Feature Beyond the Fire-Hazard Mentality of Medicine: The Ecology of Infectious Diseases Jane Bradbury

ifty years ago, many experts able to predict or ameliorate disease and so cholera remains an important believed that the war against outbreaks’. global health problem. Because her infectious diseases had largely studies showed that virtually all the V. F From Ecology to Disease been won. But in the last 30 years of cholerae in water supplies are attached the 20th century, as people entered Prevention: The Cholera Example to 200 µm–long zooplankton, Colwell previously untouched wild areas A good example of how ecological reasoned that it might be possible to or wreaked wide-scale changes on studies can suggest new ways to prevent make water safe to drink simply by established ecosystems, numerous disease outbreaks is provided by the filtering it through layers of cloth. In a viruses (for example, Ebola) have work of Rita Colwell, director of recent trial in rural Bangladesh, cholera jumped from their long-time animal the United States’ National Science rates were halved when villagers filtered hosts to people who, not having the Foundation (Arlington, Virginia, their drinking water through eight appropriate immune layers of sari cloth, a defence, often succumb cheap but effective to virulent ‘emerging’ and socially acceptable diseases. At the same intervention, explains time, old enemies Colwell (Figure 1). such as dengue and Kathryn Cottingham hantavirus pulmonary (Dartmouth College, syndrome have re- Hanover, New emerged to cause Hampshire, United important human States) and her epidemics. All too team are also doing often when faced ecological studies on V. with these emerging cholerae that may help and re-emerging to improve cholera diseases, says hantavirus control in developing researcher Terry Yates countries. ‘We are (University of New recording the temporal Mexico, Albuquerque, dynamics of both free- New Mexico, United living and attached States), ‘society has bacteria in two ponds adopted a fire-hazard in Bangladesh, one that DOI: 10.1371/journal.pbio.0000022.g001 mentality. We have an is largely untouched outbreak and we go Figure 1. Women at a Village Pond in Matlab, Bangladesh, Washing Utensils and by people and one in in and put out the fire Vegetables a village’, she explains. The woman on the right is putting a sari filter onto a water-collecting pot (or without ever asking kalash) to filter water for drinking. (Picture courtesy of Anwar Huq, University ‘By doing this, we hope why there was a fire in of Maryland Biotechnology Institute, Baltimore, Maryland, United States.) to get a better idea of the first place’. Yates which physical and and other experts are now calling for United States). In the 1960s, Colwell chemical changes prompt changes in an integrated approach to disease discovered that pathogenic strains of the V. cholerae population’, information prevention and control, based on a Vibrio cholerae, the cause of cholera, that can be used to build a predictive detailed understanding not only of the could be isolated from Chesapeake model of when and where cholera biology and but also of the ecology of Bay in the United States. Her discovery outbreaks might occur, as can other disease. For animal-borne (zoonotic) created a furore and people were studies that Colwell has underway that and vector-borne diseases, but also for initially reluctant to accept that use satellites to monitor large-scale diseases like cholera, which constantly V. cholerae was a marine organism. environmental changes. re-emerge around the world, ‘it is not However, subsequent studies showed Cottingham’s studies may also lead sufficient to know who the players that V. cholerae is an abundant, naturally are’, says Lyme disease researcher occurring component of aquatic Abbreviations: AHF, Argentine haemorrhagic fever; Rick Ostfeld (Institute of Ecosystem ecosystems worldwide, where it is CDC, United States Centers for Disease Control and Prevention; DHF, dengue haemorrhagic fever Studies, Millbrook, New York, United associated with phytoplankton and States). ‘We also need to know how the zooplankton, in particular copepods. Jane Bradbury is a freelance science news hosts, vectors, and infectious organisms Although boiling removes V. cholerae writer based in Cambridge, United Kingdom. E-mail: [email protected] interact with each other and with their from water, this is often not done environment if we are going to be in villages in the developing world, DOI: 10.1321/journal.pbio.000022

PLoS Biology | http://biology.plosjournals.org Volume 1 | Issue 2 | Page 148 to the development of another low- Carolina, United States) has been tech approach to cholera control. V. trying to discover which, if any, of cholerae do not attach only to copepods, these changes were responsible for she explains. They also attach to the emergence of DHF in Sri Lanka cladocerans, zooplankton that moult in 1989. His recently published regularly throughout their lifetime conclusion, after looking at all the and graze on unattached V. cholerae. available data on changes in the Cottingham’s hope is that by changing human population, exposure to the fishing practices in rural ponds, fish Aedes aegypti vector, the environment, communities can be established that and the virus itself, is that ‘very little prey on copepods in preference to happened in Sri Lanka apart from a cladocerans, thus reducing bacterial change in the virus that could explain loads in drinking water. the