International Journal of Infectious Diseases 113S (2021) S68–S72Contents lists available at ScienceDirect
International Journal of Infectious Diseases
journal home page: www.elsevier .com/ locat e/ i j id
Zoonotic Tuberculosis – The Changing Landscape
Richard a,* Kock , Anita L. Michelb, Dorothy Yeboah-Manuc, Esam I. Azhard ,
Jordi B. Torrellese, Simeon I. Cadmusf, Lucy Bruntona, Jeremiah M. Chakayag,h          ,
Ben i,j Marais , Leonard Mboerak , Zeaur l Rahim , Najmul Haidera, Alimuddin Zumlam,n 
a Pathobiology and Population Sciences Department, Royal Veterinary College, Hatfield, AL9 7TA, UK
bDepartment of Veterinary Tropical Diseases, Bovine Tuberculosis and Brucellosis Research Programme, Faculty of Veterinary Sciences, University of Pretoria,
Onderstepoort, Pretoria, South Africa
cBacteriology Department, Noguchi Memorial Institute for Medical Research, University of Ghana, Ghana
d Special Infectious Agents Unit, King Fahd Medical Research Center, and Medical Laboratory Technology Department, Faculty of Applied Medical Sciences,
King Abdulaziz University, Jeddah, Saudi Arabia
e Population Health Program, Texas Biomedical Research Institute, San Antonio, TX, USA
fDepartment of Veterinary Public Health and Preventive Medicine, University of Ibadan, Ibadan, Nigeria
gDepartment of Medicine, Therapeutics, Dermatology and Psychiatry, Kenyatta University, Nairobi, Kenya
hDepartment of Clinical Sciences, Liverpool School of Tropical Medicine UK
i Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
jMarie Bashir Institute for Infectious Diseases and Biosecurity, Sydney, NSW, Australia
k SACIDS Foundation for One Health, Sokoine University of Agriculture, Morogoro, Tanzania
l International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Mohakhali, Dhaka, 1212, Bangladesh
mDivision of Infection and Immunity, University College London, London, UK
nNational Institute for Health Research Biomedical Research Centre, University College London Hospitals National Health Service Foundation Trust, London,
UK
A R T I C L E I N F O A B S T R A C T
Article history: Despite slow reductions in the annual burden of active human tuberculosis (TB) cases, zoonotic TB (zTB)
Received 29 January 2021 remains a poorly monitored and an important unaddressed global problem. There is a higher incidence in
Received in revised form 22 February 2021 some regions and countries, especially where close association exists between growing numbers of cattle
Accepted 23 February 2021 (the major source of Mycobacterium bovis) and people, many suffering from poverty, and where dairy
products are consumed unpasteurised. More attention needs to be focused on possible increased zTB
Keywords: incidence resulting from growth in dairy production globally and increased demand in low income
Zoonotic TB countries in particular. Evidence of new zoonotic mycobacterial strains in South Asia and Africa (e.g. M.
Bovine TB
Mycobacterium bovis orygis), warrants urgent assessment of prevalence, potential drivers and risk in order to develop 
M orygis appropriate interventions. Control of M. bovis infection in cattle through detect and cull policies remain
zooanthroponosis the mainstay of reducing zTB risk, whilst in certain circumstances animal vaccination is proving
beneficial. New point of care diagnostics will help to detect animal infections and human cases. Given the
high burden of human tuberculosis (caused by M. tuberculosis) in endemic areas, animals are affected by
reverse zoonosis, including multi-drug resistant strains. This, may create drug resistant reservoirs of
infection in animals. Like COVID-19, zTB is evolving in an ever-changing global landscape.
© 2021 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-
nd/4.0/).
Introduction
* Corresponding author. A zoonosis is an infection directly transmissible from animals to  
E-mail addresses: rkock@rvc.ac.uk (R. Kock), anita.michel@up.ac.za humans naturally (WHO) (WHO, 2020b) and for this to happen     
(A.L. Michel), dyeboah-manu@noguchi.ug.edu.gh (D. Yeboah-Manu), regularly, there needs to be a reservoir in an animal population. The
eazhar@kau.edu.sa (E.I. Azhar), JTorrelles@txbiomed.org (J.B. Torrelles), majority of zoonoses occur where there is close contact between
sib.cadmus@ui.edu.ng (S.I. Cadmus), lbrunton@rvc.ac.uk (L. Brunton),
chakaya.jm@gmail.com (J.M. Chakaya), ben.marais@health.nsw.gov.au (B. Marais),
lmboera@gmail.com (L. Mboera), zeaur@icddrb.org (Z. Rahim), nhaider@rvc.ac.uk
(N. Haider), a.zumla@ucl.ac.uk (A. Zumla).
