Abstract
Dr. Pedro Fernando da Costa Vasconcelos is head of the Instituto Nacional de Ciência e Tecnologia para Febres Hemorrágicas Virais-INCT-FHV (Brazil's National Institute of Science and Technology for Viral Hemorrhagic Fevers), located at the headquarters of the Instituto Evandro Chagas (IEC), Brazil's Ministry of Health, in Ananindeua, Pará state. Dr. Vasconcelos is also the head of the IEC Arbovirology and Hemorrhagic Fevers Department; a fellow researcher of Brazil's Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq – National Council for Scientific and Technological Development); and director of the WHO Collaborating Center for Arbovirus Reference and Research at the IEC. He completed his medical degree at the Medical School of the Universidade Federal do Pará, in Belém, and pursued a specialty in Tropical Medicine at Universidade de São Paulo. Dr. Vasconcelos received a PhD from Universidade Federal da Bahia, in Salvador, and completed his post-doctoral studies in Molecular Virology in the Department of Pathology at the University of Texas Medical Branch, in Galveston (USA). He is a member of the editorial boards of three scientific journals: Revista Pan-Amazônica de Saúde (and an Associate Editor for the Virology area); Open Epidemiology Journal; and Vector-Borne and Zoonotic Diseases.
Arboviruses and hantaviruses cover a vast area in the Pan-Amazonian region, which comprises the areas of the Amazonia in Brazil, Bolivia, Colombia, Ecuador, Peru, Venezuela, and the Guyanas. The arboviruses include pathogens that represent important public health risks, such as the dengue, yellow fever, Oropouche, Mayaro, the equine encephalitis viruses (eastern; EEEV), (western; WEEV) and Venezuelan (VEEV), and Saint Louis encephalitis virus (SLEV). These have all been investigated by the IEC. Arboviruses are important causal agents of disease in humans. Some are associated with high morbidity and lethality rates, such as yellow fever and dengue, and others tend to cause significant morbidity without fatal outcomes, such as Oropouche, Mayaro, and the encephalitogenic arboviruses in Brazil. It is important to emphasize that the encephalitis-causing viruses—EEEV, WEEV, VEEV, and SLEV—have rarely caused illness in Brazil or in other South and Central American countries, except for Argentina, where cases of encephalitis have been reported. On the other hand, these viruses have been associated with outbreaks or epidemics of encephalitis in the United States, leading to considerable fatality rates.
In relation to the hantaviruses, the IEC has focused on the viruses found in the Amazon Region. We have described, for example, the hantaviruses associated with outbreaks of Hantavirus Pulmonary Syndrome (HPS) in Maranhão State (Anajatuba and Rio Mearim viruses) and their associated rodents. We have discovered the transmitters of the hantavirus Castelo dos Sonhos, the main hantavirus associated with HPS in Pará State, which was identified in 1995; but only recently was the species responsible for its transmission registered, the rodent Oligoryzomys utiaritensis. We have also demonstrated that in Mato Grosso State, in the midwestern Region of Brazil, the hantaviruses Castelo dos Sonhos and Laguna Negra are associated with human cases of HPS. Furthermore, we have identified the transmitter of the Laguna Negra virus in Brazil, the rodent Oligoryzomys callidus.
We have also studied the rabies virus and the complex interactions with its sylvatic transmitters, especially the hematophagous bat species Desmodus rotundus (the common vampire bat), which is associated with transmission of the disease in the Brazilian Amazon.
As human beings increasingly occupy forested areas, the risk of contact between humans and vectors/transmitters of zoonotic disease agents including arboviruses, hantaviruses, arenaviruses, rabies and others increases. I do not believe in a magical solution. We must first understand the ecology of vectors/transmitters and the epidemiology of the diseases. We need to prioritize scientific research because it will only be possible to minimize the harmful effects these viruses and other zoonotic agents can have on humanity if we base our efforts on data obtained through scientific methods.
