Opportunistic bacteria and mass mortality in ungulates: lessons from an extreme event

Robinson, S., Milner-Gulland, E. J., Grachev, Y., Salemgareyev, A., Orynbayev, M., Lushchekina, A., Morgan, E., Beauvais, W., Singh, N., Khomenko, S., Cammack, R., & Kock, R. (2019). Opportunistic bacteria and mass mortality in ungulates: lessons from an extreme event. Ecosphere, 10(6), [e02671]. https://doi.org/10.1002/ecs2.2671 Published in: Ecosphere

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Opportunistic bacteria and mass mortality in ungulates: lessons from an extreme event 1, 1 2 3 SARAH ROBINSON , E. J. MILNER-GULLAND, YURI GRACHEV, ALBERT SALEMGAREYEV, 4 5 6 7 8 MUKHIT ORYNBAYEV, ANNA LUSHCHEKINA, ERIC MORGAN, WENDY BEAUVAIS , NAVINDER SINGH, 9 10 11 SERGEI KHOMENKO, ROSIE CAMMACK, AND RICHARD KOCK

1Department of Zoology, University of Oxford, Oxford OX2 6GG UK 2Institute of Zoology, 93 Al Farabi Street, Akademgorodok, Almaty 480060 Kazakhstan 3Association for the Conservation of Biodiversity of Kazakhstan, 18 Beibitshilik Street, Astana 020000 Kazakhstan 4Laboratory for Monitoring of Bacterial and Viral Infections, Research Institute for Biological Safety Problems, 2-13 Pionerskaya Street, Gvardeiskiy, Kordaiskiy Rayon, Zhambylskaya Oblast 080409 Kazakhstan 5A.N. Severtsov Institute of Ecology and Evolution, Laboratory for Biodiversity Conservation, 33 Lenin Prospekt, Moscow 119071 Russia 6Institute for Global Food Security, Queen’s University Belfast, University Road, Belfast BT7 1NN UK 7Ivanek Laboratory, Cornell University College of Veterinary Medicine, 602 Tower Road, Ithaca, New York 14853-6401 USA 8Swedish University of Agricultural Sciences, Almas Alle 8, Umea, V€asterbotten SE-901 83 Sweden 9Animal Production and Health Division, Food and Agriculture Organisation, Viale delle Terme di Caracalla, Rome 00153 Italy 10University of Oxford, Saint Hilda’s College, Oxford OX4 1DY UK 11Pathobiology and Population Sciences, Royal Veterinary College, 4 Royal College Street, London NW1 0TU UK

Citation: Robinson, S., E. J. Milner-Gulland, Y. Grachev, A. Salemgareyev, M. Orynbayev, A. Lushchekina, E. Morgan, W. Beauvais, N. Singh, S. Khomenko, R. Cammack, and R. Kock. 2019. Opportunistic bacteria and mass mortality in ungulates: lessons from an extreme event. Ecosphere 10(6):e02671. 10.1002/ecs2.2671

Abstract. Mass mortality events in wildlife are a growing concern. Under conditions of rapid global change, opportunistic responses in bacterial commensals, triggered by environmental stressors, may be increasingly implicated in die-offs. In 2015, over 200,000 saiga antelope died of hemorrhagic septicemia caused by the pathogen Pasteurella multocida serotype B. We use this case to explore die-offs from commen- sal bacteria more broadly, looking at factors which might favor such extreme events. We review other recorded disease outbreaks caused by Pasteurellaceae organisms, firstly in saiga and secondly in other wild ungulates, and ask whether the 2015 die-off was unprecedented in terms of mortality rates, numbers dead, spatial scale, and in the nature of the predisposing or environmental factors involved. We also compare these outbreaks with mass mortality events associated with commensal bacteria in wildlife more generally. We identify three additional major die-offs in saiga in which Pasteurellaceae organisms may be implicated, of which one in 1988 closely resembles the 2015 hemorrhagic septicemia event. No other recorded cases in wild ungulates approach the magnitude of these cases for any of the metrics considered, possible excep- tions being die-offs in Mongolian gazelles, in which the role of these pathogens is poorly substantiated. Environmental triggers were the most commonly suggested factor leading to pathogenesis, with warm humid conditions most commonly associated with hemorrhagic septicemia. Life history may also be signif- icant—saigas are migratory and the largest pasteurellosis outbreaks outside this species also occur in migratory species of bird or other temperate ungulates aggregating in large numbers. Cases provoked by other commensals tend to be small in magnitude. Exceptions involve interactions between multiple patho- gens and climatic conditions or sets of climatic conditions acting on different stages of the host–pathogen life cycle, leading to time lags between infection and subsequent disease. Overall, the scale and rapidity of the saiga die-offs appear unprecedented among mortality events caused by bacterial commensals in wild mammals. Experimental research into the genetics and microbiology of host–pathogen interactions upon changes in the external environment, and monitoring of animals and conditions at calving sites, may even- tually reveal the underlying causes of these die-offs.

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Key words: commensal bacteria; hemorrhagic septicemia; Kazakhstan; mass mortality event; opportunistic pathogen; Pasteurellaceae; saiga antelope.

Received 11 January 2019; accepted 7 February 2019. Corresponding Editor: Andrew R. Wargo. Copyright: © 2019 The Authors. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. E-mail: [email protected]

INTRODUCTION infections occur across many vertebrate taxa, but ungulates feature prominently in the literature. Mass mortality events (MMEs) in wildlife are of By focusing on this group, we minimize variabil- increasing concern as human activity renders ity in basic host biology and the pathogen strains declining populations more vulnerable. There is to which they are vulnerable and therefore are some evidence that the frequency of such events able to draw out more generalizable lessons. may be rising (Fey et al. 2015) as host or range First, we introduce the saiga antelope and the shifts bring new combinations of pathogens, hosts, 2015 mass mortality event which prompted this and climatic conditions into contact (Harvell et al. review. We then examine the Pasteurellaceae 1999) or as climate influences host–parasite inter- family and associated diseases of interest, as the actions in ways which cause higher rates of mor- relationships between these are complex and still tality (Rohr et al. 2013). In light of rapid global poorly understood. We go on to review key char- change and increases in environmental stressors, acteristics of mass mortality events from different those bacterial commensals which become lethal expressions of pasteurellosis in saiga and other pathogens under particular conditions, appear wild ungulates worldwide, grouping these into particularly likely candidates for an increasing role cases of hemorrhagic septicemia and pneumonic in disease and mortality. These organisms are pasteurellosis (which includes bovine respiratory opportunists, living apparently harmlessly in disease), the two major syndromes associated hosts for long periods of time and causing clinical with these pathogens in ungulates. We also ask disease when host immunity is compromised or whether the patterns observed for pasteurellosis following changes in the pathogen. in saigas and in other wild ungulates are similar Evidence for the role of commensals as oppor- to cases of this group of diseases in other taxa, or tunistic pathogens in wildlife MMEs is scattered to MMEs caused by other opportunistic bacteria and has not so far been considered in a struc- living as commensals in ungulates, focusing par- tured way. A particularly dramatic example ticularly on predisposing factors and the envi- occurred in saiga antelopes in 2015, and was ronmental conditions which favored these attributed to Pasteurella multocida serotype B, in outbreaks. We end by considering what our combination with climatic triggers (Kock et al. review of case studies tells us about possible 2018). This example is unusually well docu- mechanisms behind the 2015 MME in saiga, mented and raises questions about whether this identify significant gaps in understanding of this extreme case is an outlier; whether similar cases event and of Pasteurellaceae behavior more gen- have occurred in the past; and what we may con- erally, and suggest future research directions to clude about their likely frequency in the future. improve our knowledge of the mechanisms In this paper, we ask whether the scale, mortal- behind the shift from harmless commensal to ity, and number dead in the 2015 event were lethal pathogen in these organisms. unprecedented in comparison with other disease outbreaks in wild ungulates (including saigas) in METHODS which Pasteurellaceae organisms have been impli- cated, exploring the evidence for environmental The information presented here on the 2015 and biological factors which may have played a die-off is based on our own primary field and role in the cases we review. Pasteurellaceae laboratory research (Kock et al. 2018, Orynbayev

