The Oldest Human Infectious Disease?

MD Anderson Researcher Uncovers Some Ancient Mysteries Of Leprosy

Charles Moore

Source - DOI: 10.1371/journal.pntd.0002544


Phylogenetic tree of several Mycobacterium species based on the amino acid sequences of rpoB protein.

New research at The University of Texas MD Anderson Cancer Center in Houston has unearthed some of the ancient mysteries behind leprosy, also known as Hansen’s disease, which has plagued mankind throughout history. The new research findings are published in the current edition of journal PLOS Neglected Tropical Diseases. According to this new hypothesis, leprosy disease may well be the oldest human-specific infection, with roots that likely stem back millions of years.

The PLOS NTG paper, entitled “On the Age of Leprosy” (doi/10.1371/journal.pntd.0002544) is co-authored 

by  Xiang Yang Han of the MD Anderson Center, and Francisco J. Silva of the Universitat de València’s Evolutionary Genetics Unit in Valencia, Spain.

Work by Xiang-Yang Han, M.D., Ph.D., a clinical pathologist and a professor in laboratory medicine at the MD Anderson Cancer Center resulted in the discovery there in 2008 of a new leprosy-causing species, called Mycobacterium lepromatosis. Prior to that finding, only one species of bacteria, called Mycobacterium leprae, was known to cause leprosy.

In their paper, Drs. Han and Silva describe Leprosy as a chronic infection of the skin and nerves caused by Mycobacterium leprae and the newly discovered Mycobacterium lepromatosis. The disease has been documented for millennia in ancient cultures including many references in the ancient Jewish scriptures and the Christian Bible. The article abstract notes that recent genomic studies of worldwide M. leprae strains have further traced Leprosy along global human dispersals during the past ~100,000 years.

Because leprosy bacilli are strictly intracellular, the researchers wonder how long humans have been affected by this disease-causing parasite, noting that based on recently published data on M. leprae genomes, M. lepromatosis discovery, leprosy bacilli evolution, and human evolution, it is most likely that the leprosy bacilli started parasitic evolution in humans or early hominids millions of years ago. That makes leprosy the oldest known human-specific infection.

They suggest that the unique adaptive evolution of the disease has likely molded the indolent growth and evasion from human immune defense that may explain leprosy pathogenesis. Accordingly, Drs. Han and Silva say leprosy can be viewed as a natural consequence of a long parasitism, and that the burden of leprosy may have affected minor selection on human genetic polymorphisms.

A MD Anderson Center release notes that there are hundreds of thousands of new cases of leprosy worldwide each year, but the disease is rare in the United States, with only about 100-200 new cases annually. Leprosy is known for attacking and horribly disfiguring a patient’s skin and dulling nerve sensation. Effective antimicrobial treatments exist today, but when the disease is misdiagnosed or left untreated, it lead to extensive skin lesions, deformities in the patient’s face and extremities, disabilities, and even death. Leprosy also carries a social stigma and diagnosis is frequently and notoriously delayed.

Work led by paper co-author and pathologist  Xiang-Yang Han, who is  a professor in laboratory medicine at the MD Anderson Center, resulted in the 2008 discovery of a new leprosy-causing bacteria species, called Mycobacterium lepromatosis. Before that time, only one species of bacteria, called Mycobacterium leprae, was known to cause leprosy.

In the past several years, Dr. Han and other researchers have found the new leprosy agent in patients from Mexico, Canada, Brazil, Singapore, and Myanmar. Dr. Han’s team, in collaboration with Dr. Silva, an evolutionary geneticist, analyzed 20 genes of Mycobacterium lepromatosis and compared them with those of Mycobacterium leprae.

They found the two leprosy bacteria came from a last common ancestor around 10 million years ago. Before the divergence, the common bacteria ancestor had undergone a massive reductive evolution that resulted in inactivation of approximately 40 percent of all the genes in its genome. Those genes went on to become non-functioning pseudogenes or were even lost. This reductive evolution, unique among all pathogenic bacteria known so far, was unearthed from genome sequencing of Mycobacterium leprae several years ago before the discovery of Mycobacterium lepromatosis, by another research team.

A Unifying Theory

In the newly published study, Drs. Han and Silva developed the hypothesis that leprosy has existed for millions of years, a theory built by connecting the dots from several known facts and published studies.

One piece of evidence is the fact that leprosy is an exclusively human disease without other hosts or reservoirs. Once outside of the human body, leprosy bacteria are unable to grow in artificial media, but Mycobacterium leprae is found in wild armadillos only in North America and South America where it is believed the animals likely first acquired the infection from early European explorers who arrives in the Americas a few hundred years ago.

Another piece of evidence suggesting that leprosy has a long history lies within the bacterial genome. The MD Anderson release notes that all worldwide Mycobacterium leprae strains analyzed so far, more than 400 in total, have been found to have essentially identical genomes, or are clonal. This suggests human beings carried the leprosy bacteria when departing Africa around 100,000 years ago to populate the rest of the world, and also indicates that leprosy bacteria are extraordinarily stable within their human hosts — a sign of mature parasitic life far older than 100,000 years.

A third element of evidence for leprosy’s antiquity relates to the last common ancestor of the two known leprosy bacteria, which completed reductive evolution around 10 million years ago, resulting in a lean genome and the loss of free-living ability. A well-adapted lean parasite is confined to its specific host species and is unlikely to switch to other host species.

Lastly, the oldest age of the leprosy bacteria’s pseudogenes suggest that gene inactivation began approximately 20 million years ago — likely the point at which the ancestor of leprosy bacteria jumped to our early human ancestors and transitioned from free-living to strictly parasitic. In essence, says the report, the theory unifies the reductive evolution of the leprosy bacteria and their strict parasitic lifestyle in humans into a single continuous, long process.

Insights Into The Pathogenesis Of Leprosy

Drs. Han and Silva also bring human evolution, host genetic diversity, and host immunity into the complex issue of leprosy, their hypothesis that leprosy existed for millions of years, offering new insights into disease pathogenesis. For example, the parasitic adaptation of the leprosy bacteria inside hominid-human hosts is similar to a very long hide-and-seek game. In this scenario, the parasite hides by mutating or removing harmful molecules while retaining protective ones. In the end, this leads to evasion from host immunity, a phenomenon commonly seen in leprosy. Finally, Drs. Han and Silva conclude that leprosy can be viewed as a natural consequence of a long parasitism.

Dr. Han, a clinical microbiologist, routinely diagnoses secondary infections caused by various kinds of microbes in patients with cancer. “Many patients who come to MD Anderson suspected of having cancer turn out to have infections instead, and we make such game-changing diagnoses nearly every day” he notes. “Discovering the new leprosy agent Mycobacterium lepromatosis was incidental. However, locating this additional leprosy cause significantly adds to our understanding of the ancient disease. In particular, tracing the ultimate origin of leprosy through the parasitic adaptive evolution of the leprosy bacteria is rather insightful, not only for this single disease but also for our better understanding of the mechanism behind other human infections. Medical historians and anthropologists may appreciate this also.”

Dr. Han’s team is currently focused on the decoded genome of Mycobacterium lepromatosis and its assembly.

University of Texas MD Anderson Cancer Center
PLOS Neglected Tropical Diseases
Institut Cavanilles de Biodiversitat i Biologia Evolutiva