Transmitted by a sandfly one-third the size of a mosquito, parasitic Leishmania protozoa are responsible for a flesh-destroying disease that kills an estimated 20,000 people per year. Two new studies offer understanding of how the parasite provides immunity through persistence and why some people suffer more virulent forms of the disease.
Though relatively unknown in the US, Leishmania infections impact more than 12 million people in tropical and subtropical regions including Africa, the Middle East, Asia, and parts of Central and South America, with over 950 million people at risk in high-burden countries.
Classified as a neglected tropical disease, Leishmania infections sometimes yield no symptoms, but the parasites often cause three disease types:
- With a fatality rate of close to 100% in third-world countries, visceral leishmaniasis, also known as kala azar and black fever, is second only to malaria as a parasitic killer. Invading internal organs, bone marrow, and the bloodstream, it almost always causes death if untreated.
- Diagnosed through characteristic lesions and disfiguring, scarring sores, cutaneous leishmaniasis can heal on its own.
- Sometimes cutaneous leishmaniasis leads to mucosal leishmaniasis when the mouth, nose, and throat are infected with painful, flesh-destroying sores.
Infecting people of all ages, whether local or tourist, Leishmania is a parasite that inhabits the body by targeting and taking over phages, cells dispatched by the immune system to destroy invading pathogens. Once inside a macrophage, the parasite divides, multiples, and spills out, infecting other phage cells.
Yet for most who suffer a Leishmania infection once, they do not suffer infection again. While this seems like the usual immunity-after-infection (such as with chickenpox), it is not.
In research published in PLOS Neglected Tropical Diseases, scientists from the Department of Molecular Microbiology at the Washington University School of Medicine in St. Louis, Missouri, suggest a connection between persistent infection and persistent immunity to the Leishmania protozoa. How?
Persistent infection occurs when the pathogen remains in the body in a latent state. The microbes hang around dormant, waiting until a weak immune system, or other factors, create favorable environmental conditions for their re-emergence.
A good example of a persistent infection is varicella zoster, the virus that causes chickenpox. People who have had chickenpox will not again suffer chickenpox, but they may suffer a painful, blistering condition called shingles. In the study, scientists already knew that Leishmania victims exhibit long-term immunity to new Leishmania infection. When animals screen completely clear of the parasite, they are susceptible to Leishmania reinfection.
Through studying genetically resistant mice, scientists made the following findings:
- Leishmania parasites reside in white blood cells, post-infection. The immune cells then regulate the size and number of parasites living within.
- Parasites continue to divide and replicate in a persistent infection, but their overall numbers remain relatively constant unless the immune system suffers compromise with another infection or with age.
- Because they are continually monitoring and killing the parasites, the immune response remains active against the parasite, stopping individuals from being reinfected with another strain.
It seems that our immunologic memory needs reminding sometimes. As the persistent parasites replicate and get killed, they are continually stimulating the immune system, keeping it primed and ready for any new encounters with the parasite.
This research raises the interesting idea that for some microorganisms, lifelong immunity might come at the cost of lifelong infection.
In the second study, published in the Proceedings of the National Academy of Sciences, a different team of researchers analyzed an endogenous, or innate, double-stranded RNA virus in the parasite called Leishmaniavirus (LRV1). The presence of LRV1 boosts the severity of a Leishmania infection. Studying mouse cells tagged with florescence and a collection of 81 compounds known to be active against Leishmania, and LRV1, the research group used capsid flow cytometry to study the RNA virus within the parasite itself, and identified novel compounds that could reduce the virulence of Leishmania infections.
Capsid flow cytometry is a technology that gives scientists the opportunity to analyze and identify microbes, compounds, and genetic material. About the findings, lead author, Dr. Matthew Kuhlmann, also from the Department of Molecular Microbiology at the Washington University School of Medicine, as well as the Division of Infectious Diseases, told WonderHowTo:
The compounds we have identified are only a starting point and much work needs to be done to identify compounds that are safe and effective in humans. More importantly, since we know that mucosal leishmaniasis is one of the most difficult to treat forms of leishmaniasis, the adjunctive therapy targeting LRV1 could be a huge benefit.
Connecting the dots about persistent immunity adds to our knowledge base of dealing with Leishmania. And refined data on the mechanisms, like LRV1, of virulent infection opens the door to develop vaccines or treatments for diseases that could safely attack the parasite and the viruses it carries—without harming human victims.
Ideally, through additional drug development, we could even find a compound that can attack not just LRV1, but also the Leishmania at the same time. This would be quite an advance in the treatment of mucosal leishmaniasis for which effective treatments are severely lacking.