❖ www.esajournals.org 2 June 2019 ❖ Volume 10(6) ❖ Article e02671 SYNTHESIS & INTEGRATION ROBINSON ET AL. et al. 2019). Concerning the rest of the review, a In the case of saiga, for which most primary lit- number of literature searches were conducted, erature on historical MMEs is in Russian, we described in the following paragraphs. sourced information from official saiga monitor- ing and disease investigation reports supplied as Documented cases of pasteurellosis in wild hard copies by the Institute of Zoology, Kaza- ungulates khstan, and from Russian language scientific A primary literature search for detailed cases journals. We provide a relatively high level of of die-offs in other ungulates caused by species detail on these sources in Appendix S1, as much of Pasteurellaceae was conducted in English of this material remains unpublished in English (both UK and U.S. spellings), using the Google and unavailable outside unpublished reports. online search engine (both general and Google Because cases in many other north-Asian ungu- scholar) for references to hemorrhagic septicemia late species are also available only in Russian, we (HS), pneumonic pasteurellosis (PP), or the gen- also conducted a general search using the Rus- eral term pasteurellosis, using the additional key sian version of the Google search engine, using words ungulate or wildlife. Similar searches the same terms used for the English search, but were conducted substituting names of the syn- in the Russian language and script. Many dromes for those of associated pathogens, Pas- sources identified online were not available elec- teurella multocida, Mannheimia haemolytica, and tronically, so were obtained as hard copies from historical variations on these. Articles with libraries in Moscow. abstracts in English but the main text in a foreign Based on our literature review of specific cases, language were translated and reviewed. we present data on mortality rate, numbers dead, Searches covered peer-reviewed articles, book temporal and spatial characteristics of outbreaks, chapters, conference proceedings, theses, and and age and sex profiles of affected individuals, gray literature. The pathogens and their associ- as well as discussing associated environmental ated syndrome were first described scientifically factors and co-pathogens. This information is in the 1870s in domestic fowl and livestock (De summarized in tables in the main body of the Alwis 1999). The earliest case we came across in paper, with more detail provided in Appendices wildlife was documented in 1911, so this is the S2, S3. effective start date of our review. The majority of retrieved sources were peer-reviewed articles, Reviews of pasteurellosis in ungulates including particularly from veterinary reviews; of the 15 domestic livestock primary articles describing outbreaks of HS, 14 Going beyond papers focusing on specific were peer-reviewed journal articles and one a cases, we also searched for more general publica- conference presentation. Some additional out- tions covering pasteurellosis in ungulates. Most breaks with lower levels of detail and substantia- Russian sources, other than those on saiga, fell tion (from secondary sources) were also into this category. Although the conditions for documented. Of the 11 primary articles describ- transmission and development of pasteurellosis ing PP cases, six were in peer-reviewed journals under farm or semi-captive conditions are very and five in conference proceedings (all at confer- different from those in the wild, pasteurellosis is ences specific to bighorn sheep (Ovis canadensis) an important disease of domestic livestock and conservation). Although many cases described as there is much to be learned from this literature. “mass mortalities in wildlife” concerned only a Here, we used the same terms listed above plus handful of animals, and in some examples the the words bovine respiratory disease, livestock, affected animals were only semi-wild, every case cattle, and buffalo. From the results, rather than identified in the literature is included here except selecting specific case studies, we selected papers those in which only one or two individuals died. and books reviewing the subject and statistical Additional articles relating to the described out- studies covering a large number of cases. breaks which offer new data or insights (for example those describing the serotyping of Genetics and microbiology of focus pathogens organisms isolated from MMEs many years The above search procedures also yielded afterward) are also included in the review. reviews on the behavior, microbiology, and

❖ www.esajournals.org 3 June 2019 ❖ Volume 10(6) ❖ Article e02671 SYNTHESIS & INTEGRATION ROBINSON ET AL. genetics of the pathogens responsible for Pas- confirmed post hoc, or from interpretations teurellosis in ungulates and other taxa. This made in the literature. This is because, due to search was then expanded and refined using their commensal nature, these organisms may be combinations of keywords for our focus syn- present but invade the body only after death, dromes and organisms, plus genetics, DNA, and thus being identified at post-mortem examina- microbiology. We selected those reviews which tion. Interactions with other pathogens, such as focused on the phylogeny and classification of viruses and mycoplasmas, may also be crucial to Pasteurellaceae organisms, and on the genetics understanding disease etiology and it is often and bio-chemistry behind their virulence. unclear whether the Pasteurellaceae organism was the major or sole pathogen, or emerged as The impact of environmental factors on an opportunist following infection by other Pasteurellaceae organisms organisms (Besser et al. 2013). These factors Many publications identified through earlier make diagnosis difficult without a combination searches contained information on environmen- of high-quality pathology and histopathological tal factors influencing pasteurellosis outbreaks or data and laboratory-based identification of bacterial activity in the laboratory. We then con- organisms to the species level (as done by Kock ducted specific searches on these factors in order et al. 2018). These issues may have affected the to ensure that we had not missed key papers or conclusions drawn by some of the earlier studies experimental work conducted in vivo. This was reviewed here which, being dependent on cul- achieved by including search terms such as cli- ture alone, may have missed co-infections with mate, weather, temperature, humidity, stress, organisms more easily detected by PCR, thus nutrition, element, mineral, and immunocompe- misidentifying pasteurellaceae organisms as sole tence along with the names of syndromes and or primary pathogens. Older Russian sources in pathogens as above. We did not specify host particular often lacked sufficient information for organisms in these searches. full diagnosis. Distinct syndromes were not always identified, the blanket term of “pasteurel- Reviews and case studies on other opportunistic losis” being used in many cases to cover both bacteria affecting wild ungulate species septicemic and pneumonic forms, despite quite In order to place our review in a broader con- different etiologies. Overall, the use of English text, we draw comparisons with mortality and Russian as primary search languages may events caused by other gastrointestinal and have caused a bias toward cases from tempera- upper respiratory tract bacteria in ungulates ture zones, which formed the overwhelming which live for long periods as commensals, majority of recorded cases. A further caveat is yet also exhibit opportunistic responses to stress that in forest or mountain species, the total num- factors, leading to tissue invasion and death of bers dead or mortality rates may be unavailable the host (see Appendix S4 for details). In these or erroneous because many carcasses were never cases, the non-exhaustive literature search ini- found. This is an issue because the perceived tially focused on review papers, followed by unprecedented nature of the saiga incidents lies acquisition of papers detailing specific cases con- in the high level of mortality; in these cases, rela- sidered to be salient for this paper. Lastly, we tively accurate carcass counts can be conducted looked for examples of mass mortality events from the air or ground over large areas, and so caused by opportunistic pathogens across all severe underestimation is less likely. types of host taxa, focusing on those holding les- sons about mechanisms through which environ- RESULTS mental triggers may act and the role of host life history (as opposed to taxonomic classification) The saiga antelope: ecology and life history in disease etiology. The saiga antelope (Saiga tatarica) is a migra- tory ungulate found in the pre-Caspian and Cen- Limitations tral Asian steppes, with population ranges Links between the presence of Pasteurellaceae covering parts of Russia, Kazakhstan, and organisms and disease cannot always be Uzbekistan and a sub-species (S.t. mongolica)in

