The role of red squirrels in leprosy dynamics in the United Kingdom: a critical review

Abstract

In the United Kingdom, the declining population of the red squirrel, the acknowledged historical reservoir for zoonotic Mycobacterium leprae leprosy, is thought to have been behind the decline in leprosy. However, remaining red squirrels are mainly plagued by Mycobacterium leprae, questioning their historical role in zoonotic M. leprae leprosy dynamics. To resolve this issue, forthcoming paleomicrobiology studies will address the M. leprae complex as a whole; investigating the remains of squirrels buried for eight centuries, and burrowing animals imported in the United Kingdom from the British Empire countries between the 16th and 19th centuries; also looking at the situation in continental Europe, to gain a more comprehensive view of the historical zoonotic dynamics of leprosy in the United Kingdom and Europe. The results may indicate that the declining red squirrel population is no more than a red herring, obscuring a broader decline in leprosy.

1. Introduction: puzzling the history of leprosy in the United Kingdom

Leprosy became a notifiable disease in England and Wales in 1951, and statistics subsequently indicated its decreasing prevalence, with all cases being imported from leprosy-endemic countries, parts of the British Empire. Rare cases of indigenous transmission were recorded, although these were ultimately traced to such imported cases [1]. In one illustrative, fatal case, the patient had, for six months, slept in the same bed as his infected brother who had returned from India [2]. The dynamics of leprosy are more puzzling when it involves data before the 20th century. The decreasing prevalence observed between the 19th and 21st centuries appears to have started in the 16th century, when the United Kingdom first colonised parts of North America, before expanding around the globe, occasioning extensive exchanges of human, animal, and plant populations, and possibly accompanying microbes. For example, this is reflected in the London Natural History Museum records, which began registering exotic animals in the 17th century (Fig. 1). Before modern times, leprosy peaked between the 9th and 11th centuries, possibly fuelled by crusades and historically attested to by pictorial representations, texts, and many leprosaria. Accordingly, populations in medieval and modern times recognised leprosy featuring pathognomonic leonine facies and distal amputations, due to neurotrophic bone deformations (also visible in buried skeletons). They addressed the endemicity of leprosy, which is reflected in social distancing and referred to in numerous texts and pictorial representations. In the Roman world (delimited in the United Kingdom by Hadrian's wall), there is no paleopathological or paleomicrobiological evidence that leprosy circulated along military and trade routes from putative Egyptian and Near East foci to southern Britain [3]. Circulating strains of the causative, yet axenically uncultured Mycobacterium leprae (M. leprae) are known only for mediaeval times, after M. leprae whole genome sequences (and mycolic acids) were recovered from bone tissues and dental calculus in the remains of eighteen individuals, buried from the 7th century onwards, which indicated five M. leprae lineages (lineages 0,1, 2, 3, and 4) [[3], [4], [5], [6], [7], [8], [9]] (Fig. 2). These data left unknown whether Mycobacterium lepromatosis (M. lepromatosis), another leprosy pathogen, played any role in the indigenous dynamics of leprosy in the United Kingdom.

Fig. 1.

Territorial expansion of the British Empire between the 16th and the 19th centuries opened up opportunities for the importation of various exotic animals, which were possibly reservoirs for the leprosy pathogens, as depicted in records held at the Natural History Museum in London (https://data.nhm.ac.uk/search). Here, light blue ◆ indicates territories occupied during the 16th century, orange ◆ indicates territories occupied during the 17th century, green ◆ indicates territories occupied during the 18th century and black ◆ indicates territories occupied during the 19th century. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 2.

Long-standing secular cohabitation of leprosy in red squirrel and human populations in Northern Europe.

Molecular evidence of Mycobacterium leprae and Mycobacterium lepromatosis in humans and red squirrels across continental Europe and the United Kingdom over a period of 18 centuries.

Panel A. Whole-genome sequences of M. leprae have been reported from individuals (and one red squirrel) recovered from 27 archaeological sites spanning nearly 1300 years (5th to 18th centuries), indicated by black stars (★). Additional detections based on PCR in human samples are marked with purple stars (★), and those based on lipid biomarkers with red stars (★).

