plague: past, present, and future by mike begon et alt

8/12/2019 Plague: Past, Present, and Future by Mike Begon et alt

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Centre for Ecological and Evolutionary Synthesis

University of Oslo

Memo: Work by the Centre for Ecological and Evolutionary Synthesis (CEES) in Kazakhstan,

Georgia and Azerbaijan (and China)

Author: Nils Chr. Stenseth (Professor and Chair of CEES (http://www.cees.uio.no/); also president

elect of the Norwegian Academy of Science and Letters;http://english.dnva.no/)

Date: 22.04.12

The Centre for Ecological and Evolutionary Synthesis(CEES) has during the last 10 years served as both chair

and partner in collaborative projects on the dynamics of the plague bacterium (Yersinia pestis, the causative

agent of plague, including the Black Death); plague continues to be a health problem and threat

(bioterrorism) around the world, not the least in Asia and Africa but also North America). Most of ourcollaborative work on the plague system has been done out of Kazakhstan (Kazakh Scientific Centre for

Quarantine and Zoonotic Diseases, Almaty); recently we have been extending this to China (working both

with the Chinese Academy of Science(Beijing) and the Chinese Academy of Military Medical Sciences

(Beijing)) as well as to the Caucasus region (Georgia and Azerbaijan)1.

Our collaborative work within Caucusus is associated with the new state-of-the-art pathogens facility

in Georgia (in Tbilisi), the Georgian Central Public Health Reference Laboratory(CPHRL) built by the U.S.

Dept. of Defense, Defense Threat Reduction Agency (DTRA)2. The facility is meant to be a reference

laboratory for strains collected in Georgia and a base for scientific work on those pathogens. CEES is at the

international forefront in combining ecological, evolutionary and genomics work on such systems with a

focus on the dynamics in the wild and thus is a complementary research unit to those institutions that take

a human focus in their studies on these diseases. Being involved in the development of these facilities gives

CEES a unique opportunity to contribute with new insights on the ecology and evolution of these bacterial

systems3.

Having published several highly visible publications in top international journals (see a list of

publications at the end of this document) together with Kazakh and Chinese scientists within an open

collaborative network, provides CEES and Norway with unique opportunities for further collaborative

work in Central Asia and the Caucasus4. Norwegian involvement in such work in this part of the world has

many obvious benefits, including positive visibility as well as getting first hand insight into such health and

threat issues.

1

During Soviet times anti-plague stations were set-up around the country in areas endemic to the plague bacterium. These stationsmonitored and recorded ecological and meteorological data associated with plague in hopes to better understand and control the

disease. In Kazakhstan, data was made available to us and our collaborators from the Pre-Balkash plague focus. From these data we

were able to describe conditions that allow plague to reach epidemic proportions. Currently we are in the process of initiating

collaborative projects to localize where the bacterium is between epizootics, a central question in eco-epidemiology: this work may

be carried out in Kazakhstan or some of the Caucasus countries.2NC Stenseth serves as a member of the Scientific Advisory Council of CPHRL and these facilities.

3In Azerbaijan, we are setting up similar collaborations; we will have access to the Georgian facility to conduct our experimental

work, and also to ecological data from their three separate and unique systems. Azerbaijan is a unique region: small in area yet

containing very unique foci for both disease strains as well as for the rodents that manifest the disease.4Building upon our work on the plague system and our general ecological and evolutionary platform, we at CEES are currently in the

process of further developing our work on the ecology and evolution of human infectious diseases with an environmental reservoir,

with a focus on Yersinia pestis (Plague), Bacillus anthracis(Anthrax), Borrelia burgdorferi(Lyme disease) and Francisella tularensis

(Tularemia). Our overall objective is to develop an overarching view on the geographical distributions and genetic variations of thesebacteria. In collaboration with several other international research institutions, the CEES will focus on the eco-evolutionary dynamics

of these sylvatic-based epidemiological systems work which will be of great value to those focusing on the human-linked part of

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Plague-themed papers authored/co-authored by Stenseth/CEES (two of the papers are included

at the end of the document).

Ben Ari, T., Gershunov, A., Gage, K.L., Snll, T., Ettestad, P., Kausrud, K.L. & Stenseth, N.C. (2008) Human plague in the USA: the

importance of regional and local climate. Biology Letters,4,737-740.

Ben Ari, T., Gershunov, A., Rouyer, T., Cazelles, B., Gage, K. & Stenseth, N.C. (2010) Interannual Variability of Human Plague

Occurrence in the Western United States Explained by Tropical and North Pacific Ocean Climate Variability.American

Journal of Tropical Medicine and Hygiene.,83,624632.Ben Ari, T., Neerinckx, S., Gage, K., Kreppel, K., Laudisoit, A., Leirs, H. & Stenseth, N.C. 2011. Plague and climate: scales matter. PLoS

Pathogen7, e1002160. (Enclosed below as Enclosure 2).

Ben Ari, T., Neerinckx, S., Agier, L., Cazelles, B., Xu, L., Zhang, Z., Fang, X., Wang, S., Liu, Q. & Stenseth, N.C. 2012. Indentifying

Enzootic Plague Foci in China Using Long-term Epidemiological data.Proceedings of National Academy of Science,

Washington(in press).

Davis, S., Begon, M., De Bruyn, L., Ageyev, V.S., Klassovskiy, N.L., Pole, S.B., Viljugrein, H., Stenseth, N.C. & Leirs, H. (2004) Predictive

thresholds for plague in Kazakhstan. Science,304,736-738.

Davis, S., Leirs, H., Viljugrein, H., Stenseth, N.C., De Bruyn, L., Klassovskiy, N., Ageyev, V. & Begon, M. (2007) Empirical assessment of

a threshold model for sylvatic plague.Journal of the Royal Society Interface,4,649-657.

Easterday, W.R., Kausrud, K.L., Star, B., Heier, L., Haley, B.J., Ageyev, V., Colwell, R.R. & Stenseth, N.C. 2012. An additional step in the

transmission of Yersinia pestis. The ISME journal, 6, 231236.

Frigessi, A., Holden, M., Marshall, C., Viljugrein, H., Stenseth, N.C., Holden, L., Ageyev, V. & Klassovskiy, N.L. (2005) Bayesian

population dynamics of interacting species: great gerbils and fleas in Kazakhstan. Biometrics,61,230-238.

Heier, L., Davis, S.A., Storvik, G.O., Viljugrein, H., Arayev, V., Klassovskaya, E. & Stenseth, N.C. 2011. Re-emergence, Spread and

Persistence of Sylvatic Plague in Kazakhstan: Comparison of invasion vs. persistence, and reemergence vs. spread.

Proceedings of the Royal Society of London, B 278, 2915-2923..