❖ www.esajournals.org 4 June 2019 ❖ Volume 10(6) ❖ Article e02671 SYNTHESIS & INTEGRATION ROBINSON ET AL. western Mongolia. The three major saiga popula- a scattering of individual mortalities spread tions in Kazakhstan are shown in Appendix S1: across the landscape and around 30,000 animals Figure S1. In Kazakhstan, saigas are highly survived, based on post-mortality ground and mobile, and cover huge areas during their sea- aerial surveys. The dates of onset (first mortal- sonal migrations, mostly north–south following ity) at each site ranged from 9 May to 29 May, vegetation gradients (Singh et al. 2010). Females but within each site onset was rapid; individual (with a few, mostly young, males) congregate in animals died over a period of hours following dense calving aggregations many thousands first symptoms, and mortality apparently strong in May, the time of peak biomass produc- reached 100% of adults within a week of the tion in the steppe. Calves are hidden for the first index case. Calves were initially unaffected, few days, but within 2–3 d are able to run, and dying after their mothers, either from starvation within 10 d they and their mothers continue their or from ingestion of Pasteurella organisms from spring migration (Kuhl€ et al. 2007). The major the milk. For this reason, transmission of a viru- known causes of large-scale natural mortality in lent form between animals via aerosol or feces saigas are heavy snowfall or freezing rain cannot alone explain the epidemiology of this (known as dzhut in Kazakh), and diseases event. As other pathogenic organisms were not described under the umbrella term of pasteurel- identified, and there was no contact between losis, recorded only in Kazakh populations aggregations at the time, it is thus hypothesized (Bekenov et al. 1998, Sokolov and Zhirnov 1998) that an environmental trigger, which must have and which we explore in the following sections. been spatially widespread in the environment Historically, the species was very abundant, and temporally specific to the period just before but large-scale hunting in the 19th century onset, may have played a role in pathogenicity. reduced its numbers substantially (Bekenov et al. Such a trigger may have affected the relation- 1998). Following a period of recovery and sus- ship between commensal bacteria and their tainable management for meat production dur- adult saiga hosts, which carry them in the ing the Soviet period, saiga numbers were nasopharynx, as part of the microbiome (Kock severely affected by poaching for horns and meat et al. 2018). during the 1990s–early 2000s, leading to a decline in numbers of over 90% during a 10-yr Pasteurellaceae: typology, classification, and period, and the species’ listing as Critically association with disease Endangered on the IUCN Red List in 2001 (Mil- Pasteurellaceae are a large family of Gram- ner-Gulland et al. 2001). Conservation efforts led negative bacteria, many of which live as commen- to recovery in some populations, and one in par- sal organisms in the upper respiratory tract of ticular, termed the Betpak-dala population, mammals and birds. Pasteurellosis is not a dis- reached 242,000 in April 2015, which was about tinct syndrome. Different diseases may be associ- 65% of average number for that population dur- ated with single or multiple species and strains of ing the 1980s (CMS 2015). these organisms, and in this review, we focus on The 2015 mass mortality event.—In May 2015, the most common manifestations of hemorrhagic the Betpak-dala population was affected by a septicemia (HS) and pneumonic pasteurellosis mass mortality event leading to the death of (PP). The most virulent strains of Pasteurellaceae around 210,000 animals, close to 88% of that pop- organisms may act as primary pathogens in sus- ulation and 62% of the global population of the ceptible animals. However, many of these bacteria species (CMS 2015). The cause of death has been live in healthy carriers and act as secondary or established as hemorrhagic septicemia, caused opportunistic pathogens (Rudolph et al. 2007). by P. multocida (Kock et al. 2018). Thus, while some of the die-offs reviewed here The outbreak occurred during the calving per- appear to be cases of introduction of a virulent iod, when saigas congregate in large groups. strain of bacteria into a na€ıve population, others Mortality was recorded at fifteen calving aggre- appear to have been at least partly triggered by gations scattered over a very large, remote land- some other factor increasing the virulence of Pas- scape (see Appendix S1: Figure S2). Unaffected teurellaceae organisms or affecting the immune aggregations were not identified, but there was system in the host. In some cases, both

❖ www.esajournals.org 5 June 2019 ❖ Volume 10(6) ❖ Article e02671 SYNTHESIS & INTEGRATION ROBINSON ET AL. mechanisms may work together, as the spread of species and biotypes (Townsend et al. 2001). novel pathogens may also lower host immunity Specific genes and factors associated with viru- and trigger activity in opportunistic bacteria. lence (e.g., toxicity, resistance to phagocytes, sur- Pasteurella multocida.—Hemorrhagic sep- face adhesion, and iron uptake) have been ticemia, the proximate cause of the 2015 die-off described for certain disease manifestations asso- in saiga, is most commonly reported in cattle and ciated with P. multocida (see Harper et al. 2006, domestic Asian buffalo and is usually associated Wilson and Ho 2013 for reviews). However, little with P. multocida type B:2 (De Alwis 1999, is known about the mechanisms behind the ini- Shivachandra et al. 2011, Wilson and Ho 2013). tial stages of acute HS development. Over 90 Acute disease appears following the multiplica- genes specific to HS-causing strains have now tion of these bacteria in the respiratory tract, been identified (Moustafa et al. 2015) and should invasion across the mucosal membrane, and help identify the specific virulence attributes of infection of internal organs. Laboratory inocula- these strains in future. The bacteriology of saiga tion suggests that following invasion, extremely Pasteurella multocida isolates, including details of rapid multiplication in the blood and host organs virulence genes present from the Kazakhstan then results in death between a few hours and outbreaks and occasional deaths, is now avail- three days later (Bastianello and Henton 1994, able (Orynbayev et al. 2019). Kharb and Charan 2012). Mannheimia haemolytica and related organisms.— Different strains of P. multocida have been clas- A group of Pasteurellaceae organisms once sified according to different systems and are known as Pasteurella haemolytica are also associ- associated with different diseases. In this review, ated with disease in ungulates. P. haemolytica was we use the species names and serotypes (identi- recently split into biotypes A and T based on the fied using specific phenotypic tests) given in the ability to ferment either arabinose or trehalose. T papers cited, as the relationship between these biotypes are now classified as Bibersteinia trehalosi names and actual organisms has changed over and most A biotypes as Mannheimia haemolytica. time. The most widely used system is a combina- A11 was given the name Mannheimia glucosida tion of Carter’s system of typing into five capsu- (Shivachandra et al. 2011). Mannheimia haemolyt- lar serogroups (A, B, D, E, and F) and ica is commonly associated with respiratory dis- Heddleston’s somatic typing of 16 serotypes ease, grouped under the term pneumonic based on their lipopolysaccharide (LPS). Thus, pasteurellosis (PP). One well-documented form, isolate designations usually consist of a capsular known as shipping fever, is linked to stress and serogroup letter followed by a somatic serotype poor air quality associated with closed transport number. In ungulates, HS cases outside Africa of livestock in poorly ventilated spaces. As noted tend to be associated with the B capsular type. above, strains of P. multocida (usually serotype In other taxa, P. multocida infections have been A:1) may also be implicated alongside this organ- recorded in species as different as humans ism as the primary agent or sole detected patho- (Weber et al. 1984), elephants, and snow leop- gen in cattle (or more rarely sheep) pneumonia ards (De Alwis 1999, Spickler et al. 2010) and are (see reviews in Harper et al. 2006, Mohamed and associated with various syndromes including Abdelsalam 2008, Wilson and Ho 2013). Other septicemias (again, often associated with B cap- species of bacteria and viruses also contribute to sular type), respiratory disease, and other rarer pathogenesis in many cases, for example in manifestations (De Alwis 1999). Pasteurella multo- bovine respiratory disease (Taylor et al. 2010), cida A:1 and 3 are most commonly associated and as we discuss in this review, interactions with avian cholera, although many more sero- between these different pathogens, and thus the types have been identified in birds (Friend 1981, etiologies of pneumonic forms of pasteurellosis, Christensen and Bisgaard 2000) and capsular are often complex and poorly understood (Besser type D is associated with atrophic rhinitis in pigs et al. 2013). (Wilson and Ho 2013). More recently, DNA sequence-based tech- Pasteurellosis in wild ungulates niques have started to replace the phenotypic Pasteurellosis has been documented in a range methods for identification of Pasteurellaceae of wild ungulate species other than saigas, with