Politicians must understand that the environmental changes caused by man have to be controlled; otherwise, it will be hard to create effective policies to prevent and control these viral diseases. Our challenge is to sensitize trendsetters and policy makers in the area of public health to the potential problems that may arise from the indiscriminate degradation of the Amazon Forest, from uncontrolled urbanization, from monocultures, from the building of new roads, and from the creation of new reservoir lakes for hydroelectric power plants, etc. All of these activities have an environmental impact, whether small or large. For example, in 1999, during an event in Rio de Janeiro, we discussed the possibility for environmental changes based on previous studies carried out by the IEC during its decades of research in the Amazon River Basin. During that period, the effects of several anthropic activities that damaged the environment were already evident. We demonstrated that inappropriate utilization of the Amazonian ecosystem invariably results in the emergence of new or the reemergence of known zoonotic viral agents such as arboviruses, hantaviruses, arenaviruses, etc.
It is worth mentioning one particularly well-documented situation: we have evidence to show that the formation of the reservoir lake (dam) of the Tucuruí hydroelectric power plant, located in Pará State, Brazil, led to the emergence of almost 40 arboviruses, and 30 of these were new to the science (Vasconcelos et al., 2001a). Thus, the environmental issues that arise as a result of human activities must be carefully handled during all phases of the colonization and/or exploration projects related to the extraction and use of the Amazon's natural resources.
The IEC was founded in 1936 and initially named Instituto de Patologia Experimental do Norte (Northern Institute for Experimental Pathology), or IPEN, by Dr. Evandro Serafim Lobo Chagas, the youngest son of the renowned Brazilian scientist Carlos Chagas, who discovered Chagas disease. In 1940, Dr. Evandro Chagas died in a plane crash, and the Pará State Government named IPEN after him, as a fair homage to its founder. In 1941, during World War II, the IEC became a federal institution and a body of Brazil's Ministry of Health, which is still its current legal status.
The IEC's first studies focused on parasitoses, including kala-azar, cutaneous leishmaniases, malaria, and bacterial diseases. Those early years of research were highly productive as demonstrated by many published articles. In 1954, the Brazilian government signed an agreement with the Rockefeller Foundation for the establishment of a laboratory to investigate the sylvatic cycle of yellow fever and the arboviruses in the Amazon region. This was initially envisioned as a relatively minor program; however, due to its fast outcomes, it evolved into a large project and led to the establishment of two important scientific groups: one that studied arboviruses (and also arenaviruses, hantaviruses, and rabies); and one that studied other viruses (enteroviruses such as polioviruses, measles, rubella, adenoviruses, influenza and other respiratory viruses, and various other viruses). These programs have become two of the most important departments of the Institute, responsible for a large output of scientific contributions recognized nationally and internationally.
I joined the IEC in 1980, when I was still an undergraduate student. I was a trainee in the Arbovirus Department, and was directly supervised by Dr. Amélia Paes de Andrade Travassos da Rosa, who is currently a member of the Department of Pathology at the University of Texas Medical Branch at Galveston). She guided me through my first years of study in the scientific world and has remained an important mentor throughout my career.
The Arbovirus Department (currently named Department of Arbovirology and Hemorrhagic Fevers) of the IEC has expanded substantially and will soon become an independent unit, to be called the Center for Arbovirology and Hemorrhagic Fevers (CENARBO). The IEC will soon be transformed into a foundation–the Fundação Instituto Evandro Chagas—which will comprise the former IEC, CENARBO and its Center for Technological Innovation, Brazil's National Primate Center, the Escola Nacional de Saúde Pública da Amazônia, the Centro de Ecologia Humana e Meio Ambiente, and an IEC unit located in Acre State. This complex, multidisciplinary institution that will operate throughout the Amazon Region reflects the importance of the scientific contributions of the IEC.
Currently, research at the IEC encompasses the areas of microbiology and infectious diseases, including virology, parasitology, bacteriology, mycology, pathology, and genetics. It also includes studies on environmental microbiology and environmental changes, such as the levels of mercury and other contaminants.
We are also focusing on the development of rapid techniques that are more sensitive and specific for the diagnosis of arboviruses and hantaviruses. We are pursuing studies of the pathogenesis and physiopathology of new arboviruses (because unknown viruses infect mammals) and the consequences of these infections, including the degree of impairment they cause, the target organs, the main infected cells, etc. Additionally, a massive investment has been made in molecular techniques, including sequencing, phylogenic analysis, genomics, and proteomics. We are really looking forward to the opportunity to contribute significantly to the development and utilization of these advanced scientific tools and methods in this part of the world.