https://doi.org/10.1016/j.ijid.2021.02.091
1201-9712/© 2021 The Author(s). Published by Elsevier Ltd on behalf of International 
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).humans and relatively abundant animal species (Johnson et al.,
2020) (i.e. mostly companion animals and those in the animal-
based food system with many indirect zoonotic infectionsSociety for Infectious Diseases. This is an open access article under the CC BY-NC-ND
R. Kock, A.L. Michel, D. Yeboah-Manu et al. International Journal of Infectious Diseases 113S (2021) S68–S72
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ccurring through meat and animal product consumption). This is and South East Asia (43,400) (Ramos et al., 2020) (WHO, 2020a).
lso true for zoonotic tuberculosis (zTB). Tuberculosis (TB) causing South-EastAsiacomprises almost 44%of the globalTBburden(WHO,
rganisms include M. tuberculosissensu stricto and M. africanum, 2020a). This region disproportionately shared TB deaths (38% of
ausing the majority of human disease. A number of other global burden) (WHO, 2020a).
rganisms from the M. tuberculosis complex (MTBC), present in Although South Asia has the highest burden of TB potentially
nimals and the environment, can cause zTB, these include related to high rates of poverty, rapid urbanization, high
. canetti, M. bovis, M. caprae, M. microti, M. pinnipedii, M. mungi, population density, higher prevalence of diabetes and high air
nd M. orygis. Here we provide a contemporary view on the status pollution (Basnyat et al., 2018), the reported burden of zTB is
f zTB globally, emerging trends, research gaps as well as recent relatively low. However, this may be partially explained by
dvances in the agricultural, veterinary and medical sciences insufficient laboratory facilities and lack of accurate identification
hich can help to re-focus and promote better policy on this of the causative agent of zTB (M. orygis seems to be the major
ersistent and still poorly documented disease. pathogen in Indian cattle, Bos indicus) (Brites et al., 2018). The
region possesses multiple risk factors for zTB including high
uman TB and the zoonotic contribution human-animal density, close and frequent physical contact with
infected animals, inadequate disease control measures, as well as
TB is consistently the most impactful bacterial disease to affect consumption of unpasteurized milk and milk products (Bapat et al.,
umanity, with a quarter of all humans infected, and is responsible 2017; Mukherjee et al., 2018). For example India has an estimated
or the greatest number of infection related deaths, as well as long 21.8 million (95% CI: 16.6, 28.4) infected cattle in a rapidly growing
erm disability (WHO, 2020c). The 2020 World Health Organiza- dairy sector (Srinivasan et al., 2018)
ion (WHO) Global Tuberculosis Report (WHO, 2020a) estimates In contrast, the TB incidence in the European region (WHO
hat in 2019, 10 million people (range, 8.9–11.0 million) developed Regional Office for Europe, 2021) is among the lowest in the world
B disease of which approximately 1.2 million people died, with a with a consistent decline since 2015 with currently being reported
urther 208,000 deaths attributed to the TB-HIV syndemic (WHO, 10 cases per 100,000 population, unevenly distributed across the
020a). In addition, effects from the coronavirus disease 2019 European Union/European Economic Area. zTB cases in this region
COVID-19) pandemic is projected to increase the number of TB as a proportion of TB cases is <0.01% (Müller et al., 2013) and most
ases by 6.3 million in the next five years or an additional 20% cases are caused by M. bovis and M. caprae.
eaths in next five years (Cilloni et al., 2020; Hogan et al., 2020; Given the limited point of care (POC) diagnostics and poor
top TB partnership, 2020), delaying the WHO End TB Strategy reporting there is no reliable data to determine if zTB incidence and
WHO, 2014). This is mainly due to reduced case finding, the prevalence is going up or down in many regions. Rapid testing
eviation of resources to handle the COVID-19 pandemic in could assist veterinarians and farmers to quickly diagnose TB, so
ndemic areas, and the interruption of TB treatment programs in infected animals can be separated from the rest of the herd.
any low-income countries. Current zTB burden and mortality estimates are all based on M.