❖ www.esajournals.org 6 June 2019 ❖ Volume 10(6) ❖ Article e02671 SYNTHESIS & INTEGRATION ROBINSON ET AL. cases including both hemorrhagic septicemia particular pasture location in both years (refer- and pneumonic pasteurellosis (Tables 1, 2). ences given in Table 3). More details about these Additional information on the characteristics of MMEs in saigas and maps of outbreak locations these cases is given in Appendix S2i, ii. Gener- are given in Appendix S1. ally, the cases concern temperate climates. In addition to cases with identified syndromes Although HS is common among domestic ungu- (recorded in Tables 1, 2) and the cases in saiga, a lates in the tropics, documented cases in wildlife number of mass mortality events in the Mongo- are rare, involve small numbers, and are often lian gazelle (Procapra gutturosa) have been attrib- closely associated with outbreaks in livestock uted to unidentified forms of pasteurellosis. The (De Alwis 1982). We only found one published largest of these occurred in 1974, killing 140,000 description of HS in free-ranging wild ungulates animals, or 35% of the Mongolian population at in tropical regions (Chandranaik et al. 2015). the time (Dash and Sokolov 1986, Lushchenkina Among reindeer, most sources describe sep- et al. 1988). These cases are discussed in detail in ticemia, but a bronchopneumonia presentation Appendix S2iii. also occurs (such as in the examples from 1956 Much of the literature on hemorrhagic sep- and 1973). These are listed in Table 1 under HS ticemia concerns semi-wild or farmed ungulates rather than under PP as the only pathogen identi- such as fallow deer or partially managed boar, fied was P. multocida; however, the etiology of living under conditions fundamentally different these cases is likely to differ from the others (see from those of wild animals (Jones and Hussaini Tryland and Kutz 2018 for an overview). Con- 1982, Carrigan et al. 1991, Eriksen et al. 1999, cerning pneumonic pasteurellosis, a dispropor- Risco et al. 2013). The reindeer examples are also tionate number of cases have been recorded in from partially managed populations. In addition bighorn sheep, a highly researched flagship spe- to the detailed case studies listed in the tables, cies in which the disease is a major population- the Russian literature on HS in Cervidae also limiting factor. There is no documentation of this appears to focus on farmed animals (Lunitsyn disease in wild ungulates living in tropical and Bakulov 1985, Lunitsyn et al. 2007, Lunitsyn regions. There is some evidence that reindeer do and Borisov 2012). This may be related to the also suffer pneumonic disease associated with crowded and stressful conditions under which Mannheimia haemolytica and Mycoplasma ovipneu- farmed animals are kept but could also be an moniae (Mørk et al. 2014), but no detailed case artifact of the ease with which they may be information was available. observed and monitored. In saigas, the number of recorded cases of Implicated pathogens.—In most of the surveyed mass mortality attributed to pasteurellosis is cases of hemorrhagic septicemia (and those of small, and all are listed in Table 3. In some of bronchopneumonia in reindeer), disease was these cases, diagnosis remains unconfirmed associated with P. multocida alone, with the B3 while in others pasteurellosis is unlikely to be the and 4 serotypes often implicated (Appendix S2i). cause. In those cases reported in the years 1974, In saiga, the confirmed case of HS in 2015 and 1981, and 2012, pasteurellosis was suggested in the highly likely case in 1988 were both associ- the cited sources as the cause of death, but the ated with P. multocida capsular type B similar to specific identity of the organism and sufficient strains in domestic livestock in Spain and South- pathology data to confirm the syndrome are East Asia (Orynbayev et al. 2019). Overall, only unavailable. There is reasonable evidence for in the case of HS in gaur (Chandranaik et al. hemorrhagic septicemia in the massive 1988 2015) does there seem to have been another “pri- event and a possibility of pneumonic pasteurel- mary” infection (in this case FMDV), which was losis in 1984, associated with the presence of spread by livestock and exploited by the oppor- M. haemolytica. In 2010 and 2011, P. multocida tunistic Pasteurella organism. The set of patho- was isolated, but full pathological examinations gens associated with pneumonic forms of could not be carried out. The symptoms resem- pasteurellosis is far larger and more complex bled those of fog fever or bloat caused by inges- than in cases of HS, including M. haemolytica and tion of protein-rich vegetation, a hypothesis various strains of P. multocida together with supported by the association of mortality with a viruses and other species of the Pasteurellaceae

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Table 1. Cases of hemorrhagic septicemia in wild species of ungulate.

Period of outbreak, Numbers dead Suggested by species Location Serotype Population size (and mortality) source/trigger References

Elk/Red Deer Cervus elaphus Winter 1985–1986 USA B:3,4 Total: >7000; 1985–1986: 38 1985–1986: rain Franson and Smith and 1986–1987 affected group individuals and wind (1988), Wilson et al. 2000–3000 (<1%); 1986– (1995) 1987†:10 individuals (<1%) January–April B:3,4 105 individuals Roffe et al. (1993), 1993 Wilson et al. (1995) Farmed or park Fallow deer Dama dama Winter: 2 Australia A:3,4 100 13% Cold, wet, Carrigan et al. outbreaks, windy (1991) 3 weeks apart 5 outbreaks Denmark B:3,4 1800 101, 56, 36, 26, Eriksen et al. (1999); from 1992 to 1996‡ and 48 see also Aalbaek individuals; (1.4 et al. (1999) –5.8%) 4 July–4 September UK B:3,4 264 animals; 22 individuals Jones and Hussaini 1979 sub-herd of 60 (36% of bachelor (1982), Rimler et al. bucks affected herd) (1987) for serotyping and Wilson et al. (1992) for DNA fingerprinting Wild and farmed fallow deer July 2010 Germany 67 wild deer Hot weather Soike et al. (2012) carcasses found; 10% of 300 farmed deer died§ Farmed axis deer Axis axis 23 April–7 Australia 130 8 individuals Campbell and Saini May 1985 (6%) (1991) Reindeer Rangifer tarandus Summer 1912, Sweden¶ 1959: 600–700 Hot weather Brandt (1914), 1913, 1924, 1959 died (70% Nordkvist and calves) # Karlson (1962) October 1911; Norway 1913: 2650 1913:275 died Hot weather, Horne (1915), Summer 1913, 1914, (10%), most parasites, stress Kummeneje (1976), 2005||, 2010; May calves‡‡ Skjenneberg (1957), 1956, 1973†† Mørk et al. (2014) American bison Bison bison 1911 USA 171 22 individuals Mohler and Eichorn (13%) (1912–1913) March 1922 Gochenour (1924) 1965–1967 USA B:3,4 480 3 calves 1 Heddleston et al. yearling (<1%)§§ (1967), see Rimler and Wilson (1994) for serotyping Semi-wild boar Sus scrofa September Spain B 23 individuals Heavy rain Risco et al. (2013) 2010 (6 d) (11%)

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(Table 1. Continued.)

Period of outbreak, Numbers dead Suggested by species Location Serotype Population size (and mortality) source/trigger References

Gaur Bos gaurus¶¶ 2013–2014 India B Unknown At least 2 FMDV infection Chandranaik et al. (probably more) (2015) † 81 animals died during winter, ten of these were positively attributed to HS but carcasses were in poor condition. ‡ Some red and sika deer also died. § 10–22% of livestock on local farms also died. Deer were considered to be the source of the infection. Another outbreak in Germany 2014 affected livestock and one wild boar (Volker€ et al. 2014). ¶ Pasteurella multocida identified in 1959 Swedish and 1956 and 1973 Norwegian cases; also in 2005 and 2010 cases serotype unknown. # 1912: 1600 individuals died of which 80–90% were calves; 1913: 1500 died of which 95% calves; 1924: 1300 of which major- ity were calves. || 1911 and 2005 cases are not fully documented but seem highly likely to have involved a pasteurellosis syndrome (Anony- mous 1913, Jystad 2005). †† 1973 and 1956 cases were diagnosed as bronchopneumonia. While like HS cases the only identified pathogen was P. mul- tocida, the etiology of these cases is likely to be different to those of HS. ‡‡ 1911: 850 calves/yearlings; 1914: 25 individuals; 1956: 50 of group of 90 yearlings (in poor condition and infected with parasites); 1973: unknown; 2005: >60 calves; 2010: 44 calves §§ An additional eight animals were also sick but recovered after antibiotic treatments. ¶¶ At least 30 chitals, 12 sambars, five blackbucks, and seven nilgais also died and were tested positive for FMDV. It is unclear whether the other species also exhibited HS symptoms. family. There is some evidence that in many of low. By contrast, in both the confirmed (2015) these cases, the primary pathogen may be the and highly likely (1988) cases of HS in saiga, over bacterium Mycoplasma ovipneumoniae. The ques- 200,000 animals died. The only recorded case in tion of the relative importance of different organ- wild ungulates involving over 1000 deaths and isms in pathogenesis has been explored in detail high mortality rates affected Swedish reindeer in bighorn sheep (see Appendix S2i). In saigas, (Nordkvist and Karlson 1962). However, all rein- while an organism described as P. haemolytica deer cases involved predominantly calves, while was isolated in the 1984 outbreak (Aikimbaev in saigas adults died first, with calves subse- et al. 1985), it is not clear whether other patho- quently dying of starvation or infection through gens were not involved or not detected. Antibod- milk. Of the other reviewed cases, there is no par- ies to Parainfluenza-3 virus have been found in ticular pattern, with young animals dispropor- Mongolian saiga, so non-detection appears plau- tionally affected in some cases, and all age sible (Enkhtuvshin et al. 2010). One of the pas- groups equally affected in others. In the cases of teurellosis cases in Mongolian gazelles has also pneumonic pasteurellosis listed in Table 2, over- been associated with a viral infection (Dash and all mortality rates in affected herds tend to be Sokolov 1986; see Appendix S2iii). Infection with high, but disease is typically limited to single macroparasites may also play a role in suscepti- herds so absolute numbers of deaths are low. bility to disease. Examples include the case of PP Outside the saiga cases, only Mongolian gazelle in chamois infected with worms Strongyloides sp., mortalities are consistently counted in the many Haemonchus sp. & Coccidia (Posautz et al. 2014) thousands of animals (Appendix S2iii). More- and the two cases of bronchopneumonia in rein- over, outbreaks of both PP and HS in other spe- deer (listed in Table 1) infected with Hypoderma cies tend to be far more restricted spatially than tarandi, Dictyocaulus vivparus, or Cephenomyia to those in saiga. Appendix S2ii provides a trompe (Skjenneberg 1957, Kummeneje 1976). detailed discussion of spatial and temporal char- Mortality rates.—It is apparent from Table 1 acteristics of outbreaks while Appendix S2iv pre- that total mortality rates in the majority of sents literature on mortality patterns in domestic reviewed HS cases in free-ranging or farmed spe- animals for comparison. cies of wild ungulate are low and constitute a A number of studies, including some of those small fraction of those observed in saiga listed in Tables 1, 2, investigated prevalence in (Table 3). Single herds or small populations tend healthy animals and mechanisms of carriage and to be affected, so absolute numbers dead are also latency (Appendix S2v). In the saiga examples,

