Abstract
Approximately 75 years on, and Dr Frazer’s words still ring true. Even with the advent of sophisticated molecular techniques, the epidemiology and pathogenesis of leprosy and other fastidious (non-culturable) slow-growing mycobacteria hold many mysteries. Indeed, the global humanitarian and economic burden of tuberculous and non-tuberculous mycobacterial disease (including leprosy) remains huge.
These infections have plagued people and animals for millennia. Human remains in the Eastern Mediterranean dating back 9000 years contain DNA evidence of tuberculous mycobacteria, 1 and mycobacterial DNA has been recovered from diseased bones of a bison trapped in permafrost circa 17,000 years ago. 2 Although there are references to leprosy in ancient Egyptian, Greek and Roman writings, the scourge of leprosy appeared to peak in the Middle Ages as the disease spread through Europe. Before modern microbiology was established, leprosy was generally believed to be a heritable disease.
Mycobacterium leprae was discovered by Gerhard Armauer Hansen in 1873 while working in a leprosarium in Bergen, Norway (an area with the highest prevalence of leprosy in Europe at the time). The inability to grow M leprae in the laboratory prevented further investigation of the bacillus by this doctor, but his discoveries paved the way for great advances in how people with leprosy were treated and, importantly, given legal protection.
A report from plague-affected Odessa, Ukraine, 30 years later documented a skin condition that microscopically and microbiologically mimicked human leprosy in approximately 5% of rats destroyed. 3 (Early researchers called this organism Mycobacterium leprae murium – ie, leprosy of rodents). Similar reports of the condition in rats in England, Australia and the USA soon followed. Interestingly, early strains derived from rats did not seem to cause overt disease in mice, although naturally occurring ‘leprosy’ was reported in a mouse (which happened to wander across the floor of a microbiology laboratory!) in San Juan, Puerto Rico in 1937. In the following decades, opinion was divided as to whether the causative agent(s) of rodent and human leprosy were identical. It was eventually concluded that they were distinct organisms and interest in murine leprosy waned.
Feline leprosy – the story begins
‘Feline leprosy’ was first described in 1962 in urban-dwelling cats from Auckland, New Zealand (NZ). Affected cats presented with subcutaneous nodules containing abundant intracellular acid-fast bacilli. 4 The index case, a young male cat with a nodule on a forelimb, was euthanased on the presumption that it had tuberculosis (TB), which at that time was the only mycobacterial disease known to occur in cats. TB remains a not uncommon condition in NZ and the cat was thought to have posed a zoonotic threat to the owner’s children. When no evidence of systemic disease was found at necropsy, and the inoculation of lesional material failed to produce disease in a guinea pig, TB seemed unlikely. Furthermore, in this and two subsequent cases, causal organisms could not be grown on mycobacterial media, and so it was concluded that this was a new disease entity. The condition was likened to human and rat leprosy with respect to the clinical and histopathological picture, and thus the moniker ‘feline leprosy’ was coined.
An identical condition was described a few years later by veterinary pathologists Bill Lawrence and Nancy Wickham in Sydney, Australia. 5 Microbiologist Daria Love obtained an Australian Research Grant to study the condition in the 1970s, but despite exhaustive attempts, could not reliably propagate the organism on synthetic culture media. Transmission studies conducted by Canadian investigators showed that M lepraemurium from rats could be transmitted to cats, 6 and thence to other cats, fulfilling some but not all of Koch’s postulates. Then, in 1997, Siobhan Hughes and colleagues from the Veterinary Sciences Division, Department of Agriculture for Northern Ireland, collaborating with GW De Lisle, an NZ pathologist, showed using molecular techniques that most feline leprosy cases in NZ were attributable to M lepraemurium, although some were attributable to novel fastidious, slow-growing mycobacteria. 7 This work was extended by one of the editorialists (RM) in collaboration with Daria Love, Paul Canfield and colleagues at the University of Sydney and Westmead Hospital, Sydney, who found systematic differences in the clinical and microscopic features of infections due to M lepraemurium and the ‘novel east coast species’ first discovered by Hughes, and these were reported in two papers in this journal.8,9
Tragically, Siobhan Hughes developed a chronic disease that made it impossible for her to continue in science, while Daria Love died after a struggle with lupus. Further work on these fastidious feline mycobacteria, and a somewhat similar disease in dogs (canine leproid granulomas), 10 required a new collaboration, and this was forged with Janet Fyfe at the Victorian Infectious Diseases Reference Laboratory (VIDRL) in Melbourne.
Feline leprosy – the story continues
One of the cases in the original JFMS paper 8 was identified as having a discordant amplicon sequence, and this turned out to be a third form of feline leproid disease: 11 the causal organism has been provisionally designated Candidatus ‘Mycobacterium tarwinense’. It was at this point that the current co-editorialist (COB) enrolled for a PhD at the VIDRL.
The PhD studies have two conceptual thrusts: (i) disease due to Mycobacterium ulcerans in companion animals (including a cat) 12 and wildlife, 13 and (ii) the three distinct leprosy-like diseases of cats which could now be reliably distinguished using ITS PCR and sequence analysis using material scraped from cytology smears. 14 Fortuitously, interruptions by two periods of maternity leave, and the establishment of a feline veterinary practice, provided scope to include a robust number of feline leproid cases recruited over a 10 year period (a time span well beyond the conventional limits for PhD projects!). For completeness, cases identified earlier by RM’s group were included, with an extended follow-up.
An article series based on these in-depth studies of feline leproid disease is being published over three ‘Clinical Practice’ issues of JFMS (see box). We hope you find them an interesting read!