Although TB remains a global challenge, cases are highly bovis, the most commonly diagnosed cause of zTB globally, but
oncentrated in very specific parts of the world, affecting areas essentially ignoring the contribution of other MTBC species.
here poverty and high population density overlap. This is not Emerging evidence suggests that several other mycobacterial
urprising for an infection that is human density depended linked species such as M. orygis are also contributing to zTB (Duffy et al.,
o poverty, social stigma, poor public awareness, and overwhelmed 2020), but laboratory services for accurate identification and
ealth systems lacking resources for TB transmission prevention speciation are not universally available, thus the true global burden
nd treatment (Bapat et al., 2017). Nearly 90% of all human TB cases of zTB is without a doubt much higher.
re located in South Asia, East Asia (China), South East Asia Past experience directs attention to areas where living
Philippines, Indonesia) and, the most populous countries in Africa conditions favour direct contact with infected cattle, that may
South Africa and Nigeria, where the addition of HIV-derived facilitate aerosol spread, or ingestion of unpasteurised milk
mmunosuppression facilitates the progression of M. tuberculosis products (e.g. queso fresco). There are rare transmission events
nfection to active TB disease) (WHO, 2020a). A further concern is from sheep and goats caused by M.caprae and from non-milk-
ncreasing multi-drug resistant (MDR)-TB, which accounted for producing species such as rodents (M. microti), banded mongooses
06,030 reported cases (30% of the estimated total) in 2019, (M. mungi), as well as seals and sea lions (M. pinnipedii) with
ssociated with an estimated 31,000 deaths (WHO, 2020a). increasing reports of M. orygis from Indian cattle (Jagielski et al.,
2016; Brites et al., 2018; Duffy et al., 2020).
nimal TB burden The detrimental impact of different MTBC species goes beyond
human health, since they also affect the health of cattle and other
The animal TB burden is highly variable across countries and animal species with consequential impact on livelihoods, animal-
ontinents, with main variations according to predominant based industrial food systems, and conservation of wildlife species,
ivestock systems. Although the available data may be biased including many iconic species such as bison, rhino’s, lions and even
ue to different sampling strategies and diagnostic capacities, the highly threatened African wild dogs (De Garine-Wichatitsky et al.,
ighest animal prevalence is reported from the Americas and 2013; Sichewo et al., 2019; Marais et al., 2019; Luciano and Roess,
urope (Ramos et al., 2020). 2020). The existence of zTB animal carriers adds to the problem
with e.g. deer, buffalo, European badgers, wild boar, brushtail
oonotic TB burden possums, bison, goats, camelids (including alpaca, llama, camels),
pigs, antelopes, dogs and cats, a number of species implicated in
Of 10 millionpeople currently with newactive TB,140,000 (range, cases in Europe in addition to the primary reservoir cattle.9,800–235,000) are estimated to be new cases of zTB (1.4%) of
hich an approximately 11,400 (8.1%, range 4,470-21,600) died
WHO, 2020a). However, zTB disease is largely underreported and,
hese wide ranges are indicative of major diagnostic challenges and
oor public health surveillance and reporting structures in endemic
ountries. The highest numbers were reported from Africa (68,900)6
However, incidence and/or risk of transmission of MTBC species
from free-living wildlife species to humans, even among those
with high prevalence such as African buffalo and European
badgers, to-date remains very low (Biet et al., 2005).
Some risk factor surveys have explored the association between
cattle TB prevalence and mixing with wildlife, and prevalence of9
R. Kock, A.L. Michel, D. Yeboah-Manu et al. International Journal of Infectious Diseases 113S (2021) S68–S72cattle with TB is estimated by some (Sichewo et al., 2019) to be high and whole genome sequencing (WGS) for adequate identification
in situations of intense co-grazing and sharing water resources in of all MTBC species. Results showed that 97.1% were MTBC, M.
Africa and USA. However, the force of infection in these studies and orygis 0.7% and M. bovis BCG 0.5%, none were from wild strains of M.
other examples cited is not conclusive and uncertainties remain on bovis and only 1.6% nontuberculous Mycobacteria. Twenty-five
this question. For example, there are questions on directionality isolates were assigned subspecies by WGS as compared with 715
and rate of transmission between badgers and cattle in TB studies MTBC sequences obtained from the database. The seven M. orygis
in the UK (Sandoval Barron et al., 2018). A rare study of this isolates from human samples have descended from cattle. This
interface in a mixed system in Uganda showed infection study presents a convincing case that zTB case definitions should
prevalence rates that were ten times higher in wild buffalo than include human TB caused by M. orygis.
in co-grazing cattle (Meunier et al., 2017), suggesting a low TB in live animals is mainly diagnosed using the intradermal
transmission rate from wildlife to cattle. tuberculin skin test (TST) to detect delayed hypersensitivity
response to tuberculin. Culture or molecular techniques (PCR
Reverse zoonoses and WGS) are used for microbiological confirmation of the TB-
causing agent. Blood tests based on host immune responses (e.g.