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Table 2. Cases of pneumonic pasteurellosis in wild species of ungulate.

Period of Numbers Suggested outbreak, Isolated dead source/ by species Location pathogens Popn. size (mortality) trigger References Bighorn sheep (Ovis canadensis) Winter USA (Idaho, P. m. multocida a& 4 herds 50–75% Stress during Cassirer et al. 1995–1996 Oregon, b & biotype U6 & gallicida; rut may play (1996), Washington) Bibersteinia trehalosi; role. Rudolph M. haemolytica†; et al. (2007), Mycoplasma ovipneumoniae; Weiser et al. parainfluenza 3 virus (PV3) (2003) Winter USA M. haemolytica 72 28% Organism of George et al. 1997–2000 (Colorado) 1G + B. trehalosi; domestic (2008) P. multocida multocida b; sheep origin E. coli; Pseudomonas fluorescens Winter 1990 USA P. haemolytica + Moraxella 600–900 25% Selenium Ryder et al. (Wyoming) spp; respiratory syncytial deficiency (1994), virus (RSV); PV3, Hnilicka chlamydia‡ et al. (2002) Winter USA P. haemolytica type A + type 60–65 (35– Disturbance; Festa- 1985–1966 (Alberta) T§ 40%)¶ nutritional Bianchet stress (1988) Winter USA P. haemolytica; P. multocida 100 67%|| Contact with Coggins 1986–1987 (Oregon) # + PV3; RSV domestic (1988) sheep; rut Winter USA M. haemolytica; 21 >30% At least one Wolfe et al. 2007–2008 (Colorado) B. trehalosi + P. multocida; organism (2010) M. ovipneumoniae; PV3; possibly of RSV livestock origin; severe winter Oct-Feb USA P. multocida; Corynebacterium 80 75–85%†† Stress: traffic, Spraker et al. 1980–1981 (Colorado) pyogenes; Prostrongylus dust; noise (1984) stilesi and harassment and lungworm Ranch-raised American Bison Bison bison December USA (N. P. haemolytica + P. multocida; 20 calves 4 (25%) Transport of Dyer and 1996 Dakota) Trueperella pyogenes; calves in cold Ward (1998) Pseudomonas aeruginosa temperatures Muskox Ovibos moschatus August/ Norway M. haemolytica + P. multocida 276 71 (25%) Warm humid Ytrehus et al. September multocida weather (2008) 2006 Chamois Rupicapra rupicapra Spring 2010 Austria M. glucosida : 30% all ages Possibly Posautz et al. B. trehalosi + Parasites exacerbated (2014) (Strongyloides sp., by parasite Haemonchus sp. & Coccidia) infestation (animals emaciated) † Multiple strains. ‡ Prevalence of organisms was similar before and after outbreak, not all may be linked to disease. § Probably Pasteurella haemolytica & Bibersteinia trehalosi. Some animals from which these organisms were recovered did not show clinical signs of pneumonia. ¶ Affected all sex/age groups; did not show the bias to older males often noted in pneumonia outbreaks among bighorns. # Prevalence not given for samples taken during the outbreak; nasal swabs taken from 20 captured adults one year after die- off indicated that 72% were P. multocida carriers; P. haemolytica detected in only one sample. || All rams over 4 yr plus lambs. Animals treated with antibiotics in mid-December. †† 100% lambs during following summer; 67% following two summers.

❖ www.esajournals.org 10 June 2019 ❖ Volume 10(6) ❖ Article e02671 SYNTHESIS & INTEGRATION ROBINSON ET AL. the sudden simultaneous death of large numbers et al. 1991). More commonly suggested stressors of animals of all age groups would seem to imply include climate, poor nutrition, or high parasite high background prevalence rates of the pathogen loads; and deficiencies in certain dietary trace combined with an environmental trigger—and elements or toxic levels of others. A second class indeed the organism has been detected at high of possible causal factor involves the presence of frequencies in the tonsils of animals which died of pathogenic strains of the Pasteurellaceae organ- other causes (Kock 2017). Some studies on cattle ism in other species (such as domestic ungu- and buffalo, in which prevalence has been studied lates), followed by transmission of these virulent most intensively, suggest relatively low rates of forms to naive populations of wild ungulate. prevalence in healthy animals, high levels during Enhanced intra-specific transmission caused by outbreaks followed by a slow decline afterward, seasonal aggregation or presence of parasitic vec- and disproportionate mortality among younger tors has also been posited. The evidence for the animals with lower immunity (see references in influence of the most commonly suggested envi- Appendix S2v). This would suggest a strong role ronmental factors in HS and PP outbreaks is pre- for transmission of virulent forms of the pathogen sented with references in Table 4 and in these cases. However, understanding of latency summarized here, while more detailed discus- has changed over time and conclusions are ham- sion of each is provided in Appendix S3. pered by sampling issues. Carriage in the Climatic factors.—Association of HS with high nasopharynx, the most commonly sampled site, is humidity, combined with temperatures over a likely to be more transient than that in the tonsil- certain threshold, appears to be well established. lar crypt, retropharyngeal lymph nodes, or other Climate has also been implicated in forms of organs where the organism is now known to be pneumonic pasteurellosis such as bovine respira- latent (De Alwis 1993). It is difficult to obtain tory disease (BRD). However, the etiology and uncontaminated samples from sites such as ton- epidemiology of BRD are different from that of sils in a consistent manner, especially from live HS and climate may operate through different individuals. The highly variable rates of preva- mechanisms, including viral activity (Taylor lence recorded in the surveyed literature may et al. 2010). The evidence cited in Table 4 sug- reflect these issues, and better methodologies are gests a direct role for climatic factors in needed to explore commensalism with this bacte- pathogenicity, but such factors also affect patho- rial family. gen survival in the environment, which may be Below, we look at the roles of environmental relevant where transmission between individuals factors and transmission between and within is important (see Appendix S3i). species in more detail. Nutritional factors.—Nutritional stress may cause host immunosuppression, particularly at Environmental factors implicated in pasteurellosis the energetically demanding periods of gestation outbreaks and lactation during which HS events in saigas Because the organisms involved are commen- occurred (Houdjik et al. 2001). In most cases con- sals, and some cases involve sudden onset in sidered here, animals were in good condition, multiple individuals, environmental factors are (exceptions being cases involving heavy parasite often implicated in die-offs. Triggers which have infestations), but this does not rule out deficien- been linked to pasteurellosis (of all kinds) cies in labile protein (Appendix S3ii). include stress due to disturbance, handling, or Trace elements.—A role for trace elements in transport (Spraker et al. 1984, Dyer and Ward susceptibility to pasteurellosis has been sug- 1998, Lunitsyn et al. 2007, Rudolph et al. 2007), gested through the impact of selenium or copper and some forms of PP in livestock are referred to deficiency on the immune response and iron as shipping fever for this reason. Intense physical availability on virulence of P. multocida. How- activity such as flight from predators has also ever, convincing links between trace element been suggested as a trigger (Statsenko 1980), and levels and disease are difficult to demonstrate in there is experimental evidence linking stressful actual outbreaks (Appendix S3iii). exercise with immunosuppression and suscepti- Between-species transmission.—Highly virulent bility to pneumonic pasteurellosis (Anderson Pasteurellaceae organisms or co-infecting

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Table 3. A summary of die-off events in saigas attributed in the listed sources to Pasteurellaceae-related syndromes or in which Pasteurellaceae organisms were isolated†.

