When it comes to finding a vaccine for chlamydia, the world's most common sexually transmitted infection, koalas may prove a key ally.
The first sign is the smell: smoky, like a campfire, with a hint of urine. The second is the koala's rear end: If it is damp and inflamed, with streaks of brown, you know the animal is in trouble. Jo, lying curled and unconscious on the examination table, had both.
Jo is a wild koala under the purview of Endeavour Veterinary Ecology, a wildlife consulting company that specialises in bringing sick koala populations back from the brink of disease. Vets noticed on their last two field visits that she was sporting "a suspect bum," as veterinarian Pip McKay put it. So they brought her and her 1-year-old joey into the main veterinary clinic, which sits in a remote forest clearing in Toorbul, north of Brisbane, for a full health check.
McKay already had an inkling of what the trouble might be. "Looking at her, she probably has chlamydia," she said.
Humans don't have a monopoly on sexually transmitted infections. Oysters get herpes; rabbits get syphilis; dolphins get genital warts. But chlamydia — a pared-down, single-celled bacterium that acts like a virus — has been especially successful, infecting everything from frogs to fish to parakeets. You might say chlamydia connects us all.
This shared susceptibility has led some scientists to argue that studying, and saving, koalas may be the key to developing a long-lasting cure for humans. "They're out there, they've got chlamydia, and we can give them a vaccine; we can observe what the vaccine does under real conditions," said Peter Timms, a microbiologist at the University of Sunshine Coast in Queensland. He has spent the past decade developing a chlamydia vaccine for koalas and is now conducting trials on wild koalas, in the hopes that his formula will soon be ready for wider release. "We can do something in koalas you could never do in humans," Timms said.
In koalas, chlamydia's ravages are extreme, leading to severe inflammation, massive cysts and scarring of the reproductive tract. In the worst cases, animals are left yelping in pain when they urinate, and they develop the telltale smell. But the bacteria responsible is still remarkably similar to the human one, thanks to chlamydia's tiny, highly conserved genome: It has just 900 active genes, far fewer than most infectious bacteria.
Because of these similarities, the vaccine trials that Endeavour and Timms are running may offer valuable clues for researchers across the globe who are developing a human vaccine.
A riddle, wrapped in a mystery
How bad is chlamydia in humans? Consider that about 1 in 10 sexually active teenagers in the United States is already infected, said Dr. Toni Darville, chief of the division of paediatric infectious diseases at the University of North Carolina. Chlamydia is the most common sexually transmitted infection worldwide, with 131 million new cases reported each year.
Antibiotics exist, but they are not enough to solve the problem, Darville said. That's because chlamydia is a "stealth organism," producing few symptoms and often going undetected for years.
"We can screen them all and treat them, but if you don't get all their partners and all their buddies at the other high schools, you have a big spring break party, and before you know it everybody's infected again," Darville said. "So they have this long-term chronic smouldering infection, and they don't even know it. And then when they're 28, and they're like, 'Oh, I'm ready to have a baby'; everything's a mess."
In 2019, Darville and her colleagues received a multiyear, US$10.7 million grant from the National Institute of Allergy and Infectious Diseases to develop a vaccine. The ideal package would combine a chlamydia and gonorrhoea vaccine with the HPV vaccine already given to most pre teenagers. "If we could combine those three, you'd basically have a fertility anti-cancer vaccine," she said.
Chlamydia's stealth and ubiquity — the name means "cloaklike mantle" — owes to its two-stage life cycle. It starts out as an elementary body, a sporelike structure that sneaks into cells and hides from the body's immune system. Once inside, it wraps itself in a membrane envelope, hijacks the host cell's machinery and starts pumping out copies of itself. These copies either burst out of the cell or are released into the bloodstream to continue their journey.
"Chlamydia is pretty unique in that regard," said Ken Beagley, a professor of immunology at Queensland University of Technology and a former colleague of Timms. "It's evolved to survive incredibly well in a particular niche, it doesn't kill its host, and the damage it causes occurs over quite a long time."
