When Humans and Animals Share a Silent Threat
In 1910, a mysterious illness swept through a small European community. Doctors were baffled—patients exhibited classic tuberculosis symptoms, yet the pattern of spread defied explanation. The culprit wasn't airborne transmission from coughs and sneezes, but something far more mundane: fresh, unpasteurized milk from local dairy cows. This historical scenario illustrates what scientists now recognize as zoonotic tuberculosis—a dangerous infectious disease crossing the species barrier from animals to humans 1 .
Estimated annual zoonotic TB cases in humans
Heterogeneity in detection rates across studies
Highest M. bovis detection rate in raw milk samples
Today, we understand that tuberculosis forms a syndemic—a convergence of multiple health threats that interact to worsen disease impact. This syndemic encompasses human TB, animal TB, and various social, economic, and ecological factors that amplify their combined destructive potential. Mycobacterium bovis, the primary cause of TB in cattle, doesn't respect species boundaries. It can infect humans through contaminated dairy products or direct animal contact, joining its close relative Mycobacterium tuberculosis (which primarily affects humans) in contributing to one of humanity's oldest infectious disease challenges 1 2 .
For millions of people worldwide, especially in low-resource regions, unpasteurized milk and traditional dairy products represent important cultural traditions and vital nutritional sources. Unfortunately, these same products can also serve as vehicles for zoonotic TB transmission 1 .
A recent comprehensive meta-analysis examining data from 2000-2024 revealed startling findings about this transmission route. The research reviewed 25 studies encompassing 10,508 samples and found detection rates of Mycobacterium bovis ranging from 0.77% to as high as 49%, depending on the diagnostic methods and region 1 .
The transmission web extends far beyond domesticated animals into wildlife populations, creating resilient reservoirs that complicate control efforts. In South Africa's Krueger National Park, for instance, African buffalo have become maintenance hosts for bovine TB, which was originally introduced to their populations from cattle 3 .
The ecological dynamics here reveal surprising complexities. Research has shown that treating buffalo for parasitic worms—a seemingly beneficial intervention—can actually increase TB transmission at the population level 3 .
In March 2025, researchers from University College Dublin, University of Edinburgh, and ETH Zurich announced a significant breakthrough in understanding why some cattle develop bovine TB while others remain resistant. Their study, published in Communications Biology, identified 115 genes associated with bTB susceptibility—the first research to directly link genetic variation with individual gene activity in TB response 4 .
The researchers employed a sophisticated approach called a transcriptome-wide association study (TWAS), which combined data on gene activity in blood samples from infected cattle with existing genome-wide association studies (GWAS) 4 .
Some of the most intriguing insights into zoonotic TB come from unexpected interactions between different pathogens. The African buffalo study mentioned earlier illustrates this complexity perfectly, showing how deworming interventions can inadvertently affect TB dynamics in wildlife populations 3 .
The research team, led by University of Georgia professor Vanessa Ezenwa, conducted meticulous fieldwork in Krueger National Park to unravel this connection 3 .
Capturing and tagging buffalo using tranquilizer darts administered from helicopters and vehicles
Collecting baseline samples and health data during initial tagging operations
Conducting biannual recaptures to retest animals for both parasitic worms and tuberculosis
Tracking disease progression in relation to parasitic status across multiple years 3
| Research Tool | Primary Application | Significance in Zoonotic TB Research |
|---|---|---|
| Polymerase Chain Reaction (PCR) | Detection of bacterial DNA in samples | Higher sensitivity (up to 49% detection) compared to culture methods; enables identification of M. bovis in dairy and clinical samples 1 |
| Click Chemistry | Drug discovery and compound optimization | Enabled development of CMX410, a promising new TB compound; allows precise linking of molecular components 5 |
| Transcriptome-Wide Association Study (TWAS) | Linking genetic variation to gene activity | Identified 115 genes associated with bTB susceptibility in cattle; combines gene expression and genomic data 4 |
| Metabolomics | Studying metabolic changes in infection | Reveals disruptions in amino acid, glutathione, and one-carbon metabolism pathways in TB; assessed through mass spectrometry and other analytical platforms 6 |
| Animal Models | Studying disease mechanisms and treatment | Provides controlled settings for TB research; mice capture approximately 4.7% of human TB-associated metabolic changes, with highest overlap in lung tissue 6 |
The research team explored more than 300 analogs to identify a compound with the right balance of potency, selectivity, and safety 5 .
Molecular techniques like PCR demonstrated significantly higher sensitivity compared to traditional culture methods 1 .
The complexity of the zoonotic TB syndemic becomes clearer when examining the variations in detection rates across different contexts. The significant heterogeneity (I² = 98.92%) observed in the meta-analysis reflects substantial differences in diagnostic approaches, geographic factors, and population characteristics—emphasizing the need for more standardized approaches 1 .
The One Health framework provides exactly this holistic perspective, emphasizing that the health of people is closely connected to the health of animals and our shared environment 1 2 4 .
Critical for breaking dairy transmission route but requires investment in equipment and regulatory oversight 1 .
The zoonotic tuberculosis syndemic represents a textbook example of how human, animal, and ecosystem health are inextricably linked. From the dairy farm to the wildlife reserve, from the genetic level to global trade networks, this complex health challenge defies simple solutions and disciplinary silos 1 2 .
What makes this syndemic so persistent is precisely what makes it so fascinating to study—the intricate web of connections between pathogens, hosts, and environments. The unexpected interaction between parasitic worms and TB in African buffalo, the genetic factors that make some cattle more susceptible than others, the invisible transmission through traditional dairy products—each piece of the puzzle reveals another layer of this complex biological and ecological story 3 4 1 .
Ultimately, overcoming the zoonotic TB syndemic will require embracing the fundamental principle that our health is connected to the health of animals and ecosystems we share this planet with—a realization that may prove to be our most powerful tool against this ancient yet evolving threat.