Syndrome/ Mortality as organism % of regional isolated‡ Population Mortality dates Calving dates Deaths % Female population§ Source

Hemorrhagic Betpak-dala 9–29 May 2015¶ 6–24 May ~210,000 96% ~88% Authors own field septicemia notes; CMS (2015), P. multocida Kock et al. (2018) [C. perfringens] Pasteurellosis; Betpak-dala 12–22 May 1988 Started 270,000 97% 75% Institute of probably before 12 May Zoology and hemorrhagic Betpak-dala State septicemia Hunting P. multocida Organisation (1988, 1989), Turgai Regional Executive Committee (1988) Pasteurellosis; Ural February– May 110,000 62% 73% Institute of possibly April 1984 Zoology and pneumonic Department of form Reserves and P. haemolytica Hunting (1984, 1985) Pasteurella given Betpak-dala 15–16 June 1974 May 1000 <1% Statsenko (1980) fi as of cial Betpak-dala 24–28 May 1981 Mid-May 70,000 15% Institute of cause, but no Zoology and detail on Department of syndrome or Reserves and organism Hunting (1981, 1982) Betpak-dala 17–30 May 2012 9–14 May >1000 98% <1% Dieterich (2012) and Zuther (2012) Symptoms Ural 18–29 May 2010 1–13 May 12,000 75% Kock (2011), Kock resemble bloat Ural 26–27 May 2011 18–19 May 400 <10% et al. (2014) and or fog fever Orynbayev et al. [P. multocida] (2013) [C. perfringens] † The evidence for confirmation of the syndrome hemorrhagic septicemia and causal organism P. multocida is definitive only for the 2015 event. ‡ Organisms in square brackets are those which were isolated from dead animals but which may not be implicated in disease or death. § Betpak-dala, Ural, or Ustiurt. ¶ Across all sites. At individual sites, deaths lasted between 6 and 10 d. pathogens implicated in outbreaks may originate potential carriers and saiga outbreaks have not in other species, in which cases transmission been established. from a reservoir species could be a key stage of Intra-species transmission.—There is evidence outbreak etiology. Such a mechanism is sug- that differences in seasonal contact rates or expo- gested in some of the reviewed literature, yet sure to sick animals or carcasses played a role in transmission does not always occur, even when some of our reviewed outbreaks. Climatic condi- it would be expected: In a case where multiple tions favoring vectors either of the commensal or species of deer were kept in the same paddock, co-pathogen (such as ticks and flies), although only one species was affected (Campbell and recorded in some commensal-related MMEs Saini 1991). Despite evidence for a high preva- (Munson et al. 2008), have not been convincingly lence of P. multocida in the saiga environment demonstrated in pasteurellosis cases. In saigas, (Appendix S3iv), relationships between other HS die-offs have always occurred in dense

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Table 4. Evidence for the influence of environmental triggers and transmission in pasteurellosis outbreaks from the reviewed case studies and the broader literature (see Appendix S3 for details).

Evidence from field studies Evidence from laboratory experiments (all syndromes Factor Hemorrhagic septicemia Pneumonic pasteurellosis and organisms)

Climate Four studies (on bovine livestock, Statistical studies on domestic Role of atmospheric pigs, saiga, and farmed deer livestock relate morbidity to cold conditions in susceptibility to species) suggest statistical links temperatures and high- infection has been between temperature and temperature variability (MacVean demonstrated for humidity, and outbreaks (Lunitsyn et al. 1986, Cusack et al. 2007). M. haemolytica (Jones and and Bakulov 1985, Dutta et al. Several case studies implicated hot Webster 1984, Jones 1987, 1990, Gao et al. 2016, Kock et al. and humid or unusually cold Woldehiwet and Rowan 1988). 2018). Saiga and Mongolian gazelle weather in outbreaks (Table 1). No studies on P. multocida cases occur at period of peak One case in saiga occurred during precipitation in their respective the winter, in contrast with HS countries. Five reviewed wildlife cases in that species. Bighorn cases present anecdotal evidence of deaths usually occur in winter unusually hot or cold conditions months, in particular among during outbreak (Table 1) with males, while calves are more consistent emphasis on hot affected in summer summers in reindeer HS cases Nutrition No evidence that this is important Nutritional stress has been linked None in HS cases, but outbreaks in saiga to bighorn lambing rates and lamb and Mongolian gazelles coincide survival following die-offs (Enk with peak nutritional demand et al. 2001) and may be associated associated with calving and/or with individual outbreaks (Festa- lactation. Bianchet 1988). Only in the reviewed case involving chamois were animals clearly in very poor condition, due to heavy parasite loads (Posautz et al. 2014) Trace elements One study on “pasteurellosis” in Selenium deficiency linked to low Virulence of M. haemolytica Mongolian gazelles found trace lamb survival following a and P. multocida increased by element levels to be different in pneumonic pasteurellosis die-off in iron compounds (Mohamed die-off areas than on neighboring bighorn sheep and poor immune and Abdelsalam 2008, Wilson pastures, but nature of syndrome competence may have been behind and Ho 2013). Unbalanced Cu: and pathogen is unconfirmed the initial outbreak (Hnilicka et al. Mo ratios and low selenium (Rotshild et al. 1988) 2002) linked to disease caused by M. haemolytica (Stabel et al. 1989, Gengelbach et al. 1997) Transmission Synchronicity between outbreaks Cases of PP in bighorn sheep are None between species in deer and livestock has been believed to originate in domestic noted on Russian deer farms sheep (Coggins 1988, Wolfe et al. (Lunitsyn et al. 2007). Two 2010), leading to all-age outbreaks examined cases involved multiple in na€ıve populations with very species of deer (Eriksen et al. 1999) high mortality (Cassirer et al. 2013) or transmission from deer and livestock (Soike et al. 2012). Rodents believed to be source of disease in former Soviet Union (Bakunina 1961, Gordienko and Kovtun 1967) Transmission Epidemiology suggests spread of There is evidence that in non-na€ıve None between disease through contact in some populations, subsequent outbreaks individuals HS cases (Brandt 1914, Eriksen restricted to adults or to calves et al. 1999) and in reindeer alone are related to geographical bronchopneumonia (Kummeneje mobility and contact rates (Cassirer 1976) P. multocida can be carried by et al. 2013). This contact is seasonal parasitic arthropods (Quan et al. and so may have been confounded 1986); vector-borne transmission with climatic factors suggested (Kummeneje 1976, Dzhupina and Kolosov 1992) but remains undemonstrated

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(Table 4. Continued.)