Kausrud, K.L., Viljugrein, H., Frigessi, A., Begon, M., Davis, S., Leirs, H., Dubyanskiy, V. & Stenseth, N.C. (2007) Climatically driven

synchrony of gerbil populations allows large-scale plague outbreaks. Proceedings of the Royal Society B: Biological Sciences,

274,1963-1969.

Kausrud, K.L., Begon, M., Ari, T.B., Viljugrein, H., Esper, J., Bntgen, U., Leirs, H., Junge, C., Yang, B., Yang, M. & Stenseth, N.C. (2010)

Modeling the epidemiological history of plague in Central Asia: Palaeoclimatic forcing on a disease system over the past

millennium. BMC biology,8 (112).

Klassovskaya, E.V., Davis, S., Leirs, H., Stenseth, N.C., Begon, M., Dubyanskiy, V.M., Burdelov, L.A., Ageyev, V.S., Sapozhnikov, V.I. and

Alipbaev, A.K. 2007. Threshold model for predicting of plague epizootics in one locality of southern Pre-Balkhash and

testing the model in 2004-2006. Quarantine and zoonozis disease in Kazakhstan, 1-2, 18-29.

Park, S., Chan, K.S., Viljugrein, H., Nekrassova, L., Suleimenov, B., Ageyev, V.S., Klassovskiy, N.L., Pole, S.B. & Stenseth, N.C. (2007)

Statistical analysis of the dynamics of antibody loss to a disease-causing agent: plague in natural populations of greatgerbils as an example.Journal of the Royal Society Interface,4,57-64.

Samia, N.I., Chan, K.-S. & Stenseth, N.C. (2007) A generalized threshold mixed model for analyzing nonnormal nonlinear time series,

with application to plague in Kazakhstan. Biometrika,94,101-118.

Samia,N., Kausrud, K., Heesterbeek,H., Ageyev, V., Begon, M., Chan, K.-S. & Stenseth, N.C. 2011. The dynamics of the plague-wildlife-

human system in Central Asia is controlled by two epidemiological thresholds. Proceedings of National Academy of Science,

Washington 108, 14527-14532.

Snll, T., Benestad, R. & Stenseth, N. (2009) Expected future plague levels in a wildlife host under different scenarios of climate

change. Global Change Biology,15,500-507.

Stenseth, N.C., Samia, N.I., Viljugrein, H., Kausrud, K.L., Begon, M., Davis, S., Leirs, H., Dubyanskiy, V.M., Esper, J., Ageyev, V.S.,

Klassovskiy, N.L., Pole, S.B. & Chan, K.S. (2006) Plague dynamics are driven by climate variation. Proceedings of the National

Academy of Sciences,103,13110-13115.

Stenseth, N.C. (2008) Plague Through History. Science,321,773-774.

Stenseth, N.C., Atshabar, B.B., Begon, M., Belmain, S.R., Bertherat, E., Carniel, E., Gage, K.L., Leirs, H. & Rahalison, L. (2008) Plague:

past, present, and future. PLoS Medicine,5,9-13. (Enclosed below as Enclosure 1)

Stesneth, N.C. 2008. Plague and climate. In: Institute of Medicine (ed) Global Climate Change and Extreme Weather Events:

Understanding the Contributions to the Emergence, Re-emergence, and Spread of Infectious Disease Washington, DC: The

National Academies Press. Pp. 130-145.

Stenseth, N.C. & Ben Ari, T. 2010. La Peste: histoire et cologie dune maladie nglige [Plague: the history and ecology of a

neglected disease]. In: Gauthier-Clerc, M. & Thomas, F. (eds.)Ecologie de la Sant et Biodiversit, De Boeck Universit,

Bruxelles 239-248.

Xu, L., Qiyong, L., Stige, L.C., Ben Ari, T., Fang, X., Chan, K.-S., Wang, S., Stenseth, N.C., Zhang, Z. 2011. Nonlinear effect of climate on

plague during the third pandemic in China. Proceedings of National Academy of Science, Washington 108, 10214-10219.

Zhang, Z., Li, Z., Tao, Y., Chen, M., Wen, X., Xu, L., Tian, H. & Stenseth, N.C. 2007. Relationship between increase rate of human

plague in China and global climate index as revealed by cross-spectral analysis and cross-wavelet analysis. Integrative

Zoology2, 144-153.


3/13PLoS Medicine | www.plosmedicine.org 0009 January 2008 | Volume 5 | Issue 1 | e3

Neglected Diseases

Recent experience with SARS (severe acute respiratory

syndrome) [1] and avian flu shows that thepublic and political response to threats from new

anthropozoonoses can be near-hysteria. This can readily makeus forget more classical animal-borne diseases, such as plague(Box 1).

Three recent international meetings on plague (Box 2)concluded that: (1) it should be re-emphasised that theplague bacillus (Yersinia pestis) still causes several thousandhuman cases per year [2,3] (Figure 1); (2) locally perceivedrisks far outstrip the objective risk based purely on thenumber of cases [2]; (3) climate change might increase therisk of plague outbreaks where plague is currently endemicand new plague areas might arise [2,4]; (4) remarkably little

is known about the dynamics of plague in its natural reservoirsand hence about changing risks for humans [5]; and,therefore, (5) plague should be taken much more seriously bythe international community than appears to be the case.

The Plague Eco-Epidemiological System

The plague bacillus causes a rapidly progressing, seriousillness that in its bubonic form is likely to be fatal (40%70%mortality). Without prompt antibiotic treatment, pneumonicand septicaemic plague are virtually always fatal. For thesereasonsY. pestisis considered one of the most pathogenicbacteria for humans.

Yersinia pestisis transmitted by fleas, while the other twospecies of Yersinia known to be pathogenic for humans

(Y. enterocolitica and Y. pseudotuberculosis) are transmittedby the faecaloral route and cause intestinal symptoms ofmoderate intensity. Yersinia pestis is believed to be a cloneof Y. pseudotuberculosis that emerged within the last 1,500 to20,000 years [6,7]. This divergence was characterised by theacquisition of a few genetic elements; more particularly, twoplasmids that play a key role in flea-borne transmission [8,9].The exceptional pathogenicity of Y. pestis compared to theenteropathogenic species may be explained by its new modeof transmission. Indeed, the only means for this bacteriumto be transferred to new hosts is through septicaemia,

which allows the bacteria present in the bloodstream to beefficiently taken up by the flea during its blood meal [10].

Soon after Yersins identification of the plague bacillus[11], it became clear that urban outbreaks were linked totransmission among commensal rats and their fleas. In thisclassic urban-plague scenario, infected rats (transported,for example, by ships) arrive in a new city and transmit theinfection to local house rats and their fleas, which then serveas sources of human infection. Occasionally, humans developa pneumonic form of plague that is then directly transmittedfrom human to human through respiratory droplets.