The focus of the research varies from project to project. Some projects are related to molecular aspects, including the phylogenetic and evolutionary relationships among viruses, whereas others aim to describe the pathogenesis and physiopathology of the infections caused by arboviruses, and especially viruses for which their capacity to infect humans has not yet been discovered; however, they could emerge as public health risks in the future. Other projects focus on developing new technologies for the diagnosis of arboviruses and hantaviruses that are considered of public health interest in Brazil and neighbor countries.
Several of the discoveries made in our laboratory have been significant for their role in advancing our own work and for enhancing our understanding of many aspects of the projects. Some of these discoveries have had major repercussions, such as the record of discovery of new arboviruses in the world at the IEC, as well as our description of the occurrence of severe adverse reactions following vaccination against yellow fever, which showed the world that we need to be more aware of the potential consequences when using of this vaccine (Vasconcelos et al., 2001b). Although it is very effective in preventing thousands of cases of yellow fever worldwide, we now know that it can also be lethal. Therefore, we need to use the 17D vaccine rationally. The published findings, like the others that followed, changed our thinking about vaccination against yellow fever.
Another important discovery was the identification and molecular characterization of Brazilian hantaviruses, as well as their role in HPS a few months after the original description of HPS by the CDC group. These viruses are closely linked to severe human cases of HPS and cause high case-fatality rates. More recently we identified several hantaviruses and associated them with the occurrence or non-occurrence of HPS in each Brazilian Amazon state (Rosa et al., 2005). It was not unusual to detect two different hantaviruses circulating in the same region or state. We also identified their transmitter rodents.
A fourth interesting outcome of our research was disproving the accepted yellow fever paradigm in which the viral disease is disseminated in epizootic waves through the movement of vector monkeys and mosquitoes. We performed a molecular study analyzing a large number of strains of yellow fever virus and showed identical viral lineages in areas that were more than 2,000 km apart from one another. This suggested that the yellow fever virus was probably carried by asymptomatic humans or humans with mild infections (Vasconcelos et al., 2004). This phenomenon was also observed by researchers from the Instituto Adolfo Lutz in the states of São Paulo and Rio Grande do Sul during the yellow fever epidemics of 2008.
Our work leading to the development of new methods of diagnosis is also remarkable. Two recent achievements were the development of a rapid IgM-ELISA for dengue and yellow fever, which reduced the testing time from 36 to 4 hours, expediting the laboratory diagnosis and, consequently, the delivery of necessary interventions (Nunes et al., 2011), and the generation of a quantitative real-time RT-PCR test for yellow fever, which enables detection of this arbovirus in blood and fresh tissues as well as in paraffin-embedded material and which can be easily adapted to other flaviviruses such as dengue. These are important advancements in the diagnosis of these two viral hemorrhagic fevers.
Yellow fever remains a serious public health threat in Brazil and in several countries in South America, especially in Peru, Colombia, and Bolivia. These four South American countries account for more than 90% of all the yellow fever cases diagnosed in the Americas during the last 20 years. Yellow is also endemic across Africa.
It is important to point out the high case-fatality rates (more than 50%) of yellow fever in these and other countries in our continent. These figures suggest under-reporting of the disease, as most of the reported cases of yellow fever are severe and almost no oligosymptomatic cases have been registered. To me, the lack of identification of mild cases and asymptomatic infections represents a powerful mechanism of viral dispersal and increases the risk of reurbanization.
Regarding the reurbanization process, it is important to recognize that the South American continent is infested with Aedes aegypti. In most parts epidemics of dengue occur without our even knowing the true infection rates and, therefore, there is a risk of reurbanization of yellow fever. Although this risk is hard to estimate, it is certainly lower than existed in the past. Barry Miller, Tom Monath, and others published an article on the epidemics of urban yellow fever in Nigeria showing that, despite the high rates of infection (greater than 40% in nearly all the epidemics), the urban transmission rates were restricted. This suggests that in the great epidemics that occurred in the 19th and 20th centuries in Buenos Aires and Rio de Janeiro, for example, the infestation rates were high, and only under these circumstances could transmission by Aedes aegypti and the maintenance of its urban cycle occur. Consider the situation in Paraguay in 2008, where few cases of urban yellow fever were reported in Laurentyl, situated approximately 20 km from the capital city Assunción, where the infestation rates reached 26%. A fast intervention aimed at achieving strict vector control combined with intensive vaccination eliminated urban transmission.