Evidence from field studies Evidence from laboratory experiments (all syndromes Factor Hemorrhagic septicemia Pneumonic pasteurellosis and organisms)

Co-infection One case study found FMDV to be All cases of pneumonic Tick-borne fever increases a possible predisposing factor pasteurellosis involve multiple susceptibility to M. haemolytica (Chandranaik et al. 2015). Lung pathogens, but not all are cytotoxin (Woldehiwet et al. parasites are associated with opportunistic commensals. Parasite 1993) bronchopneumonia cases in loads associated with one case reindeer (Skjenneberg 1957, (Posautz et al. 2014) Kummeneje 1976) Note: Mongolian gazelle cases listed under HS but in fact the syndrome is unidentified. calving aggregations, yet the rapidity and syn- intertidal temperature ranges facilitate high rates chrony of mortality at distant locations and the of asymptomatic infection by an intracellular presence of dead animals outside aggregations bacterium associated with rickettsial disease. suggest a different etiology. Symptoms are then triggered by subsequent periods of high temperatures (Ben-Horn et al. Mortality events caused by other opportunistic 2013). This lag between infection and disease bacteria—in ungulates and beyond expression can lead to sudden and extremely Outbreaks in ungulates caused by the other high rates of mortality in the wild, which are not organisms reviewed here follow a similar pattern mitigated by the reduction in host density which to most Pasteurellosis outbreaks, with relatively would usually slow the spread of disease epi- low mortality and/or small numbers of animals demics. Conditions favoring colonization or affected (see Appendix S4 for details). Outside infection by the initially harmless pathogen are ungulates, Pasteurellosis cases in wildlife compa- separate in time from those triggering disease rable in magnitude to that of saiga MMEs and death. Such physiological mechanisms may include outbreaks caused by P. multocida in be common in ectotherms such as amphibians, waterfowl, which may cause deaths in the tens of whose internal temperature is close to that of the thousands (Friend 1981), but mortality rates do environment (Rohr et al. 2013) but are likely to not approach 100% and much smaller outbreaks be rarer in mammals. also regularly occur (Samuel et al. 2004). The syndrome, avian cholera, is caused by a different DISCUSSION serotype of P. multocida and is generally consid- ered to be an epizootic disease transmitted We started this review by asking whether the between individuals rather than the opportunis- 2015 mortality event in saiga was unprecedented. tic response of a pathogen to an environmental We found that the only HS case of similar magni- trigger. As such, research has tended to focus on tude in wild or domestic ungulates was also survival and transmission of virulent strains in recorded in saigas (in 1988). Hemorrhagic sep- wetland environments (Bredy and Botzler 1989, ticemia outbreaks recorded in other wild ungu- Samuel et al. 2004, Blanchong et al. 2006). The lates bear little resemblance to these events. ungulate commensal E. rhusiopathiae has also Often restricted to single herds and a limited spa- been shown to cause very high mortality in tial range, both the numbers dead and mortality migratory birds and may now be emerging as an rates tend to be low, even in dense populations. important pathogen in arctic ungulate species The fact that many recorded cases of HS in wild (Appendix S4). ungulate species occurred in managed or farmed The broader literature on commensals suggests populations may reflect stressful living condi- a mechanism through which exceptional combi- tions or the fact that these animals are closely nations of climatic factors may cause extreme monitored. It is possible that many cases in wild mortality events. Laboratory studies on abalone populations go unnoticed (Preece et al. 2017), (Haliotis cracherodii) have demonstrated that large but it is unlikely that events on the scale of those

❖ www.esajournals.org 14 June 2019 ❖ Volume 10(6) ❖ Article e02671 SYNTHESIS & INTEGRATION ROBINSON ET AL. observed in saiga would be undetected, although septicemia. Although conditions anecdotally large die-offs among caribou and reindeer in the associated with cases vary widely, the few stud- subarctic arboreal forests might be an exception ies taking a statistical approach (including our and a 50% reduction in the population of these study on saigas; Kock et al. 2018) tend to find animals has been noted in the past 20 yr (Russell associations with warmth and relative humidity. et al. 2018). However, in saigas, although climatic conditions Pneumonic pasteurellosis may virtually wipe in the MME years were unusual, they were not out single herds, for example bighorn sheep, but unprecedented (Kock et al. 2018), and there are again infections tend to be local and thus abso- no obvious differences between the ecology and lute numbers dead are generally low. From this environment of the four main saiga populations point of view, if the 1984 MME in the Ural saiga (excluding the Mongolian population) that population was a form of pneumonic pasteurel- would explain why one (Betpak-dala) has suf- losis, then it must also be considered to be extre- fered repeated episodes of HS, another (Ural) is mely unusual in its scale. However, as we have implicated in other Pasteurellaceae-related seen, it is possible that other unidentified organ- events, and the other two have apparently not isms may have been implicated in this event. been subject to similar events. A further issue Cases of possible pasteurellosis most resem- with the climate hypothesis is why conditions bling those in saigas are found in Mongolian led to rapid and total mortality in saiga cases gazelles. Although overall mortality was lower, and not in other cases reviewed here. Although deaths were in the tens of thousands and die-offs relative humidity in particular was very high in repeatedly occurred at a particular season and 2015 relative to long-term averages at the Kazakh location, suggesting that a specific set of condi- region concerned, the absolute amount of mois- tions may trigger the disease. But the documen- ture in the atmosphere was probably low com- tation of these die-offs is insufficient to confirm pared to typical levels in countries such as India the identity of the syndrome or micro-organism where HS cases in domestic animals have been responsible. linked to the monsoon. It is possible that in Kaza- Mortality from other commensal opportunists in khstan, humidity is much higher for short peri- ungulates also tends to be low and geographically ods in the mornings at ground level than would restricted. More broadly, of all disease-related have been detected by Kock et al. (2018), who mass mortality events in mammals, examples used data measured at 2 m above the ground. affecting over 10,000 individuals have been Also, relative humidity itself is problematic as an recorded in only a handful of cases since the indicator of atmospheric moisture because it 1950s (Fey et al. 2015). Devastating mass mortal- measures the moisture content of air as a propor- ity is more often associated with acute epizootic tion of total possible moisture content. The latter viral diseases such as rinderpest or PPR in ungu- increases exponentially with temperature, mean- lates (Preece et al. 2017), or similar morbilliviruses ing that the effects of temperature and atmo- in marine mammals (Di Guardo et al. 2005). spheric water content are confounded in many These generally involve the introduction of the climate-disease studies (Shaman and Kohn 2009). virus into a naive population, sometime com- Measures of absolute humidity such as specific bined with immune suppression by environmen- humidity and vapor pressure may be more bio- tal pollutants in marine examples (De Swart et al. logically meaningful. 1995). Fungal diseases have been implicated in In order to address these questions, statistical extremely large MMEs in bats and in amphibians, comparisons of conditions at calving sites leading to extinction in some cases (Preece et al. between different saiga populations should be 2017). But very severe MMEs caused by commen- carried out. New data collection at calving sites sal organisms following the action of a stress fac- should include portable ground weather-station tor appear to be extremely rare. data for comparison with remotely sensed indi- cators and studies should include collection of Future research specific humidity data. Climatic factors are the most consistently However, statistical associations of outbreaks hypothesized trigger in reports of hemorrhagic with specific sets of environmental conditions

