Leprosy – we’ve much left to learn,but are looking to squirrels,cows and cats for insights

As the article series on feline leprosy draws to a close in this issue with a paper on Candidatus ‘Mycobacterium lepraefelis’ (see pages 919–932), lead authors Richard Malik and Carolyn O’Brien discuss how squirrels and cows, as well as cats, are providing new insights into a disease of antiquity.

Leprosy is a fascinating disease: one that was pivotal in our understanding of bacterial pathogens and one so old we can read about it in the Old Testament. It was shown to be an infectious disease in 1873 by the Norwegian physician Hansen, who detected bacteria in lesions from human patients using microscopy and special stains. Unlike its mycobacterial relatives belonging to the Mycobacterium tuberculosis complex, which cause disease in humans and a wide variety of domestic and wildlife mammalian hosts including elephants, pinnipeds, cattle, pigs, cats, dogs, badgers and voles, leprosy was traditionally thought to occur only in humans, primates and nine-banded armadillos. ¹ In the laboratory, it could also be grown in the foot pads of mice.

One might think that, in 2017, we would have a comprehensive understanding of disease caused by Mycobacterium leprae. Actually, we have much left to learn. The major limitation of studies concerning leprosy stems from the fact that the pathogen is so well adapted to a parasitic existence that it has lost key enzymes required to exist as a free-living agent in the environment (reductive evolution). ² As a result, M leprae cannot be grown on synthetic media and subjected to classic laboratory investigations.

Leprosy in squirrels: a wholly unexpected finding

Remarkably, three letters in the Veterinary Record since 2014^3-5 and a paper published late last year in Science ⁶ have shown that leprosy is a naturally occurring infection of red squirrels in the UK. This finding was completely unexpected and is tantalising in two respects. Firstly, the whole genome sequence of M leprae from one population of red squirrels was a perfect match for the sequence recovered from a human case from medieval times. Secondly, in a geographically disparate squirrel population, disease was caused by Mycobacterium lepromatosis, ⁷ a ‘new’ form of human leprosy first described in Mexico in 2008. ⁸ The implications of these findings are yet to be fully realised, but no doubt novel insights will lead to fruitful avenues for further research.

The two organisms that cause leprosy – M leprae and M lepromatosis – typically affect humans in poor socioeconomic settings, including aboriginal communities. ⁹ The genomes of M leprae and M lepromatosis are quite similar, as are the human disease conditions they produce. ¹⁰ Yet despite the presence of both of these leprosy bacilli in red squirrel populations in the UK, there has seemingly been no ’spill over’ of leprosy into human hosts, companion animals or other wildlife species in the UK. This is in contrast to the situation with Mycobacterium bovis and Mycobacterium microti, two potential causes of zoonotic tuberculosis in human patients in Europe, which spill over from reservoir hosts such as badgers and field mice, respectively.

Disease in cattle – and cats

What further fascinates veterinarians interested in mycobacteriology is that there are several leprosy-like conditions in animals that involve organisms with a genetic signature which is very close to the human leprosy agents.

A New Zealand cat with a severe disseminated Candidatus ‘M lepraefelis’ infection

Cytology from a needle aspirate from a lesion of a cat with feline leprosy. The bacteria appear as ‘negatively stained rods’, thrown into relief by the purple component of the Diff Quik stain. Bar = 20 µm. Courtesy of George Reppas

The first is a disease of dairy cattle – bovine nodular thelitis – where nodular lesions appear on the teats. ¹¹ This disease has been described in Japan, France and Switzerland. ¹⁰ Phylogenetic studies have shown that the mycobacteria which cause this disease are very closely related to the two human leprosy agents. The location of lesions (close to the ground) raises the possibility that cattle might be infected by the bites of a rodent (eg, vole or squirrel-like animal) or ferret.

Closer to home, we have been studying a disease of domestic cats known colloquially as feline leprosy. ¹² Feline leproid disease can be caused by a variety of agents, including a novel mycobacterial species, ¹³ found along the East Coast of Australia, and in both the North and South Islands of New Zealand, ¹⁴ which we tentatively refer to as Candidatus ‘Mycobacterium lepraefelis’ (see pages 919–932). We are aware of a human case caused by the same mycobacterium. This pathogen has a propensity to occur in elderly cats with immunosuppression. Candidatus ‘M lepraefelis’ infections are clinically manifest as multinodular skin disease (illustrated on page 977), sometimes accompanied by involvement of internal organs, typically the liver. Microscopically, the condition resembles the lepromatous form of human leprosy, but without the characteristic nerve involvement that causes sensory denervation and disfigurement. A closely related organism called Candidatus ‘Mycobacterium visibile’^15,16 occurs in North America and causes a similar disseminated feline infection.

In Australasia, we suspect that Candidatus ‘M lepraefelis’ exists in some environmental reservoir species, and spills over into domestic cats from time to time. It would have to be an animal more common in eastern Australia and New Zealand, as the disease has not been seen in Western Australia to the best of our knowledge. We suspect it will be a native animal – perhaps a possum or a bandicoot. Anecdotally, some infected cats have been known to have fights with possums. This is a plausible hypothesis, as the agent that causes Buruli or Bairnsdale ulcer in humans (Mycobacterium ulcerans) is known to cause disease in possums. ¹⁷ Such a wildlife reservoir would fit into the human/armadillo/squirrel conceptual framework that is emerging. Alternatively, perhaps the definitive environmental niche might be in a saprophytic protozoan or helminth, such as an Acanthamoeba species.

‘M leprae complex’?

Our speculation is that all these five organisms – M leprae, M lepromatosis, Candidatus ‘M lepraefelis’, Candidatus ‘M visibile’ and the cattle organism that causes nodular thelitis – will one day be grouped together as the M leprae complex. Furthermore, they will have in common one or more mammalian reservoirs, permitting a parasitic existence in animals rather than the environment (where the vast majority of other mycobacterial species reside). Much more work needs to be done, especially on the animal side, but we are well poised to achieve this in Australia.