The epidemiology of plague, however, is much more

complicated than this urban-plague scenario suggests,involving several othermore likelypathways oftransmission (Box 3 and Figure 2). This complicatedepidemiology necessitates a reconsideration of plagueecology.

The Past

Plague has given rise to at least three major pandemics.The first (the Justinian plague) spread around theMediterranean Sea in the 6th century AD, the second (theBlack Death) started in Europe in the 14th century andrecurred intermittently for more than 300 years, and the thirdstarted in China during the middle of the 19th century and

spread throughout the world. Purportedly, each pandemicwas caused by a different biovar of Y. pestis, respectively,Antiqua (still found in Africa and Central Asia), Medievalis

Plague: Past, Present, and FutureNils Chr. Stenseth*, Bakyt B. Atshabar, Mike Begon, Steven R. Belmain, Eric Bertherat, Elisabeth Carniel, Kenneth L. Gage,

Herwig Leirs, Lila Rahalison

Funding:This article emerged from a meeting at the Norwegian Academy ofScience and Letters in Oslo, a meeting funded by that academy, the University ofOslo, and by the European Commission INCO-COPERNICUS programme (STEPICA;ICA 2-CT2000-10046). The organizations played no further role, including no role inthe submission of this article.

Competing Interests: NCS declares that he is the project leader of the researchcontract number ICA 2-CT2000-10046 granted from the European CommissionINCO-COPERNICUS programme for the STEPICA project that has contributedresearch on the ecology of plague in Central Asia; BBA, MB, EC, and HL participatedin the same project. MB declares that he is the project leader of the researchcontract number 063576/Z/01/Z granted from the Wellcome Trust. SRB declaresthat he is the technical coordinator and project leader of research contract number

ICA4 2002 10056 granted from the European Commission INCO-DEV programmefor the RATZOOMAN project that has contributed to research on the ecology ofplague in southern Africa. HL declares that he participated in the same project andthat he is holding a research grant from the Fund for Scientific Research (Flanders)to investigate the distribution of plague in Africa.

Citation: Stenseth NC, Atshabar BB, Begon M, Belmain SR, Bertherat E, et al.(2008) Plague: Past, present, and future. PLoS Med 5(1): e3. doi:10.1371/journal.pmed.0050003

Copyright:This is an open-access article distributed under the terms of theCreative Commons Public Domain declaration, which stipulates that, once placedin the public domain, this work may be freely reproduced, distributed, transmitted,modified, built upon, or otherwise used by anyone for any lawful purpose.

Abbreviations: DRC, Democratic Republic of Congo; WHO, World HealthOrganization

Nils Chr. Stenseth is with the Centre for Ecological and Evolutionary Synthesis,Department of Biology, University of Oslo, Oslo, Norway. Bakyt B. Atshabar iswith the Kazakh Scientific Centre for Quarantine and Zoonotic Diseases, Almaty,Kazakhstan. Mike Begon is with the School of Biological Sciences, BiosciencesBuilding, University of Liverpool, Liverpool, United Kingdom. Steven R. Belmainis with the Natural Resources Institute, University of Greenwich, Kent, UnitedKingdom. Eric Bertherat is with Epidemic Readiness and Interventions, Departmentof Epidemic and Pandemic Alert and Response, World Health Organization, Geneva,Switzerland. Elisabeth Carniel is with the Yersinia Research Unit, Institut Pasteur,Paris, France. Kenneth L. Gage is with the Flea-Borne Diseases Laboratory, Centersfor Disease Control and Prevention, Fort Collins, Colorado, United States of America.Herwig Leirs is with the Evolutionary Ecology Group, University of Antwerp,Antwerpen, Belgium, and the Danish Pest Infestation Laboratory, Universityof Aarhus, Faculty of Agricultural Sciences, Department of Integrated PestManagement, Kongens Lyngby, Denmark. Lila Rahalison is with the LaboratoireCentral de la Peste, Institut Pasteur de Madagascar, Antananarivo, Madagascar.

* To whom correspondence should be addressed. E-mail: [email protected]

The Neglected Diseases section focuses attention either on a specific disease or

describes a novel strategy for approaching neglected health issues in general.



(currently limited to Central Asia), and Orientalis (almostworldwide in its distribution) [12,13].

The Black Death decimated Medieval Europe, andhad a major impact on the continents socio-economicdevelopment, culture, art, religion, and politics [14,15].Several high-profile critiques have questioned whetherthe Black Death was indeed caused by Y. pestis[16,17].Proponents of both sides of the debate came together at last

years Oslo and London meetings (Box 2). It was generallyaccepted that the epidemiology of Black Death plague, asreflected in historical records, did not always match theclassical rat-flea-human plague cycle. However, the reported

medical symptoms were very similar during each pandemic. Inaddition, the international experience of modern-day plaguerepresented at the Oslo meeting made it clear that classicalplague epidemiology is only one of several possibilities toexplain the Black Death, and may not even be the most typicalof the different plague ecology systems [18]. Discovery of Y.

pestisgenetic material in those who died from the Black Deathand are buried in medieval graves [19] further supports the

view that Y. pestiswas the causative agent of the Black Death.

The Present

Given this history, plague is often classified as a problem ofthe past. However, it remains a current threat in many parts

of the world (Figure 1A), particularly in Africa, where boththe number of cases (Figure 1B) and the number of countriesreporting plague (Figure 1C) have increased during recentdecades. Following the reappearance of plague during the1990s in several countries, plague has been categorised as are-emerging disease [20,21].

Plague is endemic in a variety of wildlife rodent speciesworldwide in a wide range of natural habitats, with commensalrats only sometimes playing a role as liaison hosts, carryingplague between the sylvatic reservoir and people. Variousother animal-to-human transmission pathways have beendocumented. Human plague may be contracted from (1)

being bitten by the fleas of wildlife rodent species in ruralsettings (e.g., in the south-western United States [22,23])or of commensal rodents that move freely between villagesand the forest habitats occupied by reservoir hosts (e.g., inTanzania); rodents movements have become more frequentas human activity has fragmented the forest [24]; (2) eatinginfected animals such as guinea pigs in Peru and Ecuador[25,26] or camels that contract the disease from rodent fleasin Central Asia and the Middle East [2731]; or (3) handlingcats infected through the consumption of plague-infectedrodents in Africa or the United States [3234]. Human-to-human transmission also occurs, either directly throughrespiratory droplets or indirectly via flea bites [3537].

doi:10.1371/journal.pmed.0050003.g001

Figure 1.The Global Distribution of Plague(A) Map showing countries with known presence of plague in wild reservoir species (red) (after [3]). For US only the mainland below 50 N is shown. (B)Annual number of human plague cases over different continents, reported to WHO in the period 19542005. (C) Cumulative number of countries thatreported plague to WHO since 1954.



