Proteophosophoglycans regurgitated by Leishmania-infected sand flies target the L-arginine metabolism of host macrophages to promote parasite survival

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Proteophosophoglycans regurgitated by Leishmania-infected sand flies target the L-arginine metabolism of host macrophages to promote parasite survival. / Rogers, Matthew; Kropf, Pascale; Choi, Beak-San et al.
In: PLoS Pathogens, Vol. 5, No. 8, e1000555, 21.08.2009.

Research output: Contribution to Journal/Magazine › Journal article › peer-review

Bibtex

@article{5074487443064ea8932a9174e72f63f3,

title = "Proteophosophoglycans regurgitated by Leishmania-infected sand flies target the L-arginine metabolism of host macrophages to promote parasite survival",

abstract = "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.",

keywords = "Animals, Arginase, Disease Models, Animal, Female, Host-Pathogen Interactions, Insect Vectors, Leishmania mexicana, Leishmaniasis, Cutaneous, Macrophages, Membrane Proteins, Mice, Mice, Inbred BALB C, Proteoglycans, Protozoan Proteins, Psychodidae, Regurgitation, Gastric",

author = "Matthew Rogers and Pascale Kropf and Beak-San Choi and Rod Dillon and Maria Podinovskaia and Paul Bates and Ingrid M{\"u}ller",

year = "2009",

month = aug,

day = "21",

doi = "10.1371/journal.ppat.1000555",

language = "English",

volume = "5",

journal = "PLoS Pathogens",

issn = "1553-7374",

publisher = "Public Library of Science",

number = "8",

}

RIS

TY - JOUR

T1 - Proteophosophoglycans regurgitated by Leishmania-infected sand flies target the L-arginine metabolism of host macrophages to promote parasite survival

AU - Rogers, Matthew

AU - Kropf, Pascale

AU - Choi, Beak-San

AU - Dillon, Rod

AU - Podinovskaia, Maria

AU - Bates, Paul

AU - Müller, Ingrid

PY - 2009/8/21

Y1 - 2009/8/21

N2 - 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.

AB - 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.

KW - Animals

KW - Arginase

KW - Disease Models, Animal

KW - Female

KW - Host-Pathogen Interactions

KW - Insect Vectors

KW - Leishmania mexicana

KW - Leishmaniasis, Cutaneous

KW - Macrophages

KW - Membrane Proteins

KW - Mice

KW - Mice, Inbred BALB C

KW - Proteoglycans

KW - Protozoan Proteins

KW - Psychodidae

KW - Regurgitation, Gastric

UR - http://www.scopus.com/inward/record.url?scp=70049092749&partnerID=8YFLogxK

U2 - 10.1371/journal.ppat.1000555

DO - 10.1371/journal.ppat.1000555

M3 - Journal article

C2 - 19696894

VL - 5

JO - PLoS Pathogens

JF - PLoS Pathogens

SN - 1553-7374

IS - 8

M1 - e1000555

ER -

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