TY - JOUR

T1 - Leishmania parasite arginine deprivation response pathway influences the host macrophage lysosomal arginine sensing machinery

AU - Madan, Evanka

AU - Ganguly, Nirmal Kumar

AU - Puri, Madhu

AU - Pawar, Harsh

AU - Selvapandiyan, Angamuthu

AU - Muthuswami, Rohini

AU - Zilberstein, Dan

AU - Madhubala, Rentala

PY - 2024/10/30

Y1 - 2024/10/30

N2 - The outcome of infection is greatly influenced by extensive interaction between the metabolic networks of the host and the pathogen. The intracellular protozoan parasite Leishmania donovani causes competition between the host and the parasite for arginine. L. donovani transports arginine via a high-affinity transporter LdAAP3, encoded by two genes LdAAP3.1 and LdAAP3.2. Earlier reports show that upon arginine starvation, cultured Leishmania parasites promptly activate an Arginine Deprivation Response (ADR) pathway, resulting in the stoichiometric up-regulation of LdAAP3.2 mRNA, protein and activity. Lysosomes, on the other hand, employ a specific sensor and an arginine-activated amino acid transporter, solute carrier family 38 member 9 (SLC38A9), which monitors intra-lysosome arginine sufficiency and subsequently up-regulates cellular mTOR kinase activity. The present study investigates the interaction between Leishmania and macrophage-lysosome arginine sensing machinery. We demonstrate that infection with L. donovani activates SLC38A9 arginine sensing in the human monocyte like-macrophage cell line (THP-1) under physiological concentrations of arginine (0.1 mM). However, THP-1 cells infected with LdAAP3.2 null mutants grown in 0.1 mM arginine exhibited reduced expression of SLC38A9 and mTOR. These results indicate that inside the host macrophage, Leishmania overcome low arginine levels by up regulating the transport of arginine via LdAAP3 and SLC38A9 signalling. Furthermore, while LdAAP3.2 null mutants were impaired in their ability to develop inside THP- 1 macrophage, their infectivity and intracellular growth were restored in SLC38A9 silenced macrophages. This study provides the first identification of regulatory role of SLC38A9 in the expression and function of LdAAP3.

AB - The outcome of infection is greatly influenced by extensive interaction between the metabolic networks of the host and the pathogen. The intracellular protozoan parasite Leishmania donovani causes competition between the host and the parasite for arginine. L. donovani transports arginine via a high-affinity transporter LdAAP3, encoded by two genes LdAAP3.1 and LdAAP3.2. Earlier reports show that upon arginine starvation, cultured Leishmania parasites promptly activate an Arginine Deprivation Response (ADR) pathway, resulting in the stoichiometric up-regulation of LdAAP3.2 mRNA, protein and activity. Lysosomes, on the other hand, employ a specific sensor and an arginine-activated amino acid transporter, solute carrier family 38 member 9 (SLC38A9), which monitors intra-lysosome arginine sufficiency and subsequently up-regulates cellular mTOR kinase activity. The present study investigates the interaction between Leishmania and macrophage-lysosome arginine sensing machinery. We demonstrate that infection with L. donovani activates SLC38A9 arginine sensing in the human monocyte like-macrophage cell line (THP-1) under physiological concentrations of arginine (0.1 mM). However, THP-1 cells infected with LdAAP3.2 null mutants grown in 0.1 mM arginine exhibited reduced expression of SLC38A9 and mTOR. These results indicate that inside the host macrophage, Leishmania overcome low arginine levels by up regulating the transport of arginine via LdAAP3 and SLC38A9 signalling. Furthermore, while LdAAP3.2 null mutants were impaired in their ability to develop inside THP- 1 macrophage, their infectivity and intracellular growth were restored in SLC38A9 silenced macrophages. This study provides the first identification of regulatory role of SLC38A9 in the expression and function of LdAAP3.

KW - Leishmania

KW - Parasitology

U2 - 10.18103/mra.v12i10.5800

DO - 10.18103/mra.v12i10.5800

M3 - Journal article

VL - 12

SP - 1

EP - 13

JO - Medical Research Archives

JF - Medical Research Archives

SN - 2375-1924

IS - 10

ER -