Over the last 20 years, there have been 1,000 to 5,000human cases of plague and 100 to 200 deaths reported to the

World Health Organization (WHO) each year [38]. However,

because of poor diagnostic facilities and underreporting,the number of cases is almost certainly much higher. Overthe years, there has been a major shift in cases from Asiato Africa (Figure 1B), with more than 90% of all casesand deaths in the last five years occurring in Madagascar,Tanzania, Mozambique, Malawi, Uganda, and the DemocraticRepublic of the Congo (DRC). Most are cases of bubonicplague contracted through contact with infected rodents andfleas. However, outbreaks of pneumonic plague still occur:the most recent large one was in October and November2006 in DRC, with hundreds of suspected cases [39], anda smaller outbreak arose just across the border in nearbyUganda in February 2007 ([40]). In December 2004 there

was a pneumonic outbreak in a miners camp in DRC,probably imported by an infected human who had travelledfrom an endemic zone. One pneumonic case even arrivedin Kisangani, a large city several hundred kilometres away[41,42]. So even rapid-reaction medical teams may not besufficient to stop plague from spreading quickly over longdistances before it is detected and managed.

Africa is particularly at risk for a number of reasons. Poorrural communities typically live in close proximity to rodents,

which are widely hunted and eaten in many plague-endemicareas. Superstitions, lack of money, and distance from healthfacilities often lead to delays in seeking health care andreceiving treatment. The public health system in large parts

of Africa is poorly organised and equipped, and political crisisand social disorganisation impede improvements. Finally,anthropogenic changes to the landscape and to patterns ofhuman mobility are increasingly favouring contact betweenplague-reservoir and peri-domestic rodents, and betweenpeople from plague-endemic and previously unaffectedregions.

Looking to the Future

Plague cannot be eradicated, since it is widespread inwildlife rodent reservoirs. Hence, there is a critical need tounderstand how human risks are affected by the dynamicsof these wildlife reservoirs. For example, the likelihood ofa plague outbreak in North American and Central Asianrodents, and the resulting risk to humans, is known to beaffected by climate [43,44]. Recent analysis of data fromKazakhstan [45] shows that warmer springs and wettersummers increase the prevalence of plague in its main host,the great gerbil. Such environmental conditions also seemto have prevailed during the emergence of the Second andThird Pandemics [46,47]conditions that might becomemore common in the future [48].

Although the number of human cases of plague is relativelylow, it would be a mistake to overlook its threat to humanity,because of the diseases inherent communicability, rapidspread, rapid clinical course, and high mortality if leftuntreated. A plague outbreak may also cause widespreadpanic, as occurred in India in 1994 when a relatively smalloutbreak, with 50 deaths, was reported in the city of Surat[49]. This led to a nationwide collapse in tourism and trade,

with an estimated cost of US$600 million [50].Outbreaks are usually tackled with a fire-fighting

approach. Teams move into an infected area to kill fleas withinsecticides, treat human cases, and give chemoprophylaxisto exposed people. Many experts have argued that this crisis-management approach is insufficient as the outbreak is likely

to be on the wane by the time action is taken. Informed,pre-emptive decisions about plague management andprevention before outbreaks occur would certainly be moresustainable and cost-beneficial. There has been some recentprogress, such as development of rapid diagnosis tools [51],some challenging of accepted dogma about the dynamicsof sylvatic plague in the United States [52] and in Central

Asia [53], and the identification of predictive critical rodentabundance thresholds for plague in Kazakhstan [54]. What

Box 1. The Plague

The causative bacterium (Yersinia pestis) was discoveredby Yersin in 1894 [11] (see also [63]). Case-fatality ratio variesfrom 30% to 100%, if left untreated. Plague is endemic in manycountries in the Americas, Asia, and Africa. More than 90% ofcases are currently being reported from Africa.

Clinical presentation:After an incubation period of 37 days,patients typically experience a sudden onset of fever, chills,

headaches, body aches, weakness, vomiting, and nausea. Clinicalplague infection manifests itself in three forms, depending onthe route of infection: bubonic, septicaemic, and pneumonic.

The bubonic form is the most common, resulting from thebite of an infected flea. The pneumonic form initially is directlytransmitted from human to human via inhalation of infectedrespiratory droplets.

Treatment:Rapid diagnosis and treatment are essential toreduce the risk of complications and death. Streptomycin,tetracyclines, and sulfonamides are the standard treatment.Gentamicin and fluoroquinolones may represent alternativeswhen the above antibiotics are not available. Patients withpneumonic plague must be isolated to avoid respiratorytransmission.

Challenges ahead:Biological diagnosis of plague remains achallenge because most human cases appear in remote areaswith scarce laboratory resources. So far, the main confirmationtechniques were based on the isolation of Y. pestis(requiring aminimum of 4 days). The recent development of rapid diagnostictests, now considered a confirmation method in endemicareas, opens new possibilities in terms of surveillance and casemanagement.

Box 2. Recent International Meetings on Plague

A meeting on plague in the present, past, and future was held

by the Academy of Science and Letters, Oslo, Norway (http://www.cees.no/oslo-plague-meeting).

A workshop focusing on the comparison of the Black Death andmodern plague was organised by the Wellcome Trust Centrefor the History of Medicine, University College, London (http://www.ucl.ac.uk/histmed/).

The World Health Organization convened an expertmeeting in Antananarivo, Madagascar updating clinicalplague definitions, diagnostic methods, vaccines, andantimicrobial therapy, as well as reservoir and vectorcontrol strategies (http://www.who.int/csr/disease/plague/interregionalmeeting2006/en/index.html).



is striking, though, is our lack of understanding of this high-profile disease in even the best-studied foci, particularly in

Africa: often, we do not even know the natural reservoir ofthe bacilli.

The capacity of the plague bacillus to form permanentfoci under highly diverse ecological conditions attests to itsextraordinary adaptability. During its emergence in Central

Asia, Y. pestisaccumulated copies of insertion sequencesrendering its genome highly plastic [55]. The capacity toundergo genomic rearrangements may thus be an efficientmeans for the plague bacillus to adapt to new ecologicalniches.Yersinia pestiswas, furthermore, recently shown to beable to acquire antibiotic resistance plasmids under naturalconditions [56,57], probably during its transit in the fleamidgut [58]. Of great concern is the recent observation ofthe presence of multidrug-resistant plasmids, almost identicalto those acquired by Y. pestis,in a variety of enterobacteriaisolated from retail meat products in the United States [59].This bacterial reservoir of mobile resistance determinantsis probably widespread globally and has the potential todisseminate to human and zoonotic bacterial pathogens,including Y. pestis. Obviously, the emergence and spread ofmulti-resistant strains of Y. pestiswould represent a majorthreat to human health.

