burglar’s exact identity. The latter on the other hand is more precise like a facial recognition technology that can catalogue the identity of the burglar and use this information to choose the most ideal weapon of combat according to the burglar’s capabilities.
Once the burglar has been identified, the threat has to be eliminated swiftly without harming the residents. Sadly, this is where our innate response falls short because it only carries a limited array of weapons that are used against all burglars alike, regardless of their skillsets. For example, an unarmed rookie burglar who shows up at the doorstep would be treated no differently than an armed professional by our innate response. Luckily, where the innate response lets down, its counterpart compensates. Our adaptive response is more versatile in combat as it can deal with burglars both in a direct and indirect manner. Namely, some soldiers from our adaptive response can march directly into combat and fight intruders face-to-face. At the same time, others stay back at their established military posts and produce tiny missiles called antibodies that target the threat.
The immune system can become our foe
Normally, a combination of speed and adaptability allows our immune system to deal with a wide range of intruders that our body encounters on a daily basis. However, a handful of sneaky invaders like dengue virus have learned ways to use our immune system to their advantage. Notably, dengue virus exploits our adaptive response, seizing control over the tiny missiles or antibodies that are produced during the infection.5
When our adaptive response meets dengue virus, it produces a broad variety of antibodies of different shapes and structures, all of which target the virus. Among this wide array of antibodies, only a select few would be functional in the battlefield when faced with dengue virus while others would be incompetent like dysfunctional missiles. In any other infection, these incompetent antibodies are like spectators in the background who pose no threat. Adversely in dengue, these antibodies can veer off-target and work with the viruses instead, helping them to gain entry into our body cells. The disastrous consequence that follows is severe illness that is seen in some dengue patients.
This deception by dengue virus is the main reason why no reliable dengue vaccine exists. In practice, vaccines are an invaluable preventive tool as they train our immune system to fight against invaders it might encounter in the future. They do this primarily by instructing our adaptive response to nurture special cells that produce antibodies. Hence, a shorter time is needed for these tiny missiles to be produced in large amounts when the real invader appears. Since antibodies and dengue virus have an inconsistent interaction, it’s not surprising why efforts to discover a dengue vaccine have been less successful.6
A healthy competition
Without vaccines, which are our most effective tool against viral diseases, how do we win the war against dengue? This unique situation has encouraged the search for other strategies beyond vaccines and drugs to combat this disease. In particular, methods that reduce dengue virus spread among Aedes mosquitoes have garnered support among scientists, public health professionals and policymakers. In simple terms, if we can strip dengue virus off its transport to reach humans, we can ultimately curb its transmission.
It turns out that dengue virus is not the only tiny organism that can infect mosquitoes because many harmless bacteria also co-exist in a similar manner. This is where our heroic bacterium, Wolbachia makes a grand entrance. This bacterium which is not naturally found in Aedes mosquitoes can be artificially introduced into them by scientists. Once inside the mosquito, Wolbachia which is rivals with dengue virus selfishly competes for dominance over the mosquito. In this competition, Wolbachia always emerges victorious. As a result, these mosquitoes can no longer offer a free ride to dengue virus, dismantling the precious mode of transportation for it to infect humans. Indeed, when Aedes mosquitoes infected with Wolbachia were released at selected areas such as Mentari Court in Kuala Lumpur, the number of dengue cases reduced.8
Even though dengue is no longer just a trouble in the tropics, with its reign reaching half the world’s population in 128 countries5, the virus has its claws wrapped most tightly around vulnerable communities in rapidly urbanising cities. While our own immune system is partly to blame for the crippling outcome seen in some patients, understanding this complex relationship may be key to developing a reliable dengue vaccine in the future. Ultimately, the road to ending dengue may not be straightforward but involve an integrated approach that includes a blend of novelty, innovation and international collaboration.
- UNICEF Malaysia. A study of urban child poverty and deprivation in low-cost flats in Kuala Lumpur [Internet]. Putrajaya, Malaysia: United Nations Childrens’ Fund, Malaysia; 2018. Available from: https://www.unicef.org/malaysia/media/261/file/Children%20Without%20(ENG).pdf
- Zainon N, Fazul Azli M, Roslan D, Abd Samat A. Prevention of Aedes Breeding Habitats for Urban High-rise Building in Malaysia. Journal of the Malaysian Institute of Planners. 2016;14(5).
- Shepard D, Undurraga E, Halasa Y, Stanaway J. The global economic burden of dengue: a systematic analysis. The Lancet Infectious Diseases. 2016;16(8):935-941.
- Sompayrac L. How the Immune System Works. 6th ed. Wiley; 2019.
- Wilder-Smith A, Ooi E, Horstick O, Wills B. Dengue. The Lancet. 2019;393(10169):350-363.
- da Silveira L, Tura B, Santos M. Systematic review of dengue vaccine efficacy. BMC Infectious Diseases. 2019;19(1).
- Flores H, O’Neill S. Controlling vector-borne diseases by releasing modified mosquitoes. Nature Reviews Microbiology. 2018;16(8):508-518.
- Nazni W, Hoffmann A, NoorAfizah A, Cheong Y, Mancini M, Golding N et al. Establishment of Wolbachia Strain wAlbB in Malaysian Populations of Aedes aegypti for Dengue Control. Current Biology. 2019;29(24):4241-4248.e5.