emergence and persistence of DHF’. That change—the arrival of Bring in the Vectors a dengue serotype 3, subtype III Zooplankton in a sense are V. virus that originated in the Indian cholerae vectors, but the term ‘disease subcontinent—was most likely caused vectors’ is more usually applied to by people bringing this virulent virus mosquitoes and other biting insects. serotype into Sri Lanka. However, the The recognition that malarial control, question remains as to what selective for example, requires an understanding pressures drove the original viral of mosquito populations goes back at change and what prevented the virulent least a century. Worryingly, however, serotype arriving in Sri Lanka earlier. DOI: 10.1371/journal.pbio.0000022.g003 numerous arboviral diseases—diseases transmitted by blood-feeding One Host or More? Figure 3. Acorns at the Base of a Red Oak (Quercus rubra) during a Heavy Year of Mast arthropods—have recently emerged Dengue is unique among arboviruses Production or become established in new in that it is fully adapted to using Many species of wildlife, including white- geographical regions. For example, human beings as its vertebrate host. footed mice (P. leucopus), an important some dengue viruses, which are also Most arboviruses have co-evolved with disease reservoir for Lyme disease, transmitted by mosquitoes, have their animal or bird hosts, which are feast on acorns during years of high availability. (Picture courtesy of Rick recently extended their range. Before required for their lifecycle, and people Ostfeld; photograph by Molly Ahearn.) 1970, the most severe form of dengue are only incidental hosts. Factoring infection—dengue haemorrhagic fever in additional hosts greatly increases (DHF)—had caused epidemics in only system complexity. Take West Nile belonging to about 10 genera. ‘Twenty- nine countries. By 1995 that figure had virus, for example, a mosquito-borne nine or so of these mosquito species more than quadrupled. disease agent that requires birds for are mammal feeders or opportunistic Greater urbanisation, human its maintenance. Until recently, the feeders, and although we have isolated population growth, increased human geographical range of West Nile virus the virus from about 25 species of travel, and a global reduction of disease extended from Africa through mammals, we simply do not know what effective mosquito control programmes the Middle East to southern and part these species play in the lifecycle have all been implicated in the eastern Europe and western Asia. Then, of West Nile’, says Gubler. Really observed changes in dengue dynamics. in 1999, the first 62 cases were reported effective control, he stresses, will rely Ecologist William Messer (University in the United States. Last year, there on knowing which vectors and hosts are of North Carolina, Chapel Hill, North were 4,156 human cases in the United critical for virus maintenance and for States and West Nile virus was found in bringing the virus into the areas around all but six states. human habitation where people Duane Gubler, director of the become infected. Division of Vector-Borne Diseases at This research will involve many the United States’ Centers for Disease different specialists, including mosquito Control and Prevention (CDC; Fort experts like Colin Malcolm (Queen Collins, Colorado, United States), is Mary, University of London, United under no illusion that preventing West Kingdom). Malcolm is trying to predict Nile virus disease outbreaks will be easy. whether West Nile virus disease could ‘We really don’t know enough about establish itself in the United Kingdom. the ecology of this disease to target our ‘There must be a big difference control efforts appropriately’, he says. between the ecology and biology of the ‘We know that the mosquito–bird–viral different physiological forms of Culex DOI: 10.1371/journal.pbio.0000022.g002 maintenance cycle requires certain pipiens in Europe, where it only causes Figure 2. The Emergence of AHF species of birds, but we don’t know all sporadic West Nile outbreaks, and the The emergence of AHF coincided the bird hosts’. Similarly, Culex pipiens United States where it has spread like with wide-scale changes in agricultural practices on the pampas of Argentina. mosquitoes are clearly important in wildfire’, says Malcolm. ‘We need to (Picture courtesy of Delia Enria, Instituto the West Nile virus lifecycle, but the understand that difference and to know Nacional de Enfermedades Virales virus has been isolated from 37 species exactly which Culex pipiens we have Humanas, Pergamino, Argentina.) of mosquito in the United States, in the UK’. The British Culex pipiens

PLoS Biology | http://biology.plosjournals.org Volume 1 | Issue 2 | Page 149 pipiens mosquito is mainly a bird biter, he explains, while the British Culex pipiens molestus is a mammal feeder. ‘But we don’t know the extent to which our bird-biting mosquito bites people or whether the human-biting form ever bites birds’, and for the virus to be transmitted from birds to people, not only does the virus have to be in birds, but there has to be a vector that will bite both. However, even if the indigenous mosquito populations in the United Kingdom do not bridge the gap between birds and people, ‘the characteristics of our native mosquitoes could change’, warns Malcolm, possibly through mating with an imported mosquito. Worryingly, Malcolm recently discovered a colony of imported Culex pipiens molestus mosquitoes in Scotland although, because