Finally, we should not overlook the fact that plague hasbeen weaponised throughout history, from catapultingcorpses over city walls, to dropping infected fleas fromairplanes, to refined modern aerosol formulations [60,61].The weaponisation research on plague carried out frombefore World War II until the 1990s fuelled a fear ofbiological warfare that may actually have stimulated researchinto surveillance and response strategies. More recently,however, fear of small-scale bioterrorism and the desire ofgovernmental authorities to more fully control all access toplague materials risks stifling the research on plague ecology,epidemiology, and pathophysiology that is required toimprove its clinical management in endemic areas. Terrorist

use of an aerosol released in a confined space could resultin significant mortality and widespread panic [60,61], andno one would wish plague weaponisation knowledge andmaterial to fall into terrorist hands. However, the need forscientifically sound studies on the dynamics of infection,transmission, outbreak management, and improvedsurveillance and monitoring systems has never been greater.

Plague may not match the so-called big three diseases(malaria, HIV/AIDS, tuberculosis; see for example [62])in numbers of current cases, but it far exceeds them in

pathogenicity and rapid spread under the right conditions.It is easy to forget plague in the 21st century, seeing it as ahistorical curiosity. But in our opinion, plague should notbe relegated to the sidelines. It remains a poorly understoodthreat that we cannot afford to ignore.

Supporting Information

Alternative Language Text S1.

Translation of article into French by EB

Found at doi:10.1371/journal.pmed.0050003.sd001 (303 KB PDF)

Alternative Language Text S2.

Translation of article into Russian by BBA

Found at doi:10.1371/journal.pmed.0050003.sd002 (356 KB PDF)

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Box 3. The Plague Bacterium within the EcologicalWeb

Maintenance of plague foci depends on a whole suite ofrodent hosts and their associated fleas (Figure 2A). Underfavourable conditions, the plague bacillus might survive inthe environment, essentially in rodent burrows [64].When aninfected flea happens to feed on a commensal rodent, thecycle continues in the latter (Figure 2B). As commensal rodentsdie, their fleas are forced to move to alternative hosts, e.g.,humans. If humans develop pneumonic plague, the infectionmay be transmitted from person to person through respiratorydroplets spread by coughing (Figure 2C). Humans may alsobecome infected through handling of infected animals (ormeat), including rodents, camels, or cats. Cats can also developpneumonic plague, passing their infection to their ownersthrough coughing. There is, finally, some evidence suggestingthat the human flea, Pulex irritans, can be involved in human-to-human transmission [37]. Mammal predators, birds of prey, andother birds that use rodent burrows for nesting may move overlarger areas than the rodents themselves, spreading the infectionover longer distances. Also, infected commensal rats or humans

may travel over long distances.

doi:10.1371/journal.pmed.0050003.g002

Figure 2. Possible Transmission Pathways for the Plague Agent, Y.pestis

These pathways include sylvatic rodent-flea cycles (A), the commensalrodent-flea cycles (B), and the pneumonic transmission in humans (C).

The colour of the arrows indicates the mechanism (flea bites, air particles,meat consumption) through which the bacteria are transferred from

one host to another. Dark blue arrows indicate ways in which plague canmove to other areas.



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Epizootiologic parameters for plague in Kazakhstan. Emerg Infect Dis 12: 268-273.54. Davis S, Begon M, De Bruyn L, Ageyev V, Viljugrein H, et al. (2004)

Predictive Thresholds for plague in Kazakhstan. Science 304: 736738.55. Parkhill J, Wren BW, Thomson NR, Titball RW, Holden MT, et al. (2001)

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Review

Plague and Climate: Scales Matter

Tamara Ben Ari1,2, Simon Neerinckx1, Kenneth L. Gage3, Katharina Kreppel4, Anne Laudisoit5, Herwig

Leirs5, Nils Chr. Stenseth1*

1 Centre for Ecological and Evolutionary Synthesis (CEES), University of Oslo, Oslo, Norway, 2 Ecole Normale Superieure, CNRS UMR 7625, Paris, France,3 Bacterial Diseases

Branch, Division of Vector-Borne Diseases, Center of Control and Prevention, Fort Collins, Colorado, United States of America, 4 Liverpool University Climate and Infectious

Diseases of Animals Group (LUCINDA), Department of Veterinary Clinical Sciences, University of Liverpool, Leahurst, Great Britain, 5 Evolutionary Ecology Group,

Department of Biology, Universiteit Antwerpen, Antwerp, Belgium

Abstract: Plague is enzootic in wildlife populations ofsmall mammals in central and eastern Asia, Africa, Southand North America, and has been recognized recently as areemerging threat to humans. Its causative agent Yersiniapestis relies on wild rodent hosts and flea vectors for itsmaintenance in nature. Climate influences all threecomponents (i.e., bacteria, vectors, and hosts) of theplague system and is a likely factor to explain some ofplagues variability from small and regional to large scales.Here, we review effects of climate variables on plaguehosts and vectors from individual or population scales tostudies on the whole plague system at a large scale.Upscaled versions of small-scale processes are ofteninvoked to explain plague variability in time and spaceat larger scales, presumably because similar scale-inde-pendent mechanisms underlie these relationships. Thislinearity assumption is discussed in the light of recentresearch that suggests some of its limitations.

Introduction

Plague is a rapidly progressing infectious disease that is

infamous for having caused the death of millions of people in

large historic pandemics [1] as well as numerous other deadly butlocalized outbreaks [2]. Plague, caused by the pathogenic

bacterium Y. pestis is transmitted from host to host by fleas viablood feeding, through consumption or handling of infectious host

tissues, or through inhalation of infectious materials. Plague is

thought to persist for long periods of time at low to very low levels

of prevalence in so-called enzootic cycles that cause little host

mortality and involve partially resistant rodents (often called

enzootic or maintenance hosts). These long periods are punctuated

by occasional outbursts or epizootics (i.e., spreading die-offs)among these hosts or epidemics, when the incidence among

humans increases. Figure 1 illustrates these intertwined cycles.Climate has long been suspected to be a key factor in the

alternation between quiescent and active periods of plague. Rogers

(1928) suggested seasonal variations in temperature and humidity

to be responsible for the seasonal patterns of human plagueincidence in India [3]. Decades later, Davis showed that human

plague outbreaks in several African countries were less frequent

when the weather was too hot (.27uC) or cold (,15uC) [4].

