The Leprosy Watcher
Armed with recent genomics data, Bill Levis ponders leprosy's immunological fork in the road--and awaits a government decision regarding his own career | By Tom Hollon
Patients come to him by referral, dreading what they may hear after being poked and palpated and scrutinized by one puzzled doctor after another, until someone wondered ominously--Leprosy?--and called William R. Levis at Bellevue Hospital in New York. It is gut-wrenching to be labeled a leper, a word that has shed little of its ancient stigma. Patients are grateful their condition has another name, Hansen disease, and if they ever risk telling someone what they have, they pray that person won't be the sort to look things up in a dictionary.
At least there is comfort in knowing that Levis is the very best. You won't end up deformed, not if he can do anything about it. "We cure them all," says Levis, who has been at this for 21 years, "but you want to cure them with no residual deformity." To do that takes experience: "You learn how to control the body's reactions without harming the patient."
The payroll of the US Public Health Service includes three physicians specializing in the treatment of leprosy. Two work at the National Hansen's Disease Programs at Summit Hospital in Baton Rouge, La., caring for a few dozen patients transferred from the now closed national leprosarium in Carville, La. Should any of the other 287,000,000 Americans need help, there is Levis.
He is more than a leprosy doctor. He is also a longtime student of the disease from the perspective of an immunologist. And as someone wearing two unusual hats, he carries two unusual messages. He tells doctors that contrary to popular belief, leprosy is spreading in the United States, affecting an unknown number of people but estimated at several thousand--with well over half, maybe even nine of every 10, undiagnosed. With researchers he shares his enthusiasm for "a clinical model that is unparalleled for understanding the immune response," hoping in particular to draw the interest of potential collaborators.
Leprosy, he announces, is terrific for studying in humans the immune responses controlled by T-helper cells: The Th1 response (cell-mediated immunity) and the Th2 antibody response. If you know what to look for, you can even watch them working against Mycobacterium leprae on a unique tableau, human skin.
THE SLOW-MOTION EPIDEMIC Leprosy is a chronic infection primarily involving the cooler regions of the body where the intracellular parasite grows best--skin, peripheral nerves, eyes, mucous membranes, and testes. (Cool core temperature explains both the testes and the strange animal model for leprosy, the armadillo.) That patients are now treated on an outpatient basis is a tribute to doctors such as Levis, one of the early pioneers of multiple-drug therapy (MDT) for leprosy. MDT dramatically reduces the duration of therapy and has a lower relapse rate than does monotherapy. Thanks to MDT, the Carville leprosarium stopped admitting new patients in the 1980s and later closed, and the number of patients worldwide declined from 18,000,000 two decades ago to 2,000,000 today.
Further progress has been difficult, however, and new cases hover at 600,000 a year. Levis attributes this to the shoestring budgets of the World Health Organization's (WHO) campaign against leprosy, in which patients with severe forms of leprosy receive two years of treatment and then are considered cured. That is misleading, he says. Unable to afford enough medicine, WHO limits and stretches out the doses and then "plays ostrich and says that their relapse rate is fine. We know that it is not fine because we see them coming into this country."
Almost all of his 382 patients are immigrants, people from leprosy hotspots including India, the Caribbean, and Brazil. They usually land on American shores not knowing they are infected; infections can incubate well beyond 10 years before symptoms erupt. Once they arrive, the slow-motion epidemic that came to the New World from Europe centuries ago continues, spreading to the natives.1 One of Levis' cases was a 73-year-old New Yorker from Queens who had never been out of the United States. He may have contracted leprosy at his church, which has a largely Asian membership. For quite some time, his autoimmune symptoms misled his primary physician and delayed the eventual diagnosis of full-blown leprosy. "You can get a number of autoimmune-like phenomena that simulate lupus or rheumatoid arthritis," says Levis, who guesses that if diagnosis were easy, he might be swamped with thousands of patients. But few doctors recognize the rare symptoms of leprosy, just as few clinical labs can use (or even inventory) the special acid-fast Fite stain applied to tissue biopsies for diagnosis.
