New research by the Yale School of Public Health and the Oswaldo Cruz Foundation/Brazilian Ministry of Health on leptospirosis, a bacterial infection largely spread by rats, sheds light on how the disease causes death and uncovered a potentially novel treatment.
While rare in the United States, leptospirosis remains an important health threat for impoverished populations in developing countries, causing more than one million illnesses and 60,000 deaths annually.
The reasons why leptospirosis causes life-threatening manifestations, such as pulmonary hemorrhage and acute kidney failure, have been poorly understood. School of Public Health researchers led by Janet Lindow, Ph.D., Elsio Wunder, D.V.M., Ph.D, and Professor Albert Ko, M.D., analyzed the transcriptome, or the spectrum of messenger RNA molecules expressed from patients with leptospirosis, to understand why some individuals die and others survive after infection.
Patients who died from leptospirosis had a defect in the expression of the gene encoding an antimicrobial peptide, cathelicidin, which is capable of killing bacteria, the researchers found. In contrast, survivors were able to mount a vigorous response to the infection as exemplified by the expression of genes that encode cathelicidin as well as those that play a role in adaptive immunity such as antigen presentation and immunoglobulin production.
“The study provides the first evidence that patients die from leptospirosis because neither the body’s innate or adaptive immune responses are operating at adequate levels to fight the pathogen that causes the disease, likely resulting in higher bacterial loads in fatal cases,” Lindow said.
The majority of leptospirosis cases and deaths occur among urban slum dwellers and rural subsistence farmers who live in settings with poor sanitation and where contact with rats and other animals that harbor the bacterial pathogen in commonplace. In Brazil alone, more than 10,000 reported cases are reported each year during seasonal outbreaks of the disease in slum communities.
The study also opened up the potential for future studies to further examine and develop cathelicidin or antibody therapies as new treatments for reducing infection in the most severely ill leptospirosis patients.
To confirm whether cathelicidin was indeed a key factor in the immune response to leptospirosis, the researchers studied the use of the molecule in an animal model. They found that administration of cathelicidin conferred significant protection against lethal leptospirosis infection, indicating cathelicidin may have potential therapeutic value in humans.
“Our findings contribute to improved understanding of the pathogenesis of such an important disease,” said Wunder. “Although further studies are needed, this knowledge can provide us with potential novel treatments for a disease that has a great social and economic impact, especially in impoverished populations worldwide.”
The findings are published in the journal PLOS Pathogens.