Subsequent studies showed an increased plague incidence in

Vietnam during the hot, dry season, when following a period of

high seasonal rainfall [5,6]. Nowadays, several studies, as we

report here, demonstrate climates impacts on plague incidence

spatial and temporal variability.

In the context of public health and wildlife conservation, we

need an improved understanding of the mechanisms underlying

the association between plague outbreaks and climate. As we will

show in this review, this understanding is only partially available at

present. There are several reasons for this. First and perhaps most

importantly, the plague cycle is complex. It is composed of three

components that interact with each other and all are influenced by

climate variables with a broad range of times lags. Also, climate

variability manifests itself at numerous temporal and spatial scales

that condition the form of the response in plague dynamics. To

cope with this series of difficulties, we break down the problem as

follows: in section 1 we review individual effects of climate

variables on each of the plague components. Our knowledge of

these effects is primarily based on small-scale studies that are usefulbecause they provide conceptual models for how larger scale

climate variability may force the plague system. The way these

conceptual models are most often used raises the issue of upscaling

conclusions by inference from the results of small scale studies, a

subject on which we focus on in section 2. Also, in the latter we

review likely impacts of climate change on plague incidence.

Climate Dependence of the Flea Vectors and

Rodent Hosts

The plague system is the result of complex interactions between

its components, the densities, life cycle, dynamics and geographical

distributions all of which are individually influenced by climate

variables. Climate variables influence the dynamics of flea vectorsand rodent hosts with responses varying considerably among

species [7,8]. Figure 1 illustrates the plague cycle in relation to

those climate variables known to be important (namely temper-

ature, humidity and precipitation) to the main plague hosts and

vectors.

It is accepted that abundance of rodent fleas is affected by

ambient temperature, rainfall, and relative humidity, with warm-

moist weather providing a likely explanation for higher flea indices

[4,5]. Indeed, temperature, rainfall, and relative humidity have

direct effects on development and survival, as well as the behavior

and reproduction of fleas and their populations [912]. For

Citation: Ben Ari T, Neerinckx S, Gage KL, Kreppel K, Laudisoit A,et al. (2011) Plague and Climate: Scales Matter. PLoS Pathog 7(9): e1002160.doi:10.1371/journal.ppat.1002160

Editor:Marianne Manchester, University of California San Diego, United States ofAmerica

Published September 15, 2011

This is an open-access article, free of all copyright, and may be freely reproduced,distributed, transmitted, modified, built upon, or otherwise used by anyone forany lawful purpose. The work is made available under the Creative Commons CC0public domain dedication.

Funding: The authors received no specific funding for this study.

Competing Interests:The authors have declared that no competing interestsexist.

* E-mail: [email protected]

PLoS Pathogens | www.plospathogens.org 1 September 2011 | Volume 7 | Issue 9 | e1002160


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example, the rate of metamorphosis of Xenopsylla cheopis (as a

primary flea of the black rat Rattus rattus,X. cheopisis likely the main

vector of plague in foci affecting humans), from egg to adult is

regulated by temperature. Fleas are ecto-thermic and hence

sensitive to temperature fluctuations; this is enhanced by the fact

that all of the immature flea stages occur off host. Flea

development rates increase with temperature until they reach a

critical value; then the survival of immature stages decreases if

high temperatures are combined with low humidity [13].

Temperature and relative humidity impact flea survival [5]:

survival is in fact inversely proportional to air saturation deficit at a

constant temperature [14]. Flea larvae are susceptible to

desiccation [15] and typically acquire water from adult excreta.

Survival of immature stages of fleas in rodent burrows is also

affected by soil moisture that is partly controlled by outsideprecipitation [16] even though detrimental moisture losses and

temperature swings are reduced by living underground [9].

Conversely, when coupled with a high organic load, excessively

wet conditions in rodent burrows (e.g., relative humidity .95%)

can promote the growth of destructive fungi that diminish larval

and egg survival [5,17].

Rodent survival and population dynamics are also affected by

climate. A direct effect occurs when high intensity rainfall causes

flooding of rodent burrows [5] but the effects of precipitation on

rodent densities are mostly bottom-up [18]. Indeed, rainfall

controls primary production which limits rodent abundances [19].

Reproduction and recruitment periods often follow wet seasons

when increases of primary production can be used to build up

juvenile populations [20]. Accordingly, rodent population densities

show clear association with annual rainfall and its seasonal

distribution e.g., in Chile [2123], Tanzania [24], and Australia

[25,26]. But the relation between precipitation patterns and rodent

densities can be complex, localized, and dependent on the timing

and the intensity of precipitation events (see also below) [8,27].

Temperature effects on rodent populations are less clear in part

because rodents are homeothermic and hence do not respond

immediately to changes in ambient temperatures. In temperate

areas, low temperatures in winter can nonetheless negatively affect

rodent populations either directly or through low food availability

[28]. Nevertheless, under some circumstances, conditions detri-

mental to hosts or vectors can favor the maintenance of plague.Evidence of hibernation as a factor of prolongation or modifica-

tion ofY. pestis infection in rodents would need further elucidation.

The flea Citellophilus tesquorum altaicus for instance, is supposedly

able to maintain a plague infection over the winter by feeding on

hibernating long-tailed Siberian souslik (Citellus undulatus) [29].

Also, populations of Tatera indica aestivating during adverse

conditions in India presumably continue to act as hosts for

infected fleas, thereby promoting the persistence of plague

infection within the area [30]. Hence, the survival ofY. pestis in

relatively plague-resistant burrowing rodents that interrupt their

activities to hibernate through winter or aestivate in summer could

Figure 1. Schematic of the plague cycle with small mammals as hosts and fleas as vectors. Arrows represent connections affected byclimate with a color-coding depending on the most influential climate variable on this link (i.e., precipitation, temperatures, and other variablesindirectly depending on them such as soil characteristics and soil moisture). Grey rectangles somewhat arbitrarily delimit epizootic, enzootic, andzoonotic cycles. Note that despite their location at the far end of the cycle, humans often provide the only available information on plague dynamics.doi:10.1371/journal.ppat.1002160.g001



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influence or prevent the transient temporal and spatial extinction

of plague occurrence.

Human Plague Incidence Is Not Unrelated to HumanFactors

Human activities and behavior in plague-infected areas are also

to be considered as important determinants of plague transmission

to humans [8]. When occurrences of plague are due to human

intrusions in natural plague areas, it is thus important to considerclimate as a second order variable that influences disease incidence

through human behavior (drought, famine, war, or other events).

