Uganda’s Zika Forest, birthplace of virus threatening the world

The turnoff into the Zika Forest is easy to miss, just a small break in the tree line along the main road between Entebbe Airport and Uganda's capital, Kampala. A worn-out sign announcing its start only comes into view after a journey down a small dirt path.

The explosive spread of the Zika virus may have caught the world by surprise, but its namesake, the forest preserve near the edge of Lake Victoria, isn't a place to just stumble on to. The researchers who have been coming here for more than a half-century come with a purpose: to study viruses and the mosquitoes that carry them.

"Every year we come across new viruses," said Julius Lutwama, lead researcher at the Uganda Virus Research Institute (UVRI), which owns the forest. "In the last five years or so, almost each year we come across a new virus in this country."

Uganda sits in the middle of seven distinct biogeographic zones. To the east: the savannahs of Kenya and Tanzania. To the west: the Congo basin rainforest. And Lutwama credits that biodiversity for attracting the first scientists here in the 1930s.

The discovery
What began as a Rockefeller Foundation-funded yellow fever outpost in 1936 soon became a leading laboratory in the study of tropical diseases and later evolved into UVRI in 1977. At the center of all that research is the Zika Forest.

Researchers, realizing in the mid-1940s that different mosquitoes are active at different elevations, constructed a massive steel structure in the middle of the forest to conduct their yellow fever experiments. The lead in the project was a Scottish medical entomologist named Alexander Haddow.

"All of my bedtime stories revolved around my grandfather or my father's experiences growing up in East Africa. As a small child I learned about the Zika Forest, Zika virus and the tower that my grandfather built with funding from the WHO," said Andrew Haddow, Alexander's grandson, who is now a researcher working for the U.S. Army Medical Research Institute of Infectious Diseases.

He says he tried other careers, but the choice should have been clear from the beginning.

"I read all of his papers and the papers that came out of the lab," Andrew Haddow said. "We owe our basic understanding of many arboviruses and their associated mosquito and reservoir species to them."

It was in April of 1947, while studying yellow fever, that Alexander Haddow and colleague George Dick first identified Zika virus after a fever developed in a rhesus monkey placed on a wooden platform on his recently constructed tower. Blood samples revealed an unknown virus that, as protocol dictated, was named Zika after the forest in which it was first identified.

The spread

They still use Haddow's tower today. Just before a recent sunset, a team from UVRI pulled up to the forest edge and unloaded two large Styrofoam coolers from the back of a pickup truck. Dry ice fog poured from the coolers' edges as they assembled the mosquito traps and headed into the forest toward Haddow's Tower.

Its sides are now rusted and a few of the wooden platforms where they now hang mosquito traps are in varying states of disrepair. Scientists say surrounding construction threatens to make this small preserve even smaller and the research they used to carry out weekly has tapered off. Just like the virus that bears its name, they say, little attention has been paid to Zika Forest.

When first identified, the virus was only proven to infect monkeys. Even in the subsequent decades, when a dozen or so isolated human cases began to emerge, the symptoms were mild and Zika was never seen as a threat in Uganda.

"It was never viewed with importance," said Lutwama. "No one is interested in making a vaccine for a virus that only causes mild symptoms."

Marilyn Parsons of the Center for Infectious Disease Research says it's also hard to distinguish Zika's symptoms from other similar arboviruses.

Halting the spread of Zika in the United States

"It was hard to quantify how much Zika infection there was and its impact, since its symptoms are quite similar to other viruses varied by the Aedes mosquitoes: dengue and chikungunya," said Parsons.

It's unclear just how long Zika has been around because some studies have found immunity in populations in Africa and Asia, perhaps due to the similarity to other viruses.

All of that changed in 2007, when the first large outbreak of Zika was reported on Yap Island in Micronesia, Haddow said. Chikungunya and West Nile followed similar courses. "West Nile circulated for at least 62 years before it emerged in New York City in 1999. The common theme of all of these viruses is that they were not widely studied and they all emerged after a long period of time to cause severe illness."

More troubling, many scientists believe the 2007 strain of Zika has mutated from the original virus found in Uganda, with increased virulence. Subsequent years saw the virus spread quickly through the Pacific islands before landing in South America and Brazil in 2015, where there's a suspected correlation to an increase in the birth defect microcephaly and other serious conditions.

'Preparing for the next Zika now'
Louis Mukwaya's office sits in a prime location on the UVRI campus in Entebbe. Just right of the main doors, it's a large space that somehow manages to have every surface filled with stacks of papers. He started at the institute in 1965, just a few years after Alexander Haddow would step down as its head. A picture of Haddow still hangs in his office. Next to it, a picture of Mukwaya with the younger Haddow from 2013 when he visited the research center his grandfather helped create.

"He was a very hardworking man," Mukwaya said of the elder Haddow, before turning his attention to the virus Haddow first identified all those years ago. "You know I keep reading on the Internet about Zika in Brazil and they keep using the word, 'emerging,' 'emerging' infection. We've known about it for a long time, but then even we don't know what will happen with the virus."

Mukwaya said the institute and others like it simply don't have the resources to properly study emerging viruses.

"We used to do routine collections once a week," said the renowned entomologist. "These days we don't get out nearly as much. Funding is poor, this is the problem."

Vaccine and drug development can take years, so basic research that lays the foundation is crucial, Parsons said. "This type of research could identify drug targets, vaccine antigen targets, and develop models for testing them," she added.

A climb to the top of the tower that Andrew Haddow's grandfather helped build more than a half-century ago reveals that the once remote research outpost now is entirely surrounded by Uganda's urban centers. Any new viruses discovered here will no longer be considered remote.

"The current Zika virus outbreak in South and Central America is another wake-up call that increased globalization and climate change will continue to lead to the emergence of viral pathogens," said Haddow. "We need to be preparing for the next Zika virus now."