The bacterium can hang out in the genital tract for months or years, wreaking reproductive havoc. Scarring and chronic inflammation can lead to infertility, ectopic pregnancy or pelvic inflammatory disease. Evidence is mounting that chlamydia harms male fertility as well: Beagley has found that the bacteria damages sperm and could lead to birth abnormalities.
All of this — except the spring break parties — is true in both humans and koalas. Researchers who work with both species note that koala chlamydia looks strikingly similar to the human version. The main difference is severity: In koalas, the bacterium rapidly ascends the urogenital tract and can jump from the reproductive organs to the bladder thanks to their anatomical proximity.
These parallels have led Timms to argue that koalas could serve as a "missing link" in the search for a human vaccine. "The koala is more than just a fancy animal model," he said. "It actually is really useful for human studies."
An ancient curse
No one knows how or when koalas first got chlamydia. But the curse is at least centuries old.
In 1798, European explorers reached the mountains of New South Wales and spied a creature that defied description: Ear-tufted and spoon-nosed, it peered down stoically from the crooks of towering eucalyptus trees. They compared it to the wombat, the sloth and the monkey. They settled on "native bear" and gave it the genus name Phascolarctos (from the Greek for "leather pouch" and "bear"), spawning the misconception that the koala bear is, in fact, a bear.
"The graveness of the visage," The Sydney Gazette wrote in 1803, "would seem to indicate a more than ordinary portion of animal sagacity."
In the late 19th century, Australian naturalist Ellis Troughton noted that the "quaint and lovable koala" was also particularly susceptible to disease. The animals suffered from an eye ailment similar to pink eye, which he blamed for waves of koala die-offs in the 1890s and 1900s. At the same time, anatomist J.P. Hill found that koalas from Queensland and New South Wales often had ovaries and uteruses riddled with cysts. Many modern scientists now believe those koalas were probably afflicted with the same scourge: chlamydia.
Koalas today have even more to worry about. Dogs, careless drivers and, recently, rampant bush fires have driven their numbers down so far that conservation groups are calling for koalas to be listed as endangered. But chlamydia still reigns supreme: In parts of Queensland, the heart of the epidemic, the disease helped fuel an 80 per cent decline over two decades.
The disease is also the one that most often sends koalas to the Australia Zoo Wildlife Hospital, the country's busiest wildlife hospital, 30 miles north of Endeavour. "The figures are 40 per cent chlamydia, 30 per cent cars, 10 per cent dogs," said Dr. Rosemary Booth, the hospital's director. "And then the rest is an interesting assortment of what trouble you can get into when you have a small brain and your habitat's been fragmented."
Booth's team treats "chlamydia koalas" with an amped-up regimen of the same antibiotics used on humans. "I get all of my chlamydia information from the CDC," she said, referring to the Centers for Disease Control and Prevention, in the United States, "because America is the great center for chlamydia."
But the cure can be as deadly as the disease. Deep inside a koala's intestines, an army of bacteria helps the animal subsist off eucalyptus, a plant toxic to every other animal. "These are the ultimate example of an animal that's completely dependent on a population of bacteria," Booth said. Antibiotics extinguish that crucial gut flora, leaving a koala unable to gain nutrients from its food.
In a 2019 trial led by Timms and Booth, one of five koalas treated with antibiotics later had to be euthanized "due to gastrointestinal complications, resulting in muscle wasting and dehydration." The problem is so dire that vets give antibiotic-treated koalas "poo shakes" — faecal transplants, essentially — in the hopes of restoring their microbiota.
For the past decade, Timms has worked to perfect a vaccine. Rather than treat animals once they are already sick, a widespread vaccine would protect koalas from any future sexual encounter and from passing the infection from mother to newborn. His formula, developed with Beagley, appears to work well: Trials have shown that it is safe to use and takes effect within 60 days and that animals show immune responses that span their entire reproductive lives. The next step is optimising it for use in the field.