❖ www.esajournals.org 15 June 2019 ❖ Volume 10(6) ❖ Article e02671 SYNTHESIS & INTEGRATION ROBINSON ET AL. cannot prove that these conditions actually led to In this review, we have focused on ungulates, bacterial proliferation and invasion. In vivo labo- but it is also possible that life history and behav- ratory experiments listed in Table 4 demonstrate ioral factors are more important than taxonomic the influence of climatic factors on M. haemolytica similarities in explaining the mortality rates, proliferation but no such work has been carried numbers dead, and spatial scale of outbreaks. out on P. multocida. Experiments using labora- Both saigas and Mongolian gazelles are temper- tory-grown saiga respiratory epithelial cells ate migratory species living in large herds rang- could be used to study the effects of changing ing over huge areas, for which the nutritionally atmospheric conditions at the mucosal surface on stressful period of calving or lactation follows a P. multocida, going some way to demonstrating severe winter and coincides with the onset of wet such a mechanism. periods. It is also possible that climatic conditions at In some ways, the large outbreaks of avian time of mortality cannot alone explain such an cholera in migratory birds are more analogous to unprecedented event. Cases involving very high these cases than are cases in other ungulates; this mortality rates in other taxa may involve interac- syndrome also follows a similar progression to tions between Pasteurella and other pathogens that of HS—of acute disease following multipli- combined with a specific set of climatic condi- cation and invasion across the respiratory tract. tions, or an initial set of environmental conditions In both HS and avian cholera, the genetic and leading to very high colonization rates, followed molecular mechanisms involved in the transition by a second climatic trigger causing extreme from latency or mild chronic pasteurellosis to virulence as we saw in abalone. In saiga, only acute disease are unknown (Shivachandra et al. one pathogen was identified, but all hypothe- 2011, Wilson and Ho 2013). Factors determining ses would imply that a very large proportion of initial attachment and invasion of host cells, individuals must have been carrying it just before which would enable improved understanding of the outbreak. However, the demonstration of how putative triggers actually work (Harper long-term commensalism is difficult as the et al. 2006), are a research priority. Although sampling of tonsillar crypts in live animals is PCR typing studies suggest that strains of P. mul- problematic and availability of fresh carcasses is tocida found in saiga are similar to those in many low. A better understanding of the different other animals, full-genome sequencing would forms of carriage, both latent and shedding; inves- provide more detailed information. Comparison tigations of saiga tonsil anatomy; and stan- of RNA in the pathogen from affected and unaf- dardization of necropsy and histopathology fected saiga may help to identify differences in protocols for long-term monitoring would con- gene expression. tribute to improved confidence in prevalence rate In the end, an explanation for the sudden and monitoring. catastrophic virulence observed in saigas in 2015 There is some evidence from the 2015 outbreak must lie in the genetics and microbiology of the that invasion also occurred through the gut host–pathogen interaction, triggered by changes (Kock et al. 2018), a phenomenon also observed in the external environment. Molecular studies, in in infection studies in ruminants (Abubakar et al. concert with experimental pathology designed to 2016). So a link to forage and vegetation cannot test specific hypotheses concerning trigger factors, be ruled out. Intake of protein-rich forage may backed up by extensive fieldwork and monitoring cause ruminal stasis, lowering bile production of animals and conditions at calving sites, may which normally inhibits the development of eventually reveal the nature of these interactions. P. multocida in the gut. There was no evidence for particularly unusual forage conditions in the ACKNOWLEDGMENTS 2015 event and vegetation composition was very different between die-off sites, but long-term The project was funded by a NERC Urgency grant vegetation monitoring and saiga fecal analysis at (NE/N007646/1), and grants from the People’s Trust for calving sites could be used to measure baselines Endangered Species, Fauna and Flora International, of nutritional composition and density for com- and the Saiga Conservation Alliance. We thank the parison if future MMEs occur. Convention on Migratory Species and Wildlife

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Conservation Network for their support and assis- out the cause of a polymicrobial disease. Preventa- tance. Particular thanks go to the Kazakhstan Ministry tive Veterinary Medicine 108:85–93. of Agriculture, Forestry and Hunting Committee. We Blanchong, J. A., M. D. Samuel, D. R. Goldberg, D. J. would also like to thank Bjørnar Ytrehus for his trans- Shadduck, and M. A. Lehr. 2006. Persistence of lations of Nordic literature on reindeer. Pasteurella multocida in wetlands following avian cholera outbreaks. Journal of Wildlife Diseases LITERATURE CITED 42:33–39. Brandt, O. 1914. Pasteurellosis in reindeer [Pasteurellos Aalbaek, B., L. Erikson, R. Rimer, P. S. Leifsson, A. hos ren]. Svensk Veterinær-Tidskrift 29:378–397 & Basse, T. Christiansen, and E. Eriksen. 1999. Typing 434–443. of Pasteurella multocida from haemorrhagic septi- Bredy, J. P., and R. G. Botzler. 1989. The effects of six caemia in Danish fallow deer Dama dama. APMIS environmental variables on Pasteurella multocida 107:913–920. populations in water. Journal of Wildlife Diseases Abubakar, M. S., M. Zamri-Saad, S. Jasni, and A. B. Z. 25:232–239. Zuki. 2016. Immunohistochemical evaluation of Campbell, G., and G. Saini. 1991. Pasteurella multocida- lesions in the gastrointestinal tract of buffalo (Buba- associated septicaemia in a chital deer (Axis axis). lus bubalis) calves orally exposed to Pasteurella mul- Australian Veterinary Journal 68:345. tocida B:2. Sokoto Journal of Veterinary Science Carrigan, M. J., H. J. Dawkins, F. A. Cockram, and A. 14:21–27. T. Hansen. 1991. Pasteurella multocida septicaemia Aikimbaev, M. A., I. L. Martinevski, A. A. Altukhov, S. in fallow deer (Dama dama). Australian Veterinary I. Ivanov, and V. F. Surov. 1985. On the analysis of Journal 68:201–203. the pathogenic Pasteurella from Saiga during Cassirer, E. F., L. E. Oldenburg, V. L. Coggins, P. February-March 1984 in the Ural region [O slu- Fowler, K. Rudolph, D. L. Hunter, and W. J. chayak vydeleniya pasterelleza ot saigakov v fev- Foreyt. 1996. Overview and preliminary analysis of rale- marte 1984 goda v Uralkskoi oblasti]. Seriya Hells Canyon bighorn sheep die-off, 1995–96. Pages Biologicheskaya 4:39–41. 78–86 in Proceedings of Northern Wild Sheep and Anderson, N. V., Y. D. Youanes, J. D. Vestweber, C. A. Goat Council’s 10th Biennial Symposium. Wild King, R. D. Klemm, and G. A. Kennedy. 1991. The Sheep Foundation, Bozeman, Montana, USA. effects of stressful exercise on leukocytes in cattle Cassirer, E. F., R. K. Plowright, K. R. Manlove, P. C. with experimental pneumonic pasteurellosis. Cross, A. P. Dobson, K. A. Potter, and P. J. Hudson. Veterinary Research Communication 15:189–204. 2013. Spatio-temporal dynamics of pneumonia in Anonymous. 1913. Veterinary service and meat control. bighorn sheep. Journal of Animal Ecology 82:518– Norwegian public statistics [Veterinærvæsenet og 528. kjøtkontrollen. Norges officielle statistik] 201:29– Chandranaik, B. M., et al. 2015. Serotyping of foot and 31. Veterinærdirektøren, Christiania, Norway. mouth disease virus and Pasteurella multocida from Bakunina, L. I. 1961. Cases of isolation of the pathogen Indian gaurs (Bos gaurus) concurrently infected for haemorrhagic septicaemia from gerbils [Sluchai with foot and mouth disease and haemorrhagic vydeleniya vozbuditelya gemorragicheskoi septit- septicaemia. Tropical Animal Health and Produc- semii or bol’nykh peschanok]. Journal of Microbi- tion 47:933–937. ology, Epidemiology and Immunology 5:122–123. Christensen, J. P., and M. Bisgaard. 2000. Fowl Cho- Bastianello, S. S., and M. M. Henton. 1994. Haemor- lera. Technical and Scientific Review of the Interna- rhagic septicaemia. Pages 1689–1694 in J. A. W. tional Office of Epizootics 19:626–637. Coetzer and R. C. Tustin, editors. Infectious dis- CMS (Convention on Migratory Species). 2015. Over- eases of livestock. Oxford University Press, Oxford, view report on conservation status and MOU UK. implementation. CMS Secretariat, Tashkent, Uzbe- Bekenov, A. B., I. A. Grachev, and E. J. Milner-Gul- kistan. https://www.cms.int/sites/default/files/docu land. 1998. The ecology and management of the ment/Saiga%20MOS3_Overview_Report_of_Conse Saiga antelope in Kazakhstan. Mammal Review rvation_Status_Eng.pdf 28:1–52. Coggins, V. L. 1988. The Lostine Rocky Mountain big- Ben-Horn, T., H. S. Lenihan, and K. D. Lafferty. 2013. horn sheep die-off and domestic sheep. Pages 57– Variable intertidal temperature explains why dis- 64 in Proceedings of the Sixth Biennial Symposium ease endangers black abalone. Ecology 94:161–168. of the Northern Wild Sheep and Goat Council. Besser, T. E., E. F. Cassirer, M. A. Highlanda, P. Wolff, Wild Sheep Foundation, Bozeman, Montana, USA. A. Justice-Allen, K. Mansfield, M. A. Davis, and W. Cusack, P. M., N. P. McMeniman, and I. J. Lean. 2007. Foreyt. 2013. Bighorn sheep pneumonia: sorting Feedlot entry characteristics and climate: their

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