James N. Mills

Isolation of Genetically Diverse Marburg Viruses from Egyptian Fruit Bats

In July and September 2007, miners working in Kitaka Cave, Uganda, were diagnosed with Marburg hemorrhagic fever. The likely source of infection in the cave was Egyptian fruit bats (Rousettus aegyptiacus) based on detection of Marburg virus RNA in 31/611 (5.1%) bats, virus-specific antibody in bat sera, and isolation of genetically diverse virus from bat tissues. The virus isolates were collected nine months apart, demonstrating long-term virus circulation. The bat colony was estimated to be over 100,000 animals using mark and re-capture methods, predicting the presence of over 5,000 virus-infected bats. The genetically diverse virus genome sequences from bats and miners closely matched. These data indicate common Egyptian fruit bats can represent a major natural reservoir and source of Marburg virus with potential for spillover into humans.

The natural history of Hendra and Nipah viruses

Pteropid bats (flying foxes), species of which are the probable natural host of both Hendra and Nipah viruses, occur in overlapping populations from India to Australia. Ecological changes associated with land use and with animal husbandry practices appear most likely to be associated with the emergence of these two agents.

The Ecology and Evolutionary History of an Emergent Disease: Hantavirus Pulmonary Syndrome

I the spring of 1993, a previously undescribed disease emerged in the Southwest, killing 10 people during an 8-week period in May and June. Early during an infection, victims experienced flu-like symptoms for several days, but their condition suddenly and rapidly deteriorated as their lungs filled with fluids; death usually occurred within hours of the onset of this crisis period. There was no cure, no successful medication or treatment, and the disease agent (virus, bacterium, or toxin) was completely unknown. For the first few weeks, the mortality rate was 70%. Researchers from many disciplines immediately focused on the outbreak, attempting to identify the agent and understand the causes and dynamics of the disease. Within weeks, scientists at the Centers for Disease Control and Prevention (CDC) identified the agent as a previously unknown hantavirus (Bunyaviridae), subsequently named Sin Nombre virus, or SNV (Nichol et al. 1993). Because hantaviruses were known to be transmitted by rodents, investigators undertook an intensive small mammal field sampling campaign in the Four Corners region of New Mexico and Arizona. Shortly thereafter, CDC identified the viral reservoir host as a common and widely distributed rodent, the deer mouse, Peromyscus maniculatus (figure 1; Childs et al. 1994). During the identification period, on the medical side, physicians and medical staff made rapid progress in developing treatment methods to stabilize and sustain patients through the crisis period, thereby substantially improving patient survivorship; nonetheless, the mortality rate fell only to about 40%, where it remains today. The emergence of this new disease prompted many questions about its history, causes, and dynamics. Was this a newly Terry L. Yates (e-mail: tyates@unm.edu) is a professor in the Departments of Biology and Pathology at the University of New Mexico, Albuquerque, NM 87131. Cheryl A. Parmenter, Robert R. Parmenter, John R. Vande Castle, Jorge Salazar-Bravo, and Jonathan L. Dunnum are with the Department of Biology and the Museum of Southwestern Biology, University of New Mexico. James N. Mills, Thomas G. Ksiazek, Stuart T. Nichol, and Joni C. Young are with the Centers for Disease Control and Prevention, Atlanta, GA 30333. Charles H. Calisher and Barry J. Beaty are with the Arthropod-borne and Infectious Diseases Laboratory, Foothills Campus, Colorado State University, Fort Collins, CO 80523. Kenneth D. Abbott is with the Department of Biology, Yavapai College, Prescott, AZ 86301. Michael L. Morrison is with the Department of Wildlife and Fisheries Sciences, University of Arizona, Tuscon, AZ 85721. Robert J. Baker is with the Department of Biology and The Museum, Texas Tech University, Lubbock, TX 79409. Clarence J. Peters is with the Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555.

A comparison of bats and rodents as reservoirs of zoonotic viruses: are bats special?

Bats are the natural reservoirs of a number of high-impact viral zoonoses. We present a quantitative analysis to address the hypothesis that bats are unique in their propensity to host zoonotic viruses based on a comparison with rodents, another important host order. We found that bats indeed host more zoonotic viruses per species than rodents, and we identified life-history and ecological factors that promote zoonotic viral richness. More zoonotic viruses are hosted by species whose distributions overlap with a greater number of other species in the same taxonomic order (sympatry). Specifically in bats, there was evidence for increased zoonotic viral richness in species with smaller litters (one young), greater longevity and more litters per year. Furthermore, our results point to a new hypothesis to explain in part why bats host more zoonotic viruses per species: the stronger effect of sympatry in bats and more viruses shared between bat species suggests that interspecific transmission is more prevalent among bats than among rodents. Although bats host more zoonotic viruses per species, the total number of zoonotic viruses identified in bats (61) was lower than in rodents (68), a result of there being approximately twice the number of rodent species as bat species. Therefore, rodents should still be a serious concern as reservoirs of emerging viruses. These findings shed light on disease emergence and perpetuation mechanisms and may help lead to a predictive framework for identifying future emerging infectious virus reservoirs.

Long-term studies of hantavirus reservoir populations in the southwestern United States: a synthesis.

A series of intensive, longitudinal, mark-recapture studies of hantavirus infection dynamics in reservoir populations in the southwestern United States indicates consistent patterns as well as important differences among sites and host-virus associations. All studies found a higher prevalence of infection in older (particularly male) mice; one study associated wounds with seropositivity. These findings are consistent with horizontal transmission and transmission through fighting between adult male rodents. Despite very low rodent densities at some sites, low-level hantavirus infection continued, perhaps because of persistent infection in a few long-lived rodents or periodic reintroduction of virus from neighboring populations. Prevalence of hantavirus antibody showed seasonal and multiyear patterns that suggested a delayed density-dependent relationship between prevalence and population density. Clear differences in population dynamics and patterns of infection among sites, sampling periods, and host species underscore the importance of replication and continuity of long-term reservoir studies. Nevertheless, the measurable associations between environmental variables, reservoir population density, rates of virus transmission, and prevalence of infection in host populations may improve our capacity to model processes influencing infection and predict increased risk for hantavirus transmission to humans.

