Weathering Hantavirus: Ecological Monitoring Provides Predictive Model

Photo: Steve Bunk Dave Tinnin, field research associate in the University of New Mexico's biology department, takes blood samples and measurements of rodents caught on the research station grounds. At the end of a freeway exit near Soccoro, N.M., the hairpin turn onto a gravel road is marked by a sign that warns, "Wrong Way." But it isn't the wrong way if you want to reach the University of New Mexico's (UNM) long-term ecological research (LTER) station. The sign's subterfuge is the first indication that you are approaching the world's only outdoor Biosafety Level 4 laboratory. From a cluster of adobe-style buildings crouched below a rocky plateau on the Sevilleta National Wildlife Refuge, UNM staff manage their studies of a quarter-million-acre "biome transition zone" encompassing desert, prairie, plateau, and woodlands. All four of these ecosystems yield the research station's star resident: a beguiling little rodent with doelike eyes called Peromyscus maniculatus, the deer mouse. It is the primary vector of Sin Nombre ("No Name") Virus (SNV), the main cause of an often-fatal respiratory disease known as hantavirus pulmonary syndrome (HPS). The Sevilleta site has been central to hantavirus research ever since a 1993 outbreak of disease in the Four Corners states sparked a multidisciplinary response that quickly led to identification of the virus and its carrier.1 Until then, hantaviruses were thought to be confined to the Eastern Hemisphere, where they long had been known to cause hemorrhagic fever with renal syndrome (HFRS). Five years on, up to 25 hantaviruses have been identified throughout the New World, including 30 states of the United States, three Canadian provinces, and eight Central and South American countries. A host for all but two of these viruses is known or suspected, and it is always a rodent. About half of the viruses have been associated with HPS, though the others are not yet known to cause human disease.2 Judging solely by statistics from the Atlanta-based Centers for Disease Control and Prevention (CDC), which has been deeply involved in hantavirus research since 1993, the syndrome might seem a minor public health concern. Only 217 HPS cases were reported in the United States from May 1993 through May 1999. The fatality rate has been 43 percent, an average of fewer than 10 deaths annually. But the implications of the continuing hantavirus research go much farther than that, as Robert R. Parmenter points out. Parmenter, director of the Sevilleta field research station, sits his guest down in a well-paneled library and proceeds to outline the significance of hantavirus research. An important antecedent, he says, was National Science Foundation funding in the early 1980s of sites across the country that conduct LTER research extending well beyond the normal three-year NSF grant. The roles of ecosystem responses and climate dynamics in natural phenomena are foremost among these stations' studies. Consequently, the 1993 outbreak of a then-unknown disease in the region led Parmenter and colleagues to consider possible ecological precipitators of the problem. The New Mexico scientists already had been studying rodents for some time, recognizing them as "keystone species" because of the major impact their burrowing and predation of insects and seeds has on the structure and functioning of regional ecosystems. In 1993 Peromyscus population numbers were the highest they had been in the past four years, a situation associated with El Niño of 1992, which led to a "trophic cascade" of extra moisture, plant growth, and increased food availability for the mice. That was followed by a mild winter that permitted the emergence of a large adult rodent population the following spring. Photo: Steve Bunk Paul Polechla, biology research associate professor at the University of New Mexico, releases and photographs tagged mice near artificial burrows where they were trapped. The background shows the desert environment and one of the research station buildings (top left). Very wet weather occurred again at the turn of 1997-98. "So, we're looking at 1999 and possibly 2000 as being some fierce years [for hantavirus]," says Parmenter. The virus occurs naturally in the rodents, which suffer no apparent ill effects. Human victims, who span all ethnic groups, endure flulike symptoms that may progress to shortness of breath and can end in rapid death from pulmonary edema, when the lungs fill with fluid. Transmission is thought to be primarily by breathing aerosolized mouse feces and urine, particularly indoors with limited ventilation. Sweeping out a cabin in spring that has been infested over the winter is a typical scenario. "It's obviously a very difficult disease to catch," Parmenter says. Why, then, is it important to study? He explains that the ecological research, in combination with viral genetic work, will result in a predictive model that not only will act as an early warning system for future outbreaks, but can help to minimize conditions leading to human transmission. "In terms of this disease, prevention is 99 percent of it." On a wider scale, the hantavirus research was among the first to link global climate change with disease outbreak. Mosquito distribution due to climatological effects likewise has been connected with outbreaks of dengue fever, encephalitis, and yellow fever, he notes. UNM biologists also are examining the relationship between rainfall and plague, and will study ecological effects on occurrences of rabies and bacterial diseases in rabbits. Such research possibilities extend to "anything that involves vector populations that respond to weather conditions," he notes. In the station's main lab, Paul Polechla dons a half-face respirator and begins to extract rodents from a sackful of traps he recently gathered. Polechla is a postdoc for Terry L. Yates, UNM biology department chairman and leader of the rodent longitudinal studies. At Sevilleta and other New Mexico sites, mark/recapture techniques are employed monthly to determine the density dependence of rodent infection through time. Similar projects, all CDC-sponsored, are being conducted in Arizona, Colorado, Utah, and Montana. Polechla anesthetizes each mouse and brings it to field research associate Dave Tinnin, who inserts and gently rotates a capillary tube under the rodent's eye, obtaining a blood sample