Project Coordination
Pontifical Catholic University of Parana, Brazil (PUCPR)

Partners
Federal University of Piaui, Brazil 
University of Sao Paulo, Brazil 
McGill University, Canada

Aim: Two variants in the LRRK2 gene were found to be strong candidates to control leprosy susceptibility in a unique family affected by leprosy. By infecting macrophages in vitro with M. leprae, this genetic susceptibility will be further studied.

Full project title:
Functional analysis of candidate variants in the early-onset leprosy phenotype using a novel cellular model

Final project summary:
Leprosy is an infectious disease caused by Mycobacterium leprae, but exposure to the bacteria alone does not explain why some people develop the disease while others remain unaffected. Scientists have long known that the body's immune response plays a critical role in determining susceptibility to leprosy, yet the genetic factors underlying this response are not fully understood.

A unique case in northeastern Brazil provided researchers with an extraordinary opportunity to explore the genetic basis of leprosy. The study focused on a family from Teresina, Piauí, including a pair of identical twin girls who were diagnosed with leprosy at just 22 months of age. This is highly unusual, as leprosy typically has a long incubation period and is rarely diagnosed in very young children. The occurrence of the disease in identical twins at such an early age suggested that inherited genetic factors could play a significant role in their susceptibility.

To investigate this possibility, researchers sequenced the genomes of family members and identified important variations in the LRRK2 gene, a gene that has previously been linked to leprosy susceptibility in different populations around the world. The LRRK2 protein is involved in regulating inflammation and immune responses, helping the body respond to infection. Additional evidence suggested that a variation in another immune-related gene, NOD2, might also contribute to disease development and influence how the immune system responds to leprosy infection.

The study aimed to better understand how these genetic variations affect human immune cells and contribute to the development of leprosy.

To achieve this, researchers used advanced cellular and genetic technologies. They generated induced pluripotent stem cells (iPSCs), which can be reprogrammed to develop into different cell types, and applied gene-editing techniques to study the effects of specific genetic variants. In parallel, they compared cells obtained from different family members based on their natural genetic makeup. The team also examined immune cells called macrophages from individuals with leprosy as well as from healthy individuals who carried the same genetic variants identified in the family.

The research revealed that variations in the LRRK2 gene, and potentially in NOD2, significantly influence how immune cells behave when exposed to biological challenges. The findings confirmed observations previously made in laboratory mouse models and demonstrated that similar mechanisms are active in human cells.

Several important cellular functions were affected by these genetic changes. Researchers observed alterations in:

• Apoptosis (programmed cell death), an essential process that helps the body eliminate infected or damaged cells.
• Production of reactive oxygen species (ROS), molecules that play an important role in destroying pathogens.
• Expression of LRRK2 and NOD2 genes, which are involved in coordinating immune responses.
• Mitochondrial metabolism, affecting the function of mitochondria, the energy-producing structures within cells that also play a critical role in immunity.

Together, these findings provide new insights into how genetic variations may influence the body's ability to respond to Mycobacterium leprae infection and help explain why certain individuals are more vulnerable to developing leprosy.

An additional innovation emerging from the project was the identification of urinary stem cells (USCs) as a promising new model for leprosy research. These cells can be collected non-invasively and may offer an accessible platform for future studies involving gene editing, cell reprogramming, and investigations of disease mechanisms. The development of this model has the potential to accelerate research into leprosy and related immune disorders.

Beyond its scientific discoveries, the project helped strengthen research capacity in Brazil. The work fostered new collaborations and expanded expertise in cell and molecular biology at the Pontifical Catholic University of Paraná (PUCPR), creating opportunities for future research into the genetic and immunological mechanisms of infectious diseases.

This study highlights the important role of genetics in determining susceptibility to leprosy and provides new evidence that variations in the LRRK2 gene can significantly influence immune cell function. By deepening our understanding of how genetic factors shape the body's response to infection, the research contributes to a growing body of knowledge that may ultimately support earlier diagnosis, improved risk assessment, and the development of more personalized approaches to leprosy prevention and treatment.

The findings also demonstrate how cutting-edge technologies such as stem cell modelling, genome sequencing, and gene editing can help unravel the complex interactions between human genetics and infectious diseases, opening new pathways for scientific discovery and innovation in leprosy research.

Impact

Dallmann-Sauer, M., Xu, Y. Z., da Costa, A. L. F., Tao, S., Gomes, T. A., Prata, R. B. D. S., ... & Schurr, E. (2023). Allele-dependent interaction of LRRK2 and NOD2 in leprosy. PLoS Pathogens, 19(3), e1011260.