At Endeavour, the vets treating Jo got a surprise: Molecular tests showed she was chlamydia-free. That meant she could be recruited for the current trial, which is testing a combined vaccine against chlamydia and the koala retrovirus known as KoRV, a virus in the same family as HIV that similarly knocks down the koala's immune system and makes chlamydia more deadly.
Timms is hoping that this trial and another in New South Wales will be the "clincher" — the last step before the government rolls out mass vaccinations in northern Australia. If he is right, it could be good news for more than just koalas.
Of mice and marsupials
Timms began his career studying chlamydia in livestock before moving on to using mice as a model for a human vaccine. Cheap, plentiful and amenable to genetic manipulation, mice have long been the gold standard for studying reproductive disease.
But the mouse model comes with serious drawbacks.
Most glaringly, mice exhibit a profoundly different immune response to chlamydia from ours, making the idea of testing a mouse for a human vaccine "completely flawed," Timms said.
After a decade of doing mouse work, he reasoned that he could take the insights he had gleaned and apply them to an animal that was actually suffering and possible to cure: the koala. "We don't need a vaccine for mice," he said. With "koala work, as hard as that is, and as difficult as that is, the results you get are the ones that matter."
The more Timms worked with koalas, the more he realized that these marsupials were not so different from humans. Here was a species that, like us, was naturally infected with several strains of chlamydia and suffered from similar reproductive outcomes, including infertility. He realized he might have a useful model animal on his hands.
"You're better off doing a bad experiment in koalas than a good experiment in mice," Timms said. "Because koalas really do get chlamydia, and they really do get reproductive tract disease, so everything you do is relevant."
Outside Australia, many researchers say the idea of a koala model is clever but difficult to implement. Darville pointed out that it would be expensive and logistically impossible to test 30 different vaccines in koalas. (According to Endeavour, it costs roughly US$2,000 to pluck one koala from its tree and give it a health exam.)
Still, Timms said, the challenge was worth attempting: "The reason that we're making a case that in between mouse and humans you should put koalas — rather than guinea pigs, minipigs and monkeys — is that koalas address all of the weaknesses, to some degree, that the others have."
Paola Massari, an immunologist at Tufts Medical School, is collaborating with Timms to test a different potential vaccine in koalas. "The koala represents a perfect clinical model, because it's an animal for which you can do some experimentation that's a little more than what you can do in humans," she said. "And at the same time, if you get results, you are curing a disease (in koalas)."
An unlikely alliance
On a February afternoon, Booth strode out into the blaring sunlight of the Australia Zoo grounds. She was heading to the chlamydia wards, which in 2018 were officially named the John Oliver Koala Chlamydia Ward after a grant was donated on the comedian's behalf. About 20 sick koalas were being treated with antibiotics that day, with dozens more on the road to recovery.
Booth stepped up to a leafy enclosure, where a fluffy gray female eyed her curiously from her perch. This koala was originally brought in for chlamydia but had since recovered; her reason for being here, listed on her cage, was "misadventure."
"This is little Lorna, who's rather interesting," Booth said. "She has a baby in her pouch, and she's had problems with her glucose metabolism" — she had diabetes.
Wasn't it unusual to have an animal that gets such humanlike diseases: diabetes, cancer and sexually transmitted infections? "We are but an animal," Booth said, throwing her hands up in a gesture of unity with the world. "We didn't think of it first."
It is still uncertain to what extent the research on koala chlamydia will help in developing a human vaccine. (Darville had been working for nine months when Covid-19 hit, shuttering her lab and slowing scientific progress.) What is certain is that the research done on human chlamydia has greatly benefited koalas. From human antibiotics to mouse insights, wildlife veterinarians have far more tools than before to save the vulnerable marsupials.
For Booth, helping koalas is more than enough. "I don't want to save humans," she said. "My emphasis is completely the other way: I want to use human research to help save other animals. Because they don't have a voice unless we speak for them."
Written by: Rachel E. Gross
Photographs by: Russell Shakespeare
© 2020 THE NEW YORK TIMES