the colony was isolated, no interbreeding with native DOI: 10.1371/journal.pbio.0000022.g004 mosquitoes seems to have occurred. Figure 4. The Host for Hantavirus Rodents, Habitat Disturbance, The deer mouse (P. maniculatus) is the reservoir host for the Sin Nombre hantavirus, the cause of hantavirus pulmonary syndrome. (Picture courtesy of the CDC and the and Disease Partnership, Inc.) Human disturbance of natural habitats can often underlie disease rodent assemblages, the prevalence of particularly well in very small forest emergence or re-emergence by hantavirus infection in the favoured fragments, exactly the sorts of areas that providing habitats that favour the host species increases’. This, explains people like having around their houses survival of disease vectors or hosts. Yates, is because when the virus is in suburban developments, notes Paddy field development and the released from a rodent, ‘some of it will Ostfeld wryly. subsequent emergence of mosquito- land on the right rodent and continue borne diseases is one well-known its lifecycle; the rest will land on the Can Ecological Studies Predict or example, but human diseases caused wrong rodent. In an ecosystem where Prevent Disease Outbreaks? by rodent-borne pathogens are also only the right rodent is left, the virus For Lyme disease, then, Ostfeld’s affected by habitat change. Delia Enria, flourishes’. Importantly, Mills and Yates ecological studies suggest that new director of the Instituto Nacional know from other work that human housing developments could be de Enfermedades Virales Humanas hantavirus outbreaks are related both designed to minimise the risk of people (Pergamino, Argentina), works on to overall rodent numbers and to the contracting Lyme disease around arenaviruses, rodent-borne viruses numbers of rodents that are infected. their homes. Furthermore, because that pass into people through contact Habitat fragmentation is one of the risk of Lyme disease is known to with rodent excreta. Enria’s team has the driving forces behind biodiversity increase two years after a good acorn been studying Junín virus, the cause of reduction, and a final rodent-borne year, a major food source for white- Argentine haemorrhagic fever (AHF), disease—Lyme disease—provides footed mice (Figure 3), one simple which first emerged in 1958. ‘To feed a good example of the need, when preventative measure, suggests Ostfeld, our population, the central pampas thinking about disease control, to might be to have a ‘Smoky the Mouse’ of Argentina were being modified at consider how people interact with the warning system, featuring posters in that time’ (Figure 2), she explains, natural environment. The disease- wilderness areas advertising local high ‘and we think that these agricultural causing agent, explains Ostfeld, is the or low Lyme disease risk predictions changes favoured corn mice (Calomys bacterium Borrelia burgdorferi, which is based on acorn crop records. For other musculinus), the Junín virus reservoir, transmitted to people by ticks of the rodent-borne diseases, an awareness of over the previously dominant species in genus Ixodes. ‘The ticks, which acquire when rodent populations are increasing the area’. the infection in their first blood meal, is already passed onto the general Indeed, the ability of host species to have extremely catholic habits in terms public, and for those rodents that thrive in disturbed habitats, often at of host preference, but only some of the enter human habitation, this can be the expense of other rodent species, hosts are competent for transmitting accompanied by advice on how to avoid may be an important factor in the the bacteria to the tick’, says Ostfeld. rodent infestations in homes. Similarly, emergence and re-emergence of many In North America the main disease for mosquito-borne diseases, education rodent-borne diseases. In the case of reservoir is the white-footed mouse about how to avoid mosquito bites can hantavirus, says James Mills, chief of the (Peromyscus leucopus), a generalist that go some way to reducing the magnitude CDC Medical Ecology Unit (Atlanta, can live virtually anywhere. Importantly, of disease outbreaks. Georgia, United States), ‘as human unlike many of their competitors and In every case, the more warning influences reduce the diversity of their predator species, these mice do that can be given of an impending

PLoS Biology | http://biology.plosjournals.org Volume 1 | Issue 2 | Page 150 Where to Find Out More For general descriptions of various emerging and re-emerging A recent paper describing an ecological and virological study of diseases, visit the World Health Organization health topics page at the emergence of dengue haemorrhagic fever in Sri Lanka in 1989. http://www.who.int/health_topics/en/ or the United States Centers West Nile Virus for Disease Control and Prevention health topics page at http: Gubler DJ (2002) The global emergence/resurgence of arboviral //www.cdc.gov/health/default.htm. diseases as public health problems. Arch Med Res 33: 330–342. Cholera Overview of the resurgence or emergence of several epidemic Colwell RR, Huq A, Islam MS, Aziz KM, Yunus NH, et al. (2003) arboviral diseases including dengue and West Nile virus. Reduction of cholera in Bangladeshi villages by simple filtration. Hantavirus and AHF Proc Natl Acad Sci U S A 100: 1051–1055. Glass GE, Yates TL, Fine JB, Shields TM, Kendall JB, et al. (2002) Field trial of sari cloth filtration to reduce cholera outbreaks, a Satellite imagery