Symbols indicate the origin of samples: human bone remains; human tooth remains; red squirrel bone remains.

Colored symbols indicate phylogenetic branches of M. leprae:

• •
  ◆yellow = branch 0.
• •
  ◆orange = branch 2F.
• •
  ◆green = branch 3.
• •
  ◆blue = branch 4.

The information linked indicates the number of samples (written as N = X) the location, date, and the numbers between square brackets indicates references in figure reference.

Panel B indicates the absence of data for the 19th and 20th centuries.

Panel C features a series of DNA-based evidence for M. leprae (red circle), M. lepromatosis (purple circle) and negative detection (black circle) in red squirrels (with clinical signs of leprosy, green circle) in the 21st century. Colour-coded squirrel icons: green icons for Tamias sibiricus, yellow for Callosciurus erythraeus, blue for Sciurus carolinensis, and black for Sciurus vulgaris.

2. Bibliography methods

In this review, we examined both historical and contemporary literature on human and zoonotic leprosy in the United Kingdom. The literature search was conducted between November 2024 and April 2025, utilizing academic databases including PubMed, Google Scholar, and ScienceDirect. Additional historical sources were accessed through Gallica—the digital library of the Bibliothèque nationale de France—and archival materials from the Natural History Museum in London. The search strategy incorporated a combination of keywords such as “leprosy,” “Mycobacterium leprae,” “Mycobacterium lepromatosis,” “red squirrel,” “zoonotic leprosy,” “medieval leprosy,” “United Kingdom,” “paleomicrobiology,” “British Empire,” and “colonial animal trade.” We included peer-reviewed scientific articles, archaeological reports, historical monographs, and government documents relevant to leprosy transmission, animal reservoirs, and the sociomedical history of the disease.

Figures for the review were created using QGIS 3.32 to map the spatial distribution of M. leprae and M. lepromatosis in human and animal remains and the historical trajectory of British colonial expansion. Supplementary illustrations, including historical depictions and timelines, were designed and formatted using Microsoft PowerPoint 365 and Adobe Illustrator 2023 to ensure visual clarity and stylistic consistency throughout the manuscript. Adopting a transdisciplinary framework, this review integrates paleomicrobiological, historical, ecological, and epidemiological perspectives to reassess the “red squirrel hypothesis critically” and the broader dynamics of leprosy in the United Kingdom.

3. Bibliometric results

Forty-one scientific articles, monographs, and reports published in English between 1889 and 2024 were reviewed to develop this narrative synthesis. The selected sources comprise peer-reviewed research articles from medical and microbiological journals, historical monographs, archaeological excavation reports, and surveillance data about leprosy in the United Kingdom. Of these, six publications specifically addressed zoonotic transmission, focusing on red squirrels as potential reservoirs of Mycobacterium leprae or Mycobacterium lepromatosis, while nineteen articles examined paleomicrobiological findings from human remains. Additionally, three documents offered insights into the sociohistorical context of leprosy, discussing aspects such as patient isolation practices, colonial-era animal trade, and public health responses during the Industrial Revolution. The majority of studies originated from research institutions in Europe and North America. Notably, there has been an increase in paleogenomic research since 2013, following the successful sequencing of medieval M. leprae genomes. Interest in M. lepromatosis has grown since 2016, particularly in the context of wildlife surveillance in the British Isles. Overall, the reviewed literature reflects a growing interdisciplinary effort to combine molecular biology, archaeology, and historical analysis to understand better the evolution and transmission dynamics of leprosy in past populations.