Reverse zoonoses or zooanthroponoses have been recorded in IFN-ɣ release assay, ELISA, ELISpot, Differentiating Infected from
studies from Africa and India (Duffy et al., 2020). Studies in Nigeria Vaccinated Animal [DIVA] test) (Waters et al., 2006; Vordermeier
(Adesokan et al., 2019) identified M. bovis in humans and a reverse et al., 2011) are also used for identification of infection with M.
zTB transmission from an emerging Uganda I M. tuberculosis strain bovis, but its accuracy for diagnosing infection with other zTB
between pastoralists and cattle evidenced by MIRU-VNTR. In this agents has not been established. For all these tests, the identifica-
study, 59.2% Uganda I/SIT46 (pastoralists =28; cattle =1), 16.3% tion of the zTB agent depends on proper collection of quality
Latin American Mediterranean/SIT61 (pastoralists =8), 2.0% specimen. However, these tests are not routinely done in high
T/SIT53 (pastoralists =1) had strains of M. tuberculosis and new burden countries, due to lack of resources and adequately trained
strains of M. bovis and M. africanum (Adesokan et al., 2019). personnel. This is particularly the case for molecular diagnostics,
Furthermore, M. tuberculosis has been isolated in a slaughtered meaning that TB data often lack the resolution required for
goat in Nigeria and this was attributed to close human-animal epidemiological studies.
contact in most settings in the country (Cadmus et al., 2009; To tackle the diagnosis challenge, we need to learn from current
Adesokan et al., 2019). efforts towards the improvement of human TB diagnosis in the
Importantly, an even more troubling possibility in some field. There are efforts to adapt current POC tests used for human
settings (particularly where there are poor animal management TB to detect potentially zTB organisms in cattle (Kelley et al., 2020)
and meat inspection coupled with high burden of MDR-TB) is the by investigating the presence of specific and unique MTBC antigens
prospect of animals serving as a vehicle of transmission for drug (biomarkers) in urine, milk and meat juice to quickly identify if an
resistant M. tuberculosis as a result of reverse zoonosis at the animal has TB (e.g. Alere DetermineTM Lipoarabinomannan (LAM)
human-animal interface (Botelho et al., 2014; Cadmus et al., 2019). Ag test, SILVAMP TB-LAM (FujiLAM) test). Other tests are based on
In India, M tuberculosis (MANU strain) was found to be more detecting the presence of specific antibodies in serum against
prevalent in cattle than M. bovis (Sweetline Anne et al., 2017). unique cell wall components of the MTBC cell wall (e.g. Lionex test,
M. tuberculosis MANU1 strain infection in cattle is likely due to P22 ELISA). Much work needs to be done to increase the sensitivity
spillover from humans in TB endemic areas (Sweetline Anne et al., of these tests to detect zTB organisms in animals.
2017; Mukherjee et al., 2018) and demonstrates the potential for While the research for new and improved tests continues, the
MDR-TB strains to acquire an animal reservoir that could then pose value of the comparative intradermal tuberculin test (CITT) in
a future risk to human TB control. Reverse zoonoses with the herd diagnosis of TB should not be ignored in settings where
M. tuberculosis has also been reported in zoo animals especially the test is logistically practical to perform. The diagnostic
in elephants, primates and felines (Montali et al., 2001). M. orygis performance offers a sensitivity and specificity comparable to
infection has also been recorded in primates in zoo environments, current blood-based tests if conducted by well-trained animal
suggesting shedding from humans or other infected animals. health professionals. The use of the CITT in developing countries
has been largely discontinued because of an erosion of technical
Molecular studies and diagnostics expertise in performing and interpreting the test. The institution of
a harmonised training programme across an endemic region,
M. orygis was first reported as a causative agent of TB in an oryx based on validated test and interpretation parameters could form a
(Oryx gazella, Family: Bovidae) (van Ingen et al., 2012), but has since valuable foundation for the monitoring of the TB status of cattle
been identified in many other species as well. These include populations and would facilitate the validation of new and
African buffalo (Gey van Pittius et al., 2012), in a dairy cow and its improved tests.
