June 28, 2023

UCalgary study provides insight into how an infectious parasite uses immune cells as a Trojan Horse

Findings could bring researchers closer to developing an effective vaccine against the chronic disease Leishmaniasis
The Peters lab, from L to R: Camila Gaio, Ramyar Azizi, Matheus Carneiro, Gabi Gee, Chukwunonso Nzelu, Nathan Peters, Deborah Ola, and Leon Melo.
The Peters lab, from left: Camila Gaio, Ramyar Azizi, Matheus Carneiro, Gabi Gee, Chukwunonso Nzelu, Nathan Peters, Deborah Ola, and Leon Melo. Bruce Perrault

Every year, one to two million people in more than 90 countries are infected by a tiny parasite carried by sand flies. Infection by the microscopic-sized Leishmania parasite causes the chronic disease Leishmaniasis. Its effects range from disfiguring skin ulcers to enlarged spleen and liver and — in some 20,000 to 50,000 people a year — death.

Experimental vaccines aimed at preventing the infection haven’t been effective. Scientists realized the parasite was somehow manipulating immune cells called neutrophils, produced by the body’s natural immune response, but this process hasn’t been well understood. Now a University of Calgary research team at the Snyder Institute for Chronic Diseases has discovered the mechanism by which the Leishmania parasite gets inside the neutrophils and is able to evade the immune response.

“This is the first study that shows how the parasite stalls the process of regular neutrophil cell death which prevents the immune system from being activated,” says Dr. Nathan Peters, PhD, associate professor in the Cumming School of Medicine (CSM) and principal investigator. 

The team found the parasite uses a receptor on the surface of the neutrophils meant to mediate the elimination of disease-causing pathogens to actually gain access inside the immune cells, where the parasite resists the neutrophils’ pathogen-killing molecules.

“The neutrophil acts like a little Trojan Horse. The parasite finds a niche inside these neutrophils.”

Nathan Peters

The parasite then makes the neutrophil look like it is a regular dying cell, a process that happens constantly and therefore doesn’t activate the immune system, he explains. The parasite essentially stalls the process of cell death in the neutrophil, enabling the parasite to persist inside the immune cell and cause the infection.

“All of this really interferes with our ability to vaccinate, because the immune system isn’t even aware that the parasite is there,” Peters says.

The study has been identified as a ‘Top Read” by its publisher, The Journal of Immunology, and is titledC3/CD11b-Mediated Leishmania major Internalization by Neutrophils Induces Intraphagosomal NOX2-Mediated Respiratory Burst but Fails to Eliminate Parasites and Induces a State of Stalled Apoptosis.”

Understanding interaction between host and pathogen is crucial

There are hundreds of species of sandflies. The ones that carry the Leishmania parasite don’t occur in Canada, and Leishmaniasis is categorized as a tropical disease. However, the disease has afflicted Canadians who have travelled to parts of the world where Leishmaniasis occurs, including Central and South America, through the Mediterranean basins including southern Europe, as well as in the Middle East, Africa and India.

In addition, scientists are concerned that with climate warming the disease is showing up in new locations.

(L) Adam Ranson, MSc., first author on the study, and Nathan Peters, principal investigator.

Adam Ranson, left, and Nathan Peters.

Nathan Peters

“Certainly, in the southern U.S. we are starting to see the first reports of locally acquired Leishmania infection,” Peters says. Travellers visiting subtropical rainforests, jungles and deserts that harbour sand flies should use insecticide and make sure they see an infectious disease specialist if they develop any unusual symptoms, he advises.

Unlike for malaria transmitted by mosquitoes, there is no vaccine to prevent or treat Leishmaniasis, which involves a chronic, lifelong infection that can flare up several years later in life.

“Understanding the earliest interactions between the parasite and the host helps explain why previous vaccination strategies against Leishmaniasis have been unsuccessful,” says Adam Ranson, first author on the study.

“Hopefully, our findings will contribute to bringing researchers closer to developing an effective vaccine against Leishmania infection,” adds Ranson, now a medical student at the CSM. 

Findings have implications for other infectious diseases

The UCalgary team’s study and co-authors included a research associate, graduate students and undergraduate students. To accomplish their work, the team used a highly specialized laboratory, called the Insectary, in the CSM. The lab enables researchers to raise sand flies infected with the Leishmania parasite; the female sand flies transmit the infection by biting mice.

Peters says his lab has already started in-vitro (in a test tube or lab) research, using human neutrophil cells infected with Leishmania, to confirm that the same immune system-manipulating mechanism seen in mice also occurs in people. Other pathogens, such as Mycobacteria and some fungal pathogens like cryptococcus — an invasive fungus that causes a potentially fatal infection of mainly the lungs — behave and manipulate the immune system in similar ways to the Leishmania parasite, Peters notes.

Understanding how different pathogens converge on and manipulate the same molecular pathway to evade the body’s adaptive immune response could open the door to using an immunotherapy approach to such infectious diseases, he adds.

Instead of developing a treatment or a drug that targets only one particular pathogen, it may be possible to develop a therapy against several different infectious diseases that use the same mechanism to evade immunity.

“Our study emphasizes the need for a vaccine that persists for an extended period to generate a rapid, robust immune response,” Peters says.

The study was supported by the Canadian Institutes of Health Research. Adam Ranson received a Graduate Student Scholarship from the Faculty of Graduate Studies at the University of Calgary. The Insectary was created with an infrastructure grant from Canadian Foundation for Innovation.

Brief video of the Insectary (1:31).

Nathan Peters is an associate professor and head of the Department of Microbiology, Immunology and Infectious Diseases at the Cumming School of Medicine (CSM). He has a cross appointment with the Faculty of Veterinary Medicine. Peters is a member of the Snyder Institute for Chronic Diseases at the CSM. 

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