Sensing Host Arginine Is Essential for Leishmania Parasites' Intracellular Development.

Area of Science:

• Parasitology
• Molecular Biology
• Cellular Metabolism

Background:

• Lysosomal arginine homeostasis is vital for mammalian cell growth.
• Macrophages' phagolysosomes are the niche for Leishmania parasites causing leishmaniasis.
• Leishmania faces arginine deprivation during macrophage infection.

Purpose of the Study:

• To investigate the role of the arginine deprivation response (ADR) pathway in Leishmania pathogenesis.
• To determine if ADR-mediated upregulation of the arginine transporter AAP3 is essential for parasite intracellular development.

Main Methods:

• Utilized CRISPR/Cas9 gene editing to create Leishmania mutants with disrupted AAP3 locus.
• Assessed parasite growth and arginine transport in vitro and within THP-1 macrophages.
• Evaluated infectivity of AAP3 mutants in BALB/c mouse models.

Main Results:

• AAP3 mutants exhibited basal arginine transport but lacked response to arginine starvation.
• Mutants showed impaired intracellular development in macrophages and significantly reduced infectivity in mice.
• ADR activation correlates with increased arginine transport, essential for parasite survival in nutrient-limited phagolysosomes.

Conclusions:

• The ADR pathway, by upregulating AAP3, is essential for Leishmania to overcome arginine starvation within host macrophages.
• Leishmania's ability to sense and adapt to host metabolite levels is critical for its pathogenesis.
• Targeting the ADR pathway or AAP3 could represent a novel therapeutic strategy against leishmaniasis.