that will go to CDC. All information about the capture is logged, including identifying marks on the mouse, which receives a subcutaneous tag that can be scanned, and an ear tag. Other captured species aside from the deer mouse that may carry the virus, such as the white-footed wood rat and the piñon mouse, also go through this procedure. Tinnin notes that UNM staff is cooperating with foreign governments and institutions to set up similar monitoring programs in several countries, including Bolivia, Chile, and Mongolia. Another step in the UNM work is being led by professor of internal medicine Frederick T. Koster. In one part of this project, under the direction of Yates, four huge outdoor enclosures--nicknamed the Very Large Mouse Array--have been constructed at Sevilleta and three other sites. Each enclosure is about 4.2 hectares in area, roughly equal to eight soccer fields. Well-fed, sheltered, and protected from all natural predators except owls, the mice are being encouraged to breed up to population densities approximating those of 1993. The objective is to study the naturally occurring infection as it builds in these wild populations, and to learn how it is related to the abundance of the rodents. Photo: Steve Bunk Paul Polechla bags a rodent with an anesthetic to prepare it for blood sampling. The second part of this National Institutes of Health-funded project is aimed at acquiring knowledge of the immunopathogenesis of HPS, and to develop capabilities in early diagnosis and therapy. An important aspect of that work centers around several smaller enclosures of about 10 meters per side, outfitted with plastic burrows that can be removed and disinfected when required. Here controlled experiments are being conducted in wild-type conditions, to densities approximating those of 1993. The objective is to study the naturally occurring infection as it builds in these wild populations, and to learn how it is related to the abundance of the rodents. The second part of this National Institutes of Health-funded project is aimed at acquiring knowledge of the immunopathogenesis of HPS, and to develop capabilities in early diagnosis and therapy. An important aspect of that work centers around several smaller enclosures of about 10 meters per side, outfitted with plastic burrows that can be removed and disinfected when required. Here contolled experiments are being conducted in wild-type conditions, to investigate questions such as mechanisms of SNV transmission among the animals, immune responses, viral survival in the host, and the demographics of infection, using both deer mice and standard laboratory mice fitted with radio transmitters. The Centers for Disease Control and Prevention maintains an active Web site on hantavirus. The site contains general information, such as how to recognize the disease and how best to prevent it, as well as technical information. The address: www.cdc.gov/ncidod/diseases/hanta/hps/index.htm "We're operating on a presumption that's fairly widely accepted in the field, that you can't really understand human disease very well without an animal model," says the project's principal investigator, UNM associate professor of pathology Brian L. Hjelle. Both deer mice and lab mice have been deliberately infected, he adds, as part of the study's long-term goals to find ways of disrupting SNV transmission among the mice, and to identify genetic immunization strategies for protecting humans. Francis A. Ennis, director of the Center for Infectious Disease and Vaccine Research at the University of Massachusetts Medical School, notes that although an animal model is useful in studying SNV replication, mice don't clear the virus as humans do. In people, he explains, "It's an acute explosive infection with an intense immune response, and the virus is cleared right after this response. In terms of the virus, the person has won the battle. The question is, are they going to survive, because of the fluids in their lungs?" Photo: Steve Bunk Paul Polechla shows a visitor how he releases mice after blood sampling. Most victims are healthy adults, rather than children or old people whose immune systems are not as strong. A recent study, on which Ennis collaborated with Koster and others, suggests that high levels of cytokine production in the lungs may play an important role in stimulating the excessive T-cell response that precipitates "capillary leakage" of fluid through endothelial cells, resulting in pulmonary edema.3 Like HIV, hantavirus has a surface envelope that makes the development of an effective vaccine a "formidable task," Ennis comments. Antiviral therapy might work if a drug could be administered before the disease did major damage. "The difficult thing is to find somebody with a fever and get some evidence rapidly that they are infected, but they haven't yet had this terrible lung catastrophe," he observes. "As we know more about the pathogenesis and risk factors, the ability to develop strategies will be more successful." Stuart T. Nichol, chief of the molecular biology section of the special pathogens branch at CDC, notes that genetic studies have helped to establish the antiquity of the viruses in the mice, probably extending through 30 million years of coevolution. The disease in humans likewise is ancient, he adds, and current hantavirus research can be especially useful to people in rural areas worldwide. He stresses the effectiveness of applying satellite weather imaging in combination with "ground-truthing" of seroprevalence and other factors, to create a predictive model of outbreaks. "I think we are going to see those kinds of approaches applied to other diseases in the next five years or so, with quite dramatic results." Steve Bunk is a contributing editor for The Scientist. K.Y. Kreeger, "Stalking the deadly hantavirus: a study in teamwork," The Scientist, 8[14]:14-15, July 11, 1994; and K.Y. Kreeger, "One year later, the hantavirus investigation continues," The Scientist, 8[15]:16-17, July 25, 1994. M.C. Monroe et al., Emerging Infectious Diseases [serial online], 5[1]:13 screens, January-February 1999. M. Mori et al., "High levels of cytokine-producing cells in the lung tissues of patients with fatal hantavirus pulmonary syndrome," Journal of Infectious Diseases, 179:295-302, February 1999.

Weathering Hantavirus: Ecological Monitoring Provides Predictive Model

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