I want to emphasize that although we are not free from the risk of urban transmission of yellow fever, compared to years ago, we now have mechanisms to interrupt the transmission of infection and, therefore, the anticipated number of urban cases in a hypothetical outbreak would be much lower. Clearly, the ideal goal would be to eliminate the risk of urban transmission, due to its great impact on public health and the economy; but short of achieving that goal, we are fortunate to have the vaccine to interrupt an eventual virus transmission and minimize its impact.
We have a better understanding now of the sylvatic cycle of dengue. Several researchers have documented these cases through the isolation and detection by RT-PCR of serotypes extracted mostly from wild mosquitoes. In Asia, where it has been more deeply studied, the findings demonstrate the low circulation and limited isolation of sylvatic dengue. The question is whether the sylvatic cycle of dengue is important. Has it always existed, or is it an inverted path compared with yellow fever? We believed that the sylvatic cycle would lead to the hyperendemicity of dengue in urban areas; that is, viremic individuals would carry the virus to forested areas and then a sylvatic cycle, with native wild mosquitoes, would begin. More recent studies however, by Scott Weaver and collaborators, have shown that sylvatic strains are different from urban ones. This suggests an independent cycle from the one occurring in cities and that the dengue virus might be restricted to forested areas without Aedes aegypti.
Regarding the importance of this cycle for the epidemiology of dengue, it seems to me that we do not have enough data to assess its participation in the transmission of the disease. My opinion is that the sylvatic cycle has no importance for the impact dengue has on urban areas.
I acknowledge the importance of these groups and committees because they discuss WHO and PAHO policies based on the scientific discoveries and knowledge. The consensual decisions they reach result in guidelines to be adopted by national ministries of health. Therefore, it is important that these discussions result in actions that aim at controlling and eradicating certain diseases.
Regarding the INCT-FHV, it is an ambitious project through which we aim to understand the physiopathology and pathogenesis of the major viral hemorrhagic fevers that occur in Brazil and their biologic characteristics on a molecular level, and to develop more rapid, sensitive and specific methods of diagnosis.
This is a big challenge, but we have already realized valuable achievements during these past two years. Among these achievements, I would like to highlight the development of the rapid IgM-ELISA, which reduced the testing time without losses in sensitivity or specificity, leading to a faster laboratory response. This test was validated in several laboratories of the Pasteur network (in French Guyana, Vietnam, and Cambodia). The test is already available to laboratories in Brazil's public health network, which will soon adopt the technique. In addition, the INCT-FHV developed a RT-PCR test that can be used to quantify the viral load of dengue and yellow fever in blood, fresh tissues, and paraffin-embedded tissues. The Brazilian government has already expressed an interest in this technique, which is going through the final stages of its validation process and will soon be submitted for publication. The INCT-FHV is also carrying out investigations on hantaviruses and viral hepatitis with good results.
Brazil has actively participated in several multilateral committees of WHO, PAHO, PDVI, MERCOSUL, etc., and Brazilian scientists have published a lot more than in the past due to the investments our government has made in the last 12 years. We know that the share of Brazil's gross domestic product (GDP) invested in science and technology, and health and education is still insufficient, but we can clearly state that there has been a significant increase.
Brazilian supporting agencies such as the National Council for Scientific and Technological Development (CNPq), Coordination of Improvement of Higher Education (CAPES) and Federal Foundation for the Brazilian Research and Development (FINEP) have more financial resources and are more accessible to new researchers. These increased investments and expansion of research groups have led to an important enhancement in our scientific production. Today Brazil is one of the 10 leading countries in scientific production, and if we continue to grow at the current pace, we will soon be ranked one of the 6 most productive countries. However, there is a mismatch between our scientific production (papers) and the generation of biotechnological products. This is the new trend the supporting agencies are focusing now.