In Argentina, plague transmission reportedly occurred during the

harvesting season [31]. In Lushoto, a plague endemic region in

Tanzania, daily and gender activities seem to impact plague levels

[32], although plague tends to peak during the season with the

least agricultural activity, which is a time when people usually

gather in houses.

What Plague Niches Reveal about PlaguesEnvironmental Preferences

Plague foci are present over an expanded geographical range

that includes the Western US, portions of South America, East

and South Africa, and Southeast Asia [33]. Long-term mainte-nance of plague in defined ecological niches may inform us about

the environmental conditions that are required for plague to

establish in permanent foci. Unfortunately, enzootic plague is

poorly described; in many foci, local reservoirs have yet to be

identified. The geographical limits of plague territories are hence

rarely defined or only by occurrence in domestic rodents and

humans [34]. It is reasonable to assert that plague manifests itself

under various ecological conditions [35,36]. It is noteworthy

though, that modern plague foci in North and East Africa,

Western North America, parts of South America, and many

scattered regions in Asia (notably China and Kazakhstan) occur

primarily in either semi-arid to arid areas or low humidity forest

types of habitat, and the disease apparently fails to persist for long

periods in humid tropical lowland areas (except from occasional

invasion through movement of infected humans or transportation

of infected rodents or fleas) [3739]. Also, plague is almost

invariably absent from the hottest and driest desert regions like the

Sahara or Sonoran deserts [37,40].

The Complexity Introduced by Interactions

among Scales and Other Nonlinearity

The previous section reviewed reported effects of climate

variables on the components of the plague cycle, indicating that

climate affects rodents and fleas individually and their population

dynamics and structures. Consequently, climate impacts the

natural cycle of plague as a whole and in ways that are not likely

to reflect simply the sum of these individual effects. In this section,

we review studies on the effects of climate (including theenvironment) on plague at different spatial levels and occurrences

ranging from rodent burrows to areas that form a coherent and

apparently self-sustaining system (a single niche or focus), or even

to larger regions that could comprise many such systems (several

foci). We emphasize the fact that (i) scales relevant to plague

ecology are nested within each other, as shown in Figure 2, so that

climate effects at a given scale may not be simply extrapolated

from those observed at a smaller scale, and (ii) processes exist that

prevent the plague system from responding to climate fluctuations

in a way that simply reflects the sum of the responses of its

individual component.

It is readily apparent that associations exist between large-scale

climate such as climate indices and plague/plague hosts dynamics;

associations that can be consistently explained by processes

detailed in the first section. Effects of precipitation patterns on

plague incidence are for instance assumed to be the results of

climates bottom-up effects on plague hosts. In Peru, climate

fluctuations associated with El Nino were related to a bubonic

plague outbreak in 1999 [41]. In northern Colorado, prairie dog

colony extinctions attributed to plague were weakly associatedwith El Nino southern oscillation [42]. In the Western US, spatial

synchrony of periods with low and high number of human plague

occurrences throughout the west revealed large scale synchrony

[43]. In most foci of the southwestern part of this region, above

normal precipitation in winter and spring was used to explain

increases in human plague cases [44], and high summer

temperatures, decreases of its incidence in the same area [45].

The El Nino/Southern Oscillation (ENSO) and the Pacific

Decadal Oscillation were similarly related to precipitation,

temperatures, food availability, and the number of plague cases

themselves [46]. Finally, the increase rate of human plague in

China is associated at the province level with the Southern

Oscillation Index and Sea Surface Temperature of the tropic

Pacific east equator [47]. An important assumption to the above-

cited studies is that large-scale climate variability producescoherent and synchronous effects on rodent hosts populations.

Few studies actually investigate the reality of the invoked

synchronous trophic forcing on plague hosts population dynamics

so as to demonstrate such a climate induced bottom-up control. At

this point, it is worth mentioning a counterexample provided by

Kausrud et al. [48], who investigated the population dynamics of

great gerbils Rhombomys opimusthe main plague host in Kazakh-stanand demonstrated spatial synchrony of their populations

over areas larger than the ones expected by migration processes.

Their results indicate that the observed synchrony of great gerbils

densities was most probably due to the effects of climate and that

similar bottom-up processes could also synchronize plague activity

in this focus.

In any case, there are caveats to inferring processes occurring atsmall scale as a means to explain the ones observed at larger scales.

First, causal relations can typically only be suggested (e.g., by a

chain of supposedly causal processes from climate indices to

relevant climate variables and from these to plague incidence) but

not demonstrated. More problematically, a variety of processes

can be expected to interfere with each other in the transition from

small to large scale. Tentatively, we propose below a classification

of these processes into two categories. The first ones pertain to the

complexity of the environment itself and the second ones to

population interactions.

An example in the first category can be provided by studies

showing that rodent burrows could be considered a climate

filter. Conditions in rodent burrows are subject to environmental

factors from nearby surroundings such as temperature, humidity,

vegetation, various soil properties (e.g., soil texture and structure,soil organic carbon content, etc.), and other landscape factors (e.g.,

slope, orientation with respect to dominant winds, sun exposure,

etc.). But, the underground location of most burrows implies that

conditions inside these structures fluctuate only moderately

[49,50]. In fact, temperatures inside and outside burrow systems

are highly correlated, but inside humidity is a complex function of

past rainfall and soil characteristics [51] rather than of present

ambient humidity [52]. Note that investigations on burrow micro-

climate have been conducted in different parts of the world

[51,53,54], including in plague-endemic regions, but these

measurements were generally obtained from only a small number



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of natural or, in some instances, artificial burrows, allowing

investigators to draw only tentative conclusions from the results of

these studies [49,55]. Perhaps more importantly for our present

purposes, climate conditions inside the burrows could specifically

influence the distribution of plague vectors so that hosts

distribution becomes insufficient to explain vectors distribution, a

situation that has been observed in plague areas in Madagascar

[5658] or plague-free areas in Israel [59,60]. These examples

emphasize the difficulty of upscaling processes by simple

extrapolation. Among the numerous other examples of environ-

ment-related complications are the landscape heterogeneities

within plague areas. In particular, strong orographic forcings

frequent in plague areas locally affect large-scale climate variability

[61]. In fact, accurate plague prediction models seem to require

high resolution environmental and climate representation (e.g.,

250-m resolution images accurately predict plague distribution

when 10-km resolution images fails in sub-Saharan Africa).

According to the authors, plague focality can not be explained

by fragmented environmental conditions at this coarse

scale [35,62].