characterizes local animal reservoir populations of low-tech, ecology-based approach to disease prevention. Sin Nombre virus in the southwestern United States. Proc Natl Acad Cottingham KL (2002) Tackling biocomplexity: The role of people, Sci U S A 99: 16817–16822. tools, and scale. BioScience 52: 793–799. Research paper describing the identification of refugia for the To understand, predict, and manage ecological responses to Sin Nombre hantavirus. anthropogenic change requires the collaboration of people from Mills JN, Childs JE (1998) Ecologic studies of rodent reservoirs: many different disciplines. In this article, Cottingham describes Their relevance for human health. Emerg Infect Dis 4: 529–537. three examples of how aquatic ecosystems are being studied using Review of how to study vertebrate host ecology and its relation a biocomplexity research approach. to human disease in the light of increasing numbers of emerging Cottingham KL, Chiavelli DA, Taylor RK (2003) Environmental diseases (including AHF) associated with small-mammal reservoirs. microbe and human pathogen: The ecology and microbiology of Yates TL, Mills JN, Parmenter CA, Ksiazek TG, Parmenter RR, et Vibrio cholerae. Front Ecol Environ 1: 80–86. al. (2002) The ecology and evolutionary history of an emergent Overview of the ecology of V. cholerae and discussion of how disease: Hantavirus pulmonary syndrome. BioScience 52: 989–998. understanding this can help in controlling the persistence and This review describes the discovery of how El Niño-driven spread of cholera. precipitation is sufficient to predict when human outbreaks of Dengue hantavirus pulmonary syndrome will occur. Gubler DJ (2002) Epidemic dengue/dengue hemorrhagic fever Lyme Disease as a public health, social and economic problem in the 21st century. LoGiudice K, Ostfeld RS, Schmidt KA, Keesing F (2003) The Trends Microbiol 10: 100–103. ecology of infectious disease: Effects of host diversity and An opinion piece describing the re-emergence of dengue and community composition on Lyme disease risk. Proc Natl Acad Sci U calling for integrated community-based prevention and control S A 100: 567–571. programmes for dengue. This research paper describes how the loss of vertebrate Messer WB, Gubler DJ, Harris E, Sivananthan K, de Silva AM (2003) biodiversity through habitat fragmentation or other anthropogenic Emergence and global spread of a dengue serotype 3, subtype III forces can increase the incidence of Lyme disease. virus. Emerg Infect Dis 9: 800–809. outbreak and the more details of its Yates, ‘we can now predict about 88% of its implications for disease outbreaks location and timing, the more that of the time what the risk of hantavirus improves, care will have to be taken can be done to reduce the human infection is at any given place about not to extrapolate from one area to disease burden. Work being done six months in advance’. More recently, another without taking account of by Mills, Yates, and their colleagues the researchers have developed their subtle differences in environmental provides a good illustration of how, at models further to predict the existence drivers, and human behaviour and least for the Sin Nombre hantavirus, of refugia, ecologically distinct areas living conditions will also have to greater predictive accuracy is becoming where the virus survives hidden within be considered. Most importantly, a reality. Hantavirus pulmonary focal mouse populations between says Gubler, ‘we must throw off the syndrome outbreaks, which are caused human outbreaks. Finally, in a complacency of the past 30 years by the Sin Nombre virus, occur when collaboration with physicists, theoretical when we focused mainly on curative deer mouse (Peromyscus maniculatus) predictive models based on wave theory medicine, surveillance, and emergency (Figure 4) populations and other have been built that, if they can be response to zoonotic and vector-borne infected rodent numbers increase. empirically verified, will provide an diseases’. In the first 60 years of the Monitoring these changes on the even earlier prediction of when and 20th century, comments Gubler, many ground can only give local information where hantavirus outbreaks will occur arboviral diseases were well controlled, and cannot provide much notice of by predicting viral spread from the but as attention turned to high-tech increased human hantavirus risk. refugia, says Yates. solutions such as vaccines, little money However, as Mills explains, long-term was provided for continued research ecological studies have shown that deer The Future Is in Integrated Research in disease ecology and prevention mice populations increase a year after Many more factors will need to be research. A return to a fully integrated El Niño climatic events as a result of an added into models like those being approach to control and prevention is increased food supply. The researchers developed by Mills, Yates, and other essential, concludes Gubler, if emerging have been able to correlate changes researchers to optimise prediction and infectious diseases are going to be in rodent populations with wide-scale control of human disease outbreaks. adequately controlled, particularly in vegetation changes detected through Climate change will have to be taken tropical countries where they continue satellite monitoring and, as a result, says fully into account as our understanding to be a pressing problem.  PLoS Biology | http://biology.plosjournals.org Volume 1 | Issue 2 | Page 151