A GENOME IN RUINS Last year's deciphering of the genome of M. leprae2 has shed some light on the problems confronting epidemiologists who study leprosy, such as why no one has ever succeeded in culturing the bacterium in vitro. To this day no one knows for certain how leprosy is transmitted--by skin contact, sexual contact, inhalation, ingestion, or insect bite--but in vitro cultures from body swabs might help in working that out.
Now, though, epidemiologists may want to forget about petri dishes and instead track transmission by using PCR. The 3.3-megabase DNA sequence revealed extraordinary gene deletion and inactivation in the M. leprae genome, an unusual case of reductive evolution caused by recombination events between widely dispersed repetitive sequence elements. Recombination-driven deletions stripped off entire metabolic pathways, which probably bears on the in vitro culture problem and also the doubling time of the bacterium--the longest on record. What remains intact of the genome may just suffice for lethargic survival. With its genome crumbling into ruin, the bacterium resembles a decrepit old prizefighter--glory days gone, yet now and then capable of a crippling wallop.
The genome possesses many families of variable-number tandem repeats, and studies with these markers divide M. leprae into at least 15 strains. Levis hopes to find a collaborator interested in applying tandem repeat analysis to his collection of leprotic tissue specimens. Findings would reveal the strains having the greatest clinical importance in his practice, and might uncover connections between strains and their myriad immunological responses.
"A HUNDRED DIFFERENT TYPES" A physician who sees leprosy more than once in a lifetime of practice might be surprised by the multitude of clinical presentations. Leprosy encompasses a spectrum of diseases in five categories: tuberculoid, borderline tuberculoid, dimorphous or midborderline, borderline lepromatous, and lepromatous. Of these, tuberculoid leprosy is the most benign; a strong cellular immune response confines the bacilli within small numbers of well-defined, hypopigmented lesions. It is not considered contagious. It is considered serious. Tuberculoid leprosy is notable for bacterial growth within Schwann's cells, which destroys peripheral nerves. The loss of sensation usually leads to bruising and ulcers, leaving wide open the door to secondary infections, gangrene, and loss of limbs. In lepromatous leprosy at the opposite end of the spectrum, "gargantuan" quantities of antibodies are powerless to control rampant bacterial growth. The skin teems with confluent, ill-defined nodules caked with bacilli, and the ridges and furrows of facial nodules impart a lion-like appearance.
Tuberculoid leprosy (least severe) elicits a 100% Th1 response, says Levis, and lepromatous (most severe), a 100% Th2 response; the other leprosies elicit mixed immune responses. Lumping everything into five categories oversimplifies, however. With all the vagaries and subtleties of Th1 and Th2 responses, Levis says, "There are a hundred different types of leprosy." After all these years of observing leprosy, he can usually tell where a patient's immune response falls on the Th1-Th2 spectrum just by looking at the skin.
Levis' maiden voyage in leprosy research was a study in the early 1980s of T-cell subsets and cytokines within different kinds of lesions. He found that CD4 and CD8 T cells, gamma interferon, and IL-2 were as abundant in tuberculoid granulomas as they were scarce in lepromatous nodules. T cells and cytokines explained why macrophages destroyed bacilli in tuberculoid leprosy but not lepromatous leprosy.
The hot topic today is why M. leprae causes the immune system to act as if there is a fork in the road: Th1 this way, Th2 that way. Why the immune response veers off to extremes presumably depends on the genetics of individual susceptibility, the bacterial dosage encountered, and perhaps the route of infection. Taking the first steps toward uncovering this immune response has led Levis into research on the Toll-like receptors (TLRs) in control of innate immunity.