4. Results and discussion

4.1. Red squirrels: a historical reservoir for zoonotic leprosy

In the United Kingdom, M. leprae has been documented in the remains of individuals from medieval times and some red squirrel populations (Sciurus vulgaris). Almost a decade ago, Meredith et al. published a groundbreaking study providing the first concrete evidence of M. leprae in red squirrels in the United Kingdom [10,11]. Combining molecular techniques, including PCR and DNA sequencing with serology, M. leprae was documented in 25 red squirrels from Brownsea Island, including eight clinically diseased squirrels. Histopathology and immunohistochemistry confirmed granulomatous lesions consistent with leprosy in infected squirrels. Infecting M. leprae strains yielded genomic sequences most closely related to those retrieved from buried individuals in 13th-century England and 14th-century Denmark. Similar sequences were also collected from the remains of one red squirrel from medieval Winchester, not far from Brownsea Island [12]. This discovery suggests that M. leprae may have persisted in the United Kingdom for centuries, even after human cases of leprosy had dramatically declined. It supports the hypothesis that the red squirrel was the reservoir for zoonotic leprosy [10]. The fact that the M. leprae strain found in red squirrels was related to a medieval European strain suggested that M. leprae had a more extended evolutionary history in Europe than previously thought. This could mean that leprosy in humans may have been sustained, in part, by animal reservoirs such as red squirrels, long after human-to-human transmission had diminished. Although the identification of M. leprae in red squirrels provided compelling evidence, the potential for zoonotic transmission (transmission from animals to humans) remains a subject of ongoing research. Unlike armadillos, which are known to transmit M. leprae to humans in some areas of the Americas [13], there is currently no direct evidence that red squirrels have transmitted leprosy to humans.

4.2. Decline in red squirrel zoonosis mirrors the decline in leprosy

The red squirrel is now an endangered species in the United Kingdom, and its population has declined to around 140,000 animals. After introducing the grey squirrel (Sciurus carolinensis) from North American deciduous forests in 1876, red squirrel populations declined in all regions, while the grey squirrel population rapidly increased to more than 2.5 million animals [14]. The grey squirrel can better exploit resources in deciduous and mixed (deciduous and coniferous) forests than the red squirrel. In England, studies comparing sites inhabited by red squirrels with sites inhabited by red and grey squirrels showed that while their spring breeding rate was similar, the red squirrels' summer breeding rate was much lower in mixed sites (about 20 % and 50 %). This reduction prevents females from producing two litters per year, probably due to lower female body weight in late spring and early summer [15]. Squirrel Poxvirus (SQPV) only appears in red squirrel populations in areas already colonised by grey squirrels, and causes a deadly infection in red squirrels (although a small proportion of red squirrels, particularly juveniles, may survive exposure to the virus by developing an immune response). In contrast, grey squirrels are spared [16]. Furthermore, SQPV outbreaks in Scotland show spatial and temporal distributions predictive of a significant reduction in red squirrel populations within the next 25 years [17]. Incidentally, no evidence of leprosy has been detected in the United Kingdom's grey squirrel population, either using anti-PGL-I serology or DNA detection [11]. The grey squirrel's success combines ecological and pathogenic factors that disadvantage the red squirrel. After the red squirrel was hypothesised to be the reservoir for zoonotic leprosy, the decline in the red squirrel population was hypothesised to be behind the decrease in leprosy [7].

4.3. Decline in red squirrel zoonosis: uplifted living standard in the United Kingdom

Opportunities for humans to come into contact with red squirrels are now limited to leisure activities in parks and forests. This was undoubtedly not the situation in medieval times, when young red squirrels were captured as companion animals for the wealthy (Supplementary Fig. 1). The fur of adult squirrels was used for clothing and shoes (perhaps the slipper that Cinderella lost when making her escape from the ball was made from squirrel fur) [18]. However, M. leprae-infected red squirrels exhibit skin lesions and swelling similar to those seen in leprosy patients, which may have discouraged hunters from capturing visibly diseased animals [10,11].

One alternative hypothesis is that red squirrels and human populations were infected from a common environmental source. As burrowing mammals, red squirrels—like armadillos in the Americas—could have come into contact with M. leprae from the soil. Indeed, M. leprae DNA has occasionally been found in soil samples [19], and organic compartments and rhizospheres are known to harbour related mycobacteria such as Mycobacterium ulcerans [20]. In addition, recent findings have shown that red squirrels are more commonly infected with M. lepromatosis than M. leprae, which challenges the red squirrel hypothesis, since only M. leprae has been identified in medieval human remains. Avanzi et al. reported M. lepromatosis in squirrels from the Isle of Wight, Ireland, and Wales without co-detection of M. leprae [11]. Subsequent studies confirmed that M. lepromatosis is detected 25 times more frequently in squirrels than M. leprae [21].