Regarding my career as a researcher, when I started medical school at UFPA, my initial goal was cardiac surgery. As time went by, I realized that I would make a terrible surgeon and, as I was interested in research, I focused on clinical and pathologic issues, as well as in discovering new viruses. The turning point came during my fourth year when I decided to take part in a public contest to become a trainee at the IEC. There was a position open in the Virology Department and I got it. I started to study arboviruses under the guidance of Dr. Amélia Travassos da Rosa and never left the Institute.
When I graduated with a degree in Medical Sciences, I was immediately hired by the IEC and got experience doing field work during epidemics of dengue, yellow fever, Oropouche fever, etc. At the same time, I started learning classical techniques in the serology and isolation of arboviruses. Hence, my scientific maturity came slowly but was well-grounded.
One aspect I consider vital in my scientific background was the two periods I went to University of Texas Medical Branch (UTMB). The first time was in 1998 (on a sandwich program during my Ph.D. studies), and the second was in 2002–2003 when I finished my post-doc. The interaction with several world renowned scientists, including Professors Robert Shope, Robert Tesh, Alan Barrett, and Amélia Travassos, was very profitable for me.
Professor Alan Barrett was a very importance mentor for me and he was my tutor during both times I was at UTMB. During the second study period, Juliet Bryant (currently at Institut Pasteur in Cambodia) was also very important because of her vast expertise in the area of molecular biology and phylogenetic analysis.
As I said, my scientific curiosity was always huge. During a clinical examination for dengue or yellow fever, for instance, I always used to (and I still do) imagine the physiopathologic phenomena that could be responsible for a clinically observed symptom. I learned to do this almost instinctively as a way to assess the severity of the patient's clinical status. Naturally, questions come to my mind; to try to answer those questions and begin a research project one just needs to get organized and follow the scientific method. My lifelong desire to understand chemical and biochemical phenomena has led me to search for more data in scientific books and journals.
Regarding my scientific production, it is a consequence of the investigations and of the habit of writing down my ideas and keeping systematic records of the results. It is especially important to be open to criticism, because in science we learn more by making mistakes and correcting them than from direct achievements. Submitting your work to be evaluated by unknown referees and defending your position or acknowledging the criticism is hard, but extremely rewarding. I got used to receiving corrections or criticism with a feeling of satisfaction, because they help me prepare the final article and develop new ideas for new investigations.
I also had good mentors and professional role models both at IEC and during medical school and my subsequent training. At IEC, Dr Amélia Travassos da Rosa was a major influence; it was the late Drs. Ronaldo Araújo and José Monteiro Leite, and Dr. José Maria Abreu from UFPA who inspired me to pursue a career in science. At IEC, I have always admired the work of Drs. Francisco Pinheiro and Ralph Lainson. I remember when I was in high school, Herculano Torres, one of my teachers, was also responsible for my initial interest in research (chemistry).
I do not consider myself to be a highly productive scientist. I have not mastered the English language, for example, which is the universal language of science. However, combining science and scientific production with a medical career is not easy, especially in the beginning. I try to tell my post-graduate students and my younger colleagues at IEC about the importance of well-grounded scientific research, of going after external financial support, and of keeping their minds open to scientific novelties.
Finally, training a new generation of virologists who will maintain the excellence of the research developed by the IEC is my most satisfying task. I know that when I retire, the small lab established by the Causeys (Otis and Calixta), Robert Shope, Jim LeDuc, Jack Woodall, Amélia Travassos, and Francisco Pinheiro, which I inherited and built up with the help of the current staff, turning it into a Research Center for Arbovirology and Hemorrhagic Fevers, will keep growing in the future. This is a priceless satisfaction.
In conclusion, I would like to adapt a sentence by Carlos Chagas Filho, which is displayed in the entrance hall of the Instituto de Biofísica Carlos Chagas Filho at the Federal University of Rio de Janeiro (UFRJ), and which reflects my vision of the IEC, which is not a university, but contributes to the education of many students: “At IEC, one teaches because one investigates.” Nothing could be more truthful and better present the correct order.