Mammalian TLRs detect molecules such as lipopolysaccharides and CpG DNA motifs that commonly occur across many microbial species. These receptors trigger early immune activity against infection, before the Th1 and Th2 responses dependent on antigen recognition get under way. Of importance to Levis, innate immunity influences the acquired immune response that comes later, though the mechanism is still not clear.
The innate immune system encounters M. leprae during indeterminate leprosy, the state prior to the disease categorized within the tuberculoid-lepromatous spectrum. In indeterminate leprosy, skin lesions are small, flat, hypopigmented, and difficult to diagnose. Innate immunity either destroys the bacilli, or drives the acquired immune response predominately toward Th1 and tuberculoid disease, or Th2 and lepromatous leprosy, or somewhere in between.
Levis and his colleagues examined responses of Toll-like receptors on mouse macrophages to lipoarabinomannan, the major carbohydrate on the bacterium's cell wall. In work submitted for publication, they show that Toll-2, the main receptor for the carbohydrate, is reinforced by Toll-4; without Toll-4, the innate response weakens. (Levis suggests that the genes for the receptors may influence susceptibility to leprosy, a topic for future research.) Moreover, Toll-2 interacts with Toll-4, revealing unsuspected intricacy in the innate response. His work is similar to that recently reported by Stephanie Vogel and her colleagues regarding recognition of Escherichia coli lipopolysaccharides by Toll-2 and Toll-4.3 Levis confirms her findings for M. leprae, adding that his paper will have new information about the mechanism of receptor interaction.
The immune spectrum, he likes to point out, is a broader issue than just leprosy. "In leprosy we know the Th1-Th2 spectrum. In most diseases we do not," he says. Seemingly disparate diseases may actually represent a spectrum of responses to the same antigens, and researchers just have not caught on. "There are a whole series of diseases that might be connected in Th1-Th2 spectrums that are thought to be separate diseases." Asked for an example, Levis speculates that pyoderma gangrenosum and Sweet syndrome, cutaneous manifestations associated with inflammatory bowel disease, have a spectral link to Crohn disease, a chronic inflammation of the ileum and colon. He also suggests a spectrum of response to HIV, citing studies of prostitutes in Nairobi, Kenya, who seem to be protected from the virus by CD8 T cells and who do not have anti-HIV antibodies. Those women have exceptional Th1 responses, in contrast to antibody responses that fail to prevent CD4 T-cell destruction.
CAREER IN SUNSET? Given Levis' stature as a researcher and a physician with a unique medical practice, it is surprising that the US Public Health Service wants him to retire. Technically, the service is merely following the rules. Levis has 30 years with the service, counting time in the 1970s when he ran a lab at the National Institutes of Health that investigated ataxia telangiectasia, and retirement after 30 years is mandatory. Nevertheless, he is contesting that policy, simultaneously pitting himself against the Hansen disease center in Baton Rouge, which he says wants the slot for his federal position transferred there.
While he awaits a decision, which may be announced by the time this sees print, he continues to see patients, pocketing as usual the extra $100 per month the government pays for this kind of hazardous duty. If the decision goes against him, he can continue doing research in the lab of his wife Georgia Levis, a respected macrophage immunologist at the New York State Institute for Basic Research, Staten Island; they have collaborated for years. If usually inflexible government rulemakers decide to bend, they may in the end do so because of the one thing his patients need that Bill Levis cannot provide. He does not have a successor.
Tom Hollon (firstname.lastname@example.org) is a freelance writer in Rockville, Md.
1. W.R. Levis, A. Cabrera, "Leprosy in the eastern United States," Journal of the American Medical Association, 283:1004-5, 2000.
2. S.T. Cole et al., "Massive gene decay in the leprosy bacillus," Nature, 409:1007-11, 2001.
3. V. Toshchakov et al., "TLR4, but not TLR2, mediates IFN-beta-induced STAT1 alpha/beta-dependent gene expression in macrophages," Nature Immunology, 3:392-8, 2002.
©2002, The Scientist Inc.