Study identifies virulence factors of Leishmania

A new study has uncovered the virulence strategy employed by the Leishmania parasite, allowing it to infect immune cells, causing Leishmaniasis. The researchers say the next step is to block or interfere with this pathway, significantly altering how the cell functions.

Previous studies have shown that the Leishmania parasite sabotages the macrophage defence system, but it was unknown how it spread.

The research was led by the Institut National de la Recherche Scientifique (INRS) in collaboration with McGill University, Université de Montréal, all Canada, and Tohoku University, Japan. The team discovered that the parasite exploits macrophage systems.

“It’s like there’s a train travelling among the different intracellular compartments that the parasite boards to deliver its virulence factors inside the infected cell,” says Professor Albert Descoteaux, the study’s lead author. “Our study sheds new light on the pathogenesis of infection.”

Two known virulence factors of Leishmania include the molecules GP63 metalloprotease and lipophosphoglycan (LPG), found on the surface of the parasite.

Upon infecting the macrophage, Leishmania enters a parasitophorous vacuole. It begins to control this, with the vacuole acting as a defence against the cell’s immunity. Leishmania then creates a section in the host cell where it can replicate.

“Most research teams study the impacts of virulence factors, but until now no one understood how Leishmania was able transfer virulence factors from the vacuole to the cytoplasm of the infected cell. That’s what we’ve just shown with our work,” says the study’s first author, Dr Guillermo Arango Duque.

They discovered that Leishmania co-opts the macrophage’s membrane fusion machinery to export virulence factors out of the vacuole. As the parasite transfers its virulence factors to the other side of the vacuole’s membrane, it was necessary to learn the compartment used to contain the factors.

They found that the virulence factors were found in a compartment called the endoplasmic reticulum (ER). The team concluded that this was crucial in the spread of virulence factors within the cell.

Using the latest genetic technology, the researchers discovered the molecules involved in intracellular trafficking. By decreasing the expression of two host cell intracellular traffic regulatory molecules, sec22b and syntaxin-5, they could block the spread of virulence factors and interfere with their actions.

“To fully understand what enables the compartment where Leishmania replicates to connect with other compartments of the infected host cell is a major step forward,” Professor Descoteaux says. “This pathway could also be exploited by other intracellular microorganisms such as Mycobacterium tuberculosis, which is the agent of tuberculosis, or Legionella pneumophila, which causes Legionnaires’ disease.”

The findings were published in PLOS Pathogens.