Proteophosophoglycans Regurgitated by Leishmania-Infected Sand Flies Target the L-Arginine Metabolism of Host Macrophages to Promote Parasite Survival

PLoS Pathogens

Beak-San Choi¹  Matthew Rogers¹  Ingrid Müller¹  Pascale Kropf¹  Maria Podinovskaia²  Paul Bates³  Rod Dillon⁴ 

[1] Department of Immunology, Imperial College of Science, Technology and Medicine, London, United Kingdom;Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom;Department of Molecular and Biochemical Parasitology, Liverpool School of Tropical Medicine, Liverpool, United Kingdom;Vector Group, Liverpool School of Tropical Medicine, Liverpool, United Kingdom

关键词: Parasitic diseases;    Macrophages;    S;    flies;    Promastigotes;    Saliva;    Leishmania;    Amastigotes;    Neutrophils;   

DOI  :  10.1371/journal.ppat.1000555

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

All natural Leishmania infections start in the skin; however, little is known of the contribution made by the sand fly vector to the earliest events in mammalian infection, especially in inflamed skin that can rapidly kill invading parasites. During transmission sand flies regurgitate a proteophosphoglycan gel synthesized by the parasites inside the fly midgut, termed promastigote secretory gel (PSG). Regurgitated PSG can exacerbate cutaneous leishmaniasis. Here, we show that the amount of Leishmania mexicana PSG regurgitated by Lutzomyia longipalpis sand flies is proportional to the size of its original midgut infection and the number of parasites transmitted. Furthermore, PSG could exacerbate cutaneous L. mexicana infection for a wide range of doses (10–10,000 parasites) and enhance infection by as early as 48 hours in inflamed dermal air pouches. This early exacerbation was attributed to two fundamental properties of PSG: Firstly, PSG powerfully recruited macrophages to the dermal site of infection within 24 hours. Secondly, PSG enhanced alternative activation and arginase activity of host macrophages, thereby increasing L-arginine catabolism and the synthesis of polyamines essential for intracellular parasite growth. The increase in arginase activity promoted the intracellular growth of L. mexicana within classically activated macrophages, and inhibition of macrophage arginase completely ablated the early exacerbatory properties of PSG in vitro and in vivo. Thus, PSG is an essential component of the infectious sand fly bite for the early establishment of Leishmania in skin, which should be considered when designing and screening therapies against leishmaniasis.

【 授权许可】

CC BY