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From Aug. 4-5, researchers from around the world converged on Arizona State University’s Biodesign Institute for the First International and Interdisciplinary Workshop on the Ecology, Evolution and Dynamics of Dengue and other Related Diseases.
The first-of-its-kind, two-day symposium was co-sponsored by the Simon A. Levin Mathematical, Computational and Modeling Sciences Center, under the direction of Carlos Castillo-Chavez, and the Biodesign Institute’s Center for Infectious Diseases and Vaccinology, directed by Roy Curtiss III, (Curtiss is also a professor at ASU's School of Life Sciences.)
The event brought together an eclectic group of experts in molecular biology, mathematics, epidemiology, cell biology, physics, economics, ecology and evolution.
A number of far-reaching lectures highlighted advanced mathematical techniques used to model disease outbreaks, forecast epidemics and design eradication strategies. Though the conference centered on dengue fever, many of the talks explored other vector-borne diseases and broad issues lying at the nexus of mathematics, economics, ecology, immunology, epidemiology and statistics.
Susan Holechek, a molecular biologist in the Biodesign Institute’s Center for Infectious Diseases and Vaccinology organized the event. A native of Peru, Holechek was working on molecular diagnostics for dengue at the National Institutes of Health (NIH) in Lima from 2000-2001, when an invading dengue strain (DENV2 Asian) caused a severe outbreak of the disease in the northern tropical area of this South American nation.
Traveling to the infected zone as part of a rapid response team, Holechek was stunned by what she found. “The doctors didn’t know what to do. They had never seen dengue hemorrhagic fever cases,” she says, referring to a severe and sometimes lethal form of the disease. “The hospital was full of patients – a lot of them, children. In less than a year, we had over 10,000 cases in one of the worst outbreaks.” Within just two years, the disease had spread to the capital.
Holechek’s face-to-face encounter with dengue planted the seed for the 2014 conference at Biodesign, drawing many participants from Latin America, where dengue remains a scourge. “Seeing this changed my life. Now every time I have a sample and analyze it to extract the RNA, I realize this comes from a person – maybe someone I met in the hospital when I was there, perhaps one of the children who was suffering.”
Castillo-Chavez kicked off the workshop, sketching out the history of the field of mathematical modeling and its implications for infectious disease research. He began by citing a 1953 paper by Enrico Fermi, John Pasta and Stanislaw Ulam, which introduced a third way of doing science. Rather than performing tests in the laboratory or working out mathematical details with pencil and paper, scientists could perform a “computer experiment.”
Sixty years after the seminal paper, this third way of doing science has radically transformed the research landscape, permitting the detailed modeling of everything from black hole formation to global weather patterns to disease outbreaks, while a fourth way of doing science has emerged, data science, or as it is commonly called, “Big Data.”
A virus stalks the globe
Dengue is a mosquito-borne infection, which affects some 50 million people annually. The culprit is a virus living inside the mosquito, which serves as a vector for spreading the disease. Two primary mosquito forms carry the dengue virus, Aedes aegypti and Aedes albopictus. (In addition to Aedes aegypti’s broad global reach, the mosquito is endemic in 27 U.S. states, including Arizona.)
A single bite from an infected mosquito can transmit the virus to a human host. In some cases, individuals may not be aware they are carrying the virus, displaying no obvious symptoms. Nevertheless, their bloodstream can act as a reservoir for the pathogen. If an individual is bitten again, the new mosquito becomes a carrier of the virus, able to transmit it to other humans. Dengue is not, however, contagious – it can’t be spread person-to-person.
Dengue is a member of a family of infectious agents known as flaviviruses, a group that includes yellow fever and West Nile virus. It occurs in four distinct forms or serotypes, each bearing a different cell surface antigen.
With many diseases, antibodies produced by the immune system after an initial encounter provide lasting protection from subsequent infection. Intriguingly, this is not the case with the dengue virus. Indeed, as many of the conference participants described, infection with one dengue serotype can actually leave an individual more susceptible to infection by a different serotype, and also at greater vulnerability for developing severe complications in the form of dengue hemorrhagic fever and, later, dengue shock syndrome. This latter form is particularly lethal in children.
The phenomenon of heightened risk for re-infection and increased susceptibility to severe manifestations of dengue is known as antibody-dependent enhancement or ADE. It was the focus of a number of lectures during the conference.
Jolanda Smit, from the Department of Medical Microbiology in Grotingen, the Netherlands, delivered the opening plenary talk, describing possible mechanisms of cell entry by the dengue virus under conditions of antibody-dependent enhancement. Other lectures focusing on ADE included Holechek, as well as Mario Castro, Ph.D., of the Instituto de Investigación Tecnológica, Universidad Pontificia Comillas, Spain.
Carmen Molina-Paris, of the Department of Applied Mathematics, University of Leeds, UK, likewise explored cell level activity in dengue, presenting a mathematical model of viral binding events and cellular fates in response to dengue infection.