Another important consideration is the mismatch in timing between the decline of leprosy in the British Isles, beginning in the 16th century, and the dramatic reduction in red squirrel populations, which only occurred after the introduction of the grey squirrel in 1876. This discrepancy suggests that other factors played a decisive role in the historical decline of leprosy in the United Kingdom, highlighted by historical sources. In his 1895 monograph [22], George Newman emphasised the critical role of social and institutional isolation of leprosy patients. He described how leprosaria were widely established across Britain and how strict segregation was enforced through both civil and religious laws. Municipal regulations often mandated the relocation of leprosy sufferers beyond city walls within fifteen days of diagnosis, and public access to communal spaces such as markets was prohibited [22]. These measures, reinforced by societal stigma and ecclesiastical doctrine, likely limited opportunities for disease transmission within the general population.

In addition to these historical practices, the Industrial Revolution, which began in the United Kingdom, significantly improved public health. Starting in the mid-19th century, urban centres in Britain undertook extensive reforms in response to recurrent epidemics and poor sanitary conditions. Implementing piped drinking water systems and large-scale sewage infrastructure, such as the network built by Joseph Bazalgette in London between 1859 and 1865, marked a turning point. The 1848 Public Health Act laid the groundwork for modern sanitation by encouraging municipalities to provide clean water and waste removal. These advancements reduced exposure to environmental sources of infection. At the same time, better housing and more diverse nutrition improved overall population immunity. While leprosy requires prolonged close contact for transmission, these sociocultural and infrastructural shifts likely contributed to reducing its spread.

4.4. Alternative working hypotheses

We propose that the replacement of M. leprae by M. lepromatosis was a major driver for the progressive decline in leprosy in the United Kingdom. In this scenario, M. lepromatosis was imported into the United Kingdom following the progressive expansion of the British Empire, starting from the 16th century expansion into Canada through to the 19th century expansion into the Middle East and New Zealand (Fig. 1). A review of historical charts held by the Natural History Museum in London [https://data.nhm.ac.uk/search] indicates that at least eight burrowing mammals (including the nine-banded armadillo (Dasypus novemcinctus)) were imported into the United Kingdom during these centuries, contemporaneously with the decline of leprosy (Supplementary Table 1). While there is no documentation of M. lepromatosis in humans or animals predating its seminal description in 2008 [23], M. lepromatosis has been further reported in red squirrels in a geographical belt limited by the 55th parallel north (in Scotland) and the 25th parallel south (in Paraguay), indicating the geographical source of its introduction. Combining this geographical indication with the time scale indicative of a 16th to 20th century event, we tentatively propose that the event was related to the introduction of M. lepromatosis-contaminated animals, most probably imported from British colonies for their fur. In this scenario, the recent decline in the red squirrel population was no more than a tangential, albeit important, event. We argue that the current lack of data regarding the dynamics of leprosy prevents us from concluding that the red squirrel was a pivotal factor in the declining reservoir for leprosy in the United Kingdom and possibly continental Europe. M. leprae and M. lepromatosis have never been detected in contemporary squirrels in continental Europe. A limited study carried out by our Institute of 251 Pallas's squirrels (Callosciurus erythraeus) caught by the French Biodiversity Agency in 2023 and 2024, found no evidence of M. leprae using qPCR-based detection (Hamza Makoudi, personal data) (Fig. 2C). These observations indicate that ancient burrowing mammals, including squirrels, should be investigated to resolve the puzzling dynamics of zoonotic leprosy in continental Europe and the United Kingdom. Testing the pathogen replacement hypothesis would rely on cumulative observations regarding the distribution of M. leprae and M. lepromatosis on a time scale from the 16th to the 20th centuries. Such a study should be conducted on a geographical scale, including the United Kingdom and continental Europe, and on a diversity scale, including, as a priority and non-exclusively, burrowing mammals potentially imported from colonised territories. Ancient materials exist in continental Europe, with red squirrels having been documented archaeologically, including in a 15th-century hospital in northern France [24] and accumulations of pelt processing waste in the 11th-century site at Dieue-sur-Meuse (Meuse), which uncovered 417 individuals [24]. This reveals the potential of archaeology to document the presence of red squirrels. Nevertheless, at the majority of sites, finds of squirrel remains are rare. An experimental approach could rely on rapid high-throughput screening for M. leprae complex aDNA in collections, on sites, in museums, and in osteological collections. While there is no longer any doubt that both the human and red squirrel populations suffered from leprosy over recent millennia in northern Europe, the prevalence trends in both populations remain unknown against the backdrop of an increasing human population and a decreasing red squirrel population. This situation has led to at least three non-contradictory hypotheses: that humans infected red squirrels (anthroponosis), that red squirrels infected humans (zoonosis), and that both humans and red squirrels were infected from a common, third source of infection. Particularly in a situation where the modes and routes of M. leprae and M. lepromatosis contamination remain unclear, the third hypothesis should not be discounted but rather investigated by challenging the presence of M. leprae and M. lepromatosis DNA in both ancient and modern environmental samples comprising animals, chiefly squirrels, and also food sources which are common to squirrels and humans. The detection of M. leprae itself (not only M. leprae DNA) in faeces collected from wild chimpanzees [25] and also from a leprosy patient also suffering from Entamoeba coli enteritis in Burkina Faso brought into question. However, it did not prove the possibility that M. leprae may colonise the digestive tract from certain food sources [26]. It was recently established that red squirrels consume potatoes, fungi, and fungi rhizomes in addition to well-known fruits, nuts, berries, and tree seeds as part of their burrowing activities. This new information should be considered when investigating the possible overlooked ecosystems where M. leprae and M. lepromatosis may persist in biotic environments. Finally, as red squirrels are widespread across Europe and parts of Asia, this could, theoretically, contribute to the transmission of leprosy outside the United Kingdom. Thus far, our findings have been restricted to the United Kingdom, while investigations of red squirrels in continental Europe have failed to document leprosy [27,28].