Ecologic and geographic distribution of filovirus disease.

We used ecologic niche modeling of outbreaks and sporadic cases of filovirus-associated hemorrhagic fever (HF) to provide a large-scale perspective on the geographic and ecologic distributions of Ebola and Marburg viruses. We predicted that filovirus would occur across the Afrotropics: Ebola HF in the humid rain forests of central and western Africa, and Marburg HF in the drier and more open areas of central and eastern Africa. Most of the predicted geographic extent of Ebola HF has been observed; Marburg HF has the potential to occur farther south and east. Ecologic conditions appropriate for Ebola HF are also present in Southeast Asia and the Philippines, where Ebola Reston is hypothesized to be distributed. This first large-scale ecologic analysis provides a framework for a more informed search for taxa that could constitute the natural reservoir for this virus family.

Guidelines for Working with Rodents Potentially Infected with Hantavirus

Because of the high morbidity and mortality associated with hantavirus pulmonary syndrome and the possibility of aerosol transmission of hantaviruses, persons handling known reservoir species in the field, laboratory, or classroom should take special precautions to minimize the risk of infection. We provide specific guidelines for personal safety while trapping, handling and releasing, transporting, sampling, and performing necropsy on potentially infected rodents or teaching field classes in areas occupied by reservoir species. Special consideration should be given to respiratory protection, choice and use of disinfectants, decontamination of instruments and traps, proper disposal of infectious wastes, and preservation and shipment of samples intended for hantavirus testing. Precautionary testing of wild rodents used to start laboratory colonies is recommended. Although we specifically address hantaviruses, the procedures described are applicable for any study of populations of small mammals when an infectious zoonotic agent transmissible by aerosol and capable of causing high morbidity and mortality is involved.

Potential Influence of Climate Change on Vector-Borne and Zoonotic Diseases: A Review and Proposed Research Plan

Background Because of complex interactions of climate variables at the levels of the pathogen, vector, and host, the potential influence of climate change on vector-borne and zoonotic diseases (VBZDs) is poorly understood and difficult to predict. Climate effects on the nonvector-borne zoonotic diseases are especially obscure and have received scant treatment. Objective We described known and potential effects of climate change on VBZDs and proposed specific studies to increase our understanding of these effects. The nonvector-borne zoonotic diseases have received scant treatment and are emphasized in this paper. Data sources and synthesis We used a review of the existing literature and extrapolations from observations of short-term climate variation to suggest potential impacts of climate change on VBZDs. Using public health priorities on climate change, published by the Centers for Disease Control and Prevention, we developed six specific goals for increasing understanding of the interaction between climate and VBZDs and for improving capacity for predicting climate change effects on incidence and distribution of VBZDs. Conclusions Climate change may affect the incidence of VBZDs through its effect on four principal characteristics of host and vector populations that relate to pathogen transmission to humans: geographic distribution, population density, prevalence of infection by zoonotic pathogens, and the pathogen load in individual hosts and vectors. These mechanisms may interact with each other and with other factors such as anthropogenic disturbance to produce varying effects on pathogen transmission within host and vector populations and to humans. Because climate change effects on most VBZDs act through wildlife hosts and vectors, understanding these effects will require multidisciplinary teams to conduct and interpret ecosystem-based studies of VBZD pathogens in host and vector populations and to identify the hosts, vectors, and pathogens with the greatest potential to affect human populations under climate change scenarios.

Experimental Evidence for Reduced Rodent Diversity Causing Increased Hantavirus Prevalence

Emerging and re-emerging infectious diseases have become a major global environmental problem with important public health, economic, and political consequences. The etiologic agents of most emerging infectious diseases are zoonotic, and anthropogenic environmental changes that affect wildlife communities are increasingly implicated in disease emergence and spread. Although increased disease incidence has been correlated with biodiversity loss for several zoonoses, experimental tests in these systems are lacking. We manipulated small-mammal biodiversity by removing non-reservoir species in replicated field plots in Panama, where zoonotic hantaviruses are endemic. Both infection prevalence of hantaviruses in wild reservoir (rodent) populations and reservoir population density increased where small-mammal species diversity was reduced. Regardless of other variables that affect the prevalence of directly transmitted infections in natural communities, high biodiversity is important in reducing transmission of zoonotic pathogens among wildlife hosts. Our results have wide applications in both conservation biology and infectious disease management.

Long-Term Studies of Hantavirus Reservoir Populations in the Southwestern United States: Rationale, Potential, and Methods

Hantaviruses are rodent-borne zoonotic agents that cause hemorrhagic fever with renal syndrome in Asia and Europe and hantavirus pulmonary syndrome (HPS) in North and South America. The epidemiology of human diseases caused by these viruses is tied to the ecology of the rodent hosts, and effective control and prevention relies on a thorough understanding of host ecology. After the 1993 HPS outbreak in the southwestern United States, the Centers for Disease Control and Prevention initiated long-term studies of the temporal dynamics of hantavirus infection in host populations. These studies, which used mark-recapture techniques on 24 trapping webs at nine sites in the southwestern United States, were designed to monitor changes in reservoir population densities and in the prevalence and incidence of infection; quantify environmental factors associated with these changes; and when linked to surveillance databases for HPS, lead to predictive models of human risk to be used in the design and implementation of control and prevention measures for human hantavirus disease.