caretaker from New Zealand (Dawson et al., 2012), in free-ranging
rhinoceros (Rhinoceros unicornis) from Nepal (Thapa et al., 2016) Vaccine development
and in 18 cattle from a dairy farm and several rhesus macaque
(Macaca mulatta) in a zoo which died of TB from Bangladesh Outcomes of clinical efficacy trials for preventing the develop-
(Rahim et al., 2017). In addition, a single case of lymphadenitis ment of active TB disease in people infected with M. tuberculosis
caused by M. orygis was reported from a person in New York, USA using the adjuvanted protein subunit vaccine M72/AS01E give
(Marcos et al., 2017). some hope at least for this form of the disease (Schrager et al.,
M. orygis is probably a previously unidentified pathogen of 2020). Historically, eradication of bovine TB from cattle herds by
Indian cattle (Brites et al., 2018), but it seems increasingly test-and-slaughter or test-and-cull of infected animals was
important as a global pathogen. Isolation of M. orygis from humans
and its apparent prevalence in cattle in South Asia raises a question
as to whether this newly recognized pathogen could be included as
additional causative agent of zTB. In this context, Duffy et al. (2020)
characterized 940 cultures of M. tuberculosis complex from
hospitalized TB patients in India by modified PCR, deletion analysis70preferred over control by vaccination of cattle. Eradication efforts,
have, however, proven unsuccessful possibly because a wildlife
reservoir is present or where eradication is not affordable or culling
is culturally unacceptable. Oral BCG administration has demon-
strated significant protection against human (Colditz et al., 1995)
and animal TB (Buddle et al., 2018).
R. Kock, A.L. Michel, D. Yeboah-Manu et al. International Journal of Infectious Diseases 113S (2021) S68–S72
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Oral BCG vaccine administered to wildlife reservoirs including rates. Food safety interventions, such as milk pasteurisation, are
uropean badgers, brushtail possums, wild boar, and deer has the best tool currently to prevent zTB. However, as the use of
hown to induce protection against TB and could prove to be a unpasteurised dairy products grows globally the incidence of zTB is
ractical means to vaccinate these species at large scale (Buddle predicted to increase, as argued for India.
t al., 2018). This offers a potential solution in settings where “test Better molecular diagnostic tools are enabling more precise
nd cull” is not an option and especially in wildlife species determination of zTB causes, driven by a variety of MTBC species,
hreatened by extinction. A major constraint of using BCG the most notable of which is M orygis in South Asia. Given this
accination in cattle is the fact that trading blocs like the European changing landscape, there is an urgent need to review the gaps in
nion prohibit the use of TB vaccines in cattle, since vaccination the Road Map for Zoonotic TB (WHO, 2017) in order to enhance the
ompromises the interpretation of traditional TB diagnostic tests. implementation of the 10 priority areas identified by WHO in
owever, these concerns have been addressed with the develop- earlier statements for tackling zTB in the world.
ent of more specific tests that differentiate infected from
accinated animals (DIVA1) (Vordermeier et al., 2011) and of a Transparency declaration
iagnostic compatible BCG vaccine strain not eliciting an immune
esponse in the compatible skin test (Chandran et al., 2019). This article is part of a supplement entitled Commemorating
lthough BCG should offer some protection against multiple MTBC World Tuberculosis Day March 24th, 2021: “The Clock is Ticking”
pecies, including M. orygis, it should be recognized that protection published with support from an unrestricted educational grant
ill not be complete and should be used to complement, rather from QIAGEN Sciences Inc.
han replace, more traditional control measures.
Ethical approval
ocusing attention on zTB emergence
Ethical approval was not required.
As currently documented, zTB only accounts for around 1.4% of
otal TB (Luciano and Roess, 2020) disease burden in humans, Conflict of interest
hich partially explains why it remains a neglected and ‘low
riority’ problem globally, though it may account for about 3% of all All authors have a specialist interest in ONE-HEALTH and
B in Africa. However, the failure of even advanced economies and zoonotic diseases. All authors declare no conflicts of interest.
ealth systems such as the UK and USA, to eliminate animal TB or
educe risk of zTB to zero in consequence, is concerning. Growing Acknowledgements
ncidence of TB and zTB in certain low and middle income
ountries, with risks to their population health and migration to RK, DY-M, NH, and AZ are part of PANDORA-ID-NET Consortium
ther countries, is a stark warning, that failure to control it now, (EDCTP Reg/Grant RIA2016E-1609) funded by the European and
oses a major risk of future emergence, especially in settings Developing Countries Clinical Trials Partnership (EDCTP2) pro-
here disease rates were traditionally low - as the consumption of gramme which is supported under Horizon 2020, the European
ilk and meat rises. Union's Framework Programme for Research and Innovation. icddr,
The developing challenge is rooted in demographic drivers and b is grateful to the Governments of Bangladesh, Canada, Sweden
isks from growing animal-based food systems and the introduc- and the UK for providing core/unrestricted support. AZ is in receipt
ion of so-called ‘improved breeds’ of cattle for dairy into many of a National Institutes of Health Research (NIHR) senior
ettings, particularly Africa, which are highly susceptible to investigator award and the PANDORA-ID-NET.
. bovis (Ohlan, 2014). Equally important is the lack of veterinary
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