5. Conclusions and perspectives

In light of current evidence regarding the historical dynamics of leprosy in the United Kingdom, the hypothesis that red squirrels served as the primary historical reservoir for zoonotic M. leprae must be reconsidered. The predominance of M. lepromatosis—until recently undocumented in medieval human remains but frequently found in contemporary red squirrels— challenged the notion of direct historical zoonotic transmission. However, forthcoming research suggesting the presence of M. lepromatosis in human remains from the medieval era may significantly alter this narrative and restore plausibility to a broader zoonotic hypothesis. In parallel, the temporal mismatch between the decline of leprosy and the later collapse of red squirrel populations points to earlier and more complex drivers. Among these, historical isolation of patients, public avoidance of visibly afflicted individuals, and systemic responses to leprosy, as extensively documented in George Newman's 1895 monograph [22], likely played decisive roles. Additionally, the Industrial Revolution ushered in improvements in public health infrastructures, including piped drinking water, sewage systems, better housing, and enhanced nutrition, which may have reduced the risk of infection and human-to-human transmission. Together, these elements argue for a multifactorial interpretation of leprosy's decline, rather than one focused solely on a single zoonotic reservoir. Future investigations should prioritise paleomicrobiological screening for both M. leprae and M. lepromatosis in ancient human and animal remains, along with environmental samples such as soil or shared dietary components. An integrative, transdisciplinary approach remains essential to resolve the long-standing enigma of leprosy dynamics in the United Kingdom and beyond.

Funding acknowledgement

This work was supported by a grant from the French Government managed by the National Research Agency under the “Investissements d'avenir (Investments for the Future)” programme with the reference ANR-10-IAHU-03 (Méditerranée Infection), by the Contrat Plan Etat-Région and the European funding FEDER IHUPERF.

CRediT authorship contribution statement

S. Souguel: Writing – original draft, Data curation, Conceptualization. T. Oueslati: Writing – original draft, Data curation, Conceptualization. G. Grine: Writing – original draft, Supervision, Formal analysis, Data curation, Conceptualization. M. Drancourt: Writing – original draft, Validation, Supervision, Resources, Methodology, Formal analysis, Data curation.

Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:

Ghiles GRINE reports was provided by Aix-Marseille University. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Appendix A. Supplementary data

Supplementary material

Data availability

Data will be made available on request.