In the second category are the complications introduced by

interactions within and between plague host and plague vector

populations in their response to climate variability. It is commonly

expected that fluctuations in abundance of rodent hosts, e.g.induced by climate variability, will translate into plague prevalence

fluctuations. However, the relationship between host abundance

and host prevalence is complex and scale dependent. Field studies

of rodent reservoirs show a negative correlation between host

abundance and host prevalence at seasonal time scale. The finding

has been explained by the juvenile dilution effect, that is, the

arrival of numerous healthy juveniles in a population [63]; an

effect likely to be relevant for diseases with no vertical transmission

such as plague (or Hantavirus [64]). In contrast, a few longer field

studies (.5 years) show a positive, although delayed relationship

between reservoir abundance and prevalence [63]. These

antagonist responses to variability at different time scales are

typical of systems in which nonlinear interactions play an essential

role. The different responses of rodent and flea populations to

climate (fast for fleas while rodents tend to integrate environmental

conditions over some years) provide another reason for question-

ing the existence of a straightforward link between abundance and

prevalence. A more complex model was proposed for the Western

US, in which human plague incidence depends both on time-

lagged precipitation events, which presumably increase rodent

numbers and favor plague epizootic, and on relatively cool

summer temperatures during the plague transmission season,

which are favorable to infectious fleas [45]. This model has been

coined trophic cascade hypothesis, although it has yet to be

tested rigorously for plague under field conditions [65] (see also

[66] for a discussion on the accuracy of the use of the term

trophic for the cascade hypothesis). In particular, the scale at

which the trophic cascade model is valid needs to be addressed.

Parmenter [44], who first introduced this model, shows its

relevance at a local scale (i.e., by demonstrating significant

associations between plague and nearby precipitation), but could

not extend this result to a state-wide level. Interestingly, a cascade

relationship was recovered at an even larger scale by Ben-Ari [46],

possibly because the integration of delayed density-dependence

effects of large-scale climate on rodents were taken into account atdecadal time scales. The study by Stenseth et al. [67] illustrates the

challenge that needs to be confronted when addressing cascading

effects of climate on plague prevalence in nature. There are

numerous relationships between climate elements (temperature

and precipitation with or without lags) and various ways these

elements can impact the plague components (in this particular case

rodent density, prevalence, and flea burden). The type of dataset

that would let us isolate/untangle the mechanisms and the spatio-

temporal scales at which processes operate may not be available.

These examples do not necessarily invalidate studies that scale

up small-scale results (individual measurements, lab experiments,

Figure 2. Illustration of the abiotic environment impact on the plague cycle as a function of spatial scale. Arrows represent connectionsaffected by climate (see Figure 1 for the meaning of color coding). Most climate variables act over a wide range of scales and only the effects wedeemed most important are represented. At the level of individuals, populations and communities hosts and vectors are influenced by climatevariability at the relevant scale (local or regional). At the smaller scale, the burrow acts as a filter on climate variables. Note that secondary hosts areplaced at the kilometer and larger scale on the basis of the type of information generally available regarding their infection.doi:10.1371/journal.ppat.1002160.g002



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local correlations, etc.) in the simplest way, but we believe they

illustrate the need for more investigation on the impact of complexinteractions and environment heterogeneities at intermediate

scales.

Implications for Climate Change

The need to understand disease responses in relation to climate

variability is made particularly acute by ongoing global climate

change. Effects of temperature rise on vector-borne diseases andnotably the ones involving free-living stages of terrestrial animals

are expected [68]. Beyond that, a lot of uncertainty remains on

whether or how climate change might affect pathogens and disease

transmission, i.e., changes in population size (for vectors or hosts),

overall prevalence, timing and seasonality, or shifts in geographical

distribution. There are various choices to be made when

addressing climate change impact on a disease like plague,

particularly with respect to the degree of complexity that should be

chosen for climate models and any associated biological models

and the relation between them.

Stenseth et al. [67] performed a sensitivity study to a one-degree

increase in temperature into a statistical host vector plague model

developed specifically for Kazakhstan. They show that this (simple)

climate change scenario would lead to a 50% increase in plagueprevalence among great gerbils. Nakazawa et al. [69] used twoGlobal Circulation Models (GCMs) to infer mean temperature

and precipitation changes between the present and a 30-year

period centered around 2055. These changes were then applied to

a higher resolution present state GCM that provided a climate

changed forcing state, which was fed into an Ecological Niche

Model (ENM) predicting plague occurrences in the US from a set

of environmental variables. They show subtle shifts of plague

habitats (generally northward). Snall et al. [70] used an elaborate

procedure to downscale climate scenarios from several GCMs

before using these data to force an explicit model for the joint host-

parasite dynamics of black-tailed prairie dogs and plague in the

Western US. A related decrease in the number of infected prairie

dog colonies (leading to an increase in prairie dog colonies) is

predicted, presumably, as a consequence of the negative impact ofincreased frequency of abnormally hot days on plague transmis-

sion.

These studies are difficult to compare with each other becauseof the specificities of their methodologies even when they lead to

contrasting results over the same region [70]. Admittedly, moreinvestigations are required. Among the numerous possible

approaches, the safest arguably would rely on using climate-

forcing sensitivities of intermediate complexity where biological

models are forced by existing modes of climate variability. This

makes sense not only because climate change will in large part

occur through a modification of these modes (which can be

extracted from Intergovernmental Panel on Climate Change

[IPCC] GCMs [61]), but also because biological data are then

available for evaluation.

Conclusion

Climate impacts all components of the plague cycle (host,

vector, and pathogen) in various ways and over a wide range of

scales (from microindividual flea life cycleto macroa plague

area composed of several disjoint foci). Several studies have

established links between plague occurrence and climate factors

that can a posteriori be justified by assuming the validity at a large

scale of relationships that have only been observed at a small scale

(assumption of linearity). We have reviewed both the successes and

the limitations of this assumption. To go beyond simple inferences

on how climate fluctuations (including long-term climate change)

affect plague, it might be necessary to select a (or a few)

preferential scale, on the basis of the fact that they would be the

most informative and/or relevant for public health policies. In thisregard, intrinsic dynamics of plague hosts and vectors should be

kept in mind as it alone greatly contributes to the entanglement of

scales that drive the overall dynamics of plague prevalence [71].

Further, assessing plague risks for humans at such scales may in

fact require investigating plague dynamics on a much wider range

of scales and presumably include a fuller description of the plague

system in its environment, as we have tried to outline in this

review.

Acknowledgments

We thank Ulf Buentgen for his help with figure preparation; Mike Begon,

Ulf Buentgen, and Sasha Gershunov for discussions on plague and climate;

and Xavier Capet for numerous comments and corrections on earlier

versions of the manuscript. We also thank two anonymous reviewers forproviding helpful comments to an earlier version of this contribution.

Author Contributions

Conceived and designed the experiments: TBA NCS. Performed the

experiments: TBA SN. Analyzed the data: TBA SN. Wrote the paper:

TBA SN KLG KK AL HL NCS.

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