Current vaccine efforts were explored in a lecture by ASU School of Life Sciences virologist and vaccinologist Jorge Reyes del Valle. Antibody-dependent enhancement has made the development of a dengue vaccine a particularly thorny challenge. Thus far, a tetravalent vaccine capable of protecting from all four serotypes, including their genetic variants, has proven elusive, despite decades of research.
Bertram Jacobs, of the Biodesign Institute and ASU School of Life Sciences described his vaccine work, though his target is a sexually transmitted, rather than vector-borne, pathogen: HIV. Jacobs presented an innovative vaccine design, making use of poxvirus carriers capable of replicating in the vaccine recipient while retaining the safety standards associated with non-replicating vaccine vectors.
As a counterpoint to research lectures at the cellular level, the conference featured a number of talks focusing on population dynamics. These included professor Charles Perrings, a researcher at ASU’s School of Life Sciences, who brought economic theory to bear in a hybrid disciple known as epidemiological economics. His lecture focused on the importance of behavioral factors driving disease incidence and transmission.
Professor James Collins, also of ASU’s School of Life Sciences, delivered a riveting lecture on emerging infectious diseases and species extinction. He described the current mass extinction of amphibian forms due to amphibian chytrid, a microscopic fungus, while raising the possibility of deliberately forcing the extinction of human pathogens, like smallpox or entire organisms posing a hazard to human health, by means of new techniques in synthetic biology. Could vectors for diseases like dengue be eradicated altogether, and what might the unintended consequences of forced extinctions be? As Collins made clear, scientific and ethical questions abound.
Abba Gumel, of the Simon A. Levin Mathematical, Computational and Modeling Sciences Center at ASU, gave the audience a primer on the challenges and opportunities of disease modeling, demonstrating the power of these techniques for exploring transmission dynamics and controlling emergent and re-emergent infectious diseases.
Biodesign Institute's Joseph Blattman (also with the School of Life Sciences) presented a multi-scale model of virus infection and immunity. A mouse model of the lymphocytic choriomeningitis virus (LCMV) was used to explore interactions between, as well as within, hosts to determine the variables most likely to affect viral transmission. The model was then tested against laboratory experiments.
Climate change is yet another factor affecting the transmission and distribution of vector-borne diseases like dengue, and will likely play an increasingly important role, as several lecturers described. Temperature, vegetation cover, rainfall and humidity are all critical factors impacting the lifecycle of disease vectors and pathogen transmission to humans.
As Claudia Romero-Vivas, of the Grupo de Investigaciones en Enfermedades Tropicales, Departamento de Medicina, Universidad del Norte, Colombia, emphasized, accurate disease modeling is dependent on acquiring good field data on dengue vectors, an often tricky and labor-intensive process. In her lecture, she described the main gestation environments for Aedes aegypti mosquito pupae (a non-feeding stage of the insect between larva and adult) in water storage containers, and a simple, low-tech method for surveying population numbers and serotype distributions in her native Colombia.
Bringing it all together
The culmination of the symposium was a closing address by Curtiss, director of the Center for Infectious Diseases and Vaccinology at the Biodesign Institute. Curtiss gave a view from above, describing the central place of microbes in shaping the evolution of life on earth, including human civilization and the possible futures in store for humanity.
Some 20 million people will die of the direct impacts of infectious disease agents this year alone, while another 15 million will succumb to other afflictions, including cancer and cardiovascular disease, which often have microbial causes.
Curtiss presented, in stark relief, two alternate fates on humanity’s horizon. In the first scenario, infectious disease agents such as pandemic influenza lay waste to our species and consign us to the same mass extinction event claiming so many other living forms.
In a more hopeful assessment, however, Curtiss suggests our boundless capacity for insight and creativity may yet provide solutions for the most pressing societal challenges. These could take the form of radical new vaccines, genetic control of vectors, bold techniques to reverse environmental decline and methods to improve human resilience to disease.
Following two days of lectures, a lively poster session took place in the Biodesign lobby.
Reflecting on the success of the conference, Castillo-Chavez spoke with enthusiasm of the breadth of science covered by conference participants. In addition to making the event an annual one, he hopes to establish a global, interdisciplinary workforce that may be brought to bear on the full range of concerns essential for the investigation and eradication of infectious diseases.
"One of the goals of this workshop is to create a multi-country research consortium based on ecology, evolution, immunology and epidemiology of neglected and vector-borne infectious diseases that incorporates the uses of mathematics from the cellular, individual to the population level,” Castillo-Chavez says. “This interdisciplinary and transdisciplinary workforce, involving researchers from Latin America, Europe, Canada and the United States, could be initiated with a $1 million investment in human resources and experimental research."
More information on dengue: http://www.cdc.gov/dengue/.