THE LIPOPHOSPHOGLYCAN OF <i>LEISHMANIA</i> PARASITES

Turco, Salvatore J.; Descoteaux, Albert

doi:10.1146/annurev.mi.46.100192.000433

Cited by 452 publications

(254 citation statements)

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“…Furthermore, the repetitive structure and glycan modifications associated with many Leishmania spp. cell-surface molecules suggest that these parasites also interact with MR and SR (Turco and Descoteaux, 1992), which have been shown to send a negative signal in other systems.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Inhibition of Interleukin-12 Promoter Activity in Leishmania Spp.–Infected Macrophages

Jayakumar

Widenmaier

et al. 2008

Journal of Parasitology

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To establish and persist within a host, Leishmania spp. parasites delay the onset of cell-mediated immunity by suppressing interleukin-12 (IL-12) production from host macrophages. Although it is established that Leishmania spp.-infected macrophages have impaired IL-12 production, the mechanisms that account for this suppression remain to be completely elucidated. Using a luciferase reporter assay assessing IL-12 transcription, we report here that Leishmania major, Leishmania donovani, and Leishmania chagasi inhibit IL-12 transcription in response to interferon-gamma, lipopolysaccharide, and CD40 ligand and that Leishmania spp. lipophosphoglycan, phosphoglycans, and major surface protein are not necessary for inhibition. In addition, all the Leishmania spp. strains and life-cycle stages tested inhibited IL-12 promoter activity. Our data further reveal that autocrineacting host factors play no role in the inhibitory response and that phagocytosis signaling is necessary for inhibition of IL-12.The hallmark of an intracellular pathogen is its ability to survive within the intracellular niche. These organisms must be resistant to, or able to evade, the host cell's microbiocidal mechanisms. This dilemma is particularly relevant to Leishmania spp. because these organisms primarily reside within vertebrate macrophages (MP). These host cells become activated for microbial destruction and cytokine secretion by exposure to immune modulators, such as interferon-gamma (IFN-γ) and CD40 ligand (CD40L) found on activated T-cells. One strategy Leishmania spp. parasites use to avoid host cell activation is to interfere with the signaling pathways that induce MP to become microbicidal (Gregory and Olivier, 2005); another is inhibiting or delaying the production of activating cytokines (Belkaid et al., 2000).The most consistent dysfunction reported from Leishmania spp.-infected MP is the aberrant production of inflammatory cytokines, specifically an inhibition of interleukin-12 (IL-12) production (McDowell and Sacks, 1999). Being essential for T-helper 1 (Th1) cell differentiation, the inability of Leishmania spp.-infected MP to produce IL-12 allows Leishmania spp. to evade acquired resistance by postponing IL-12 production and the induction of IFN-γ, thereby allowing the establishment of the infection; both clinical and experimental studies indicate that the onset of Th1-mediated immunity and Leishmania spp. killing is indeed delayed (Melby, 1991). Inhibition of MP IL-12 production and resulting Th1 responses is not unique to Leishmania; viruses (Chehimi et al., 1994;Chougnet et al., 1996;Karp et 1996) and bacteria (Marth and Kelsall, 1997;Sutterwala et al., 1997;Matsunaga et al., 2003) also exploit this mechanism to avoid clearance.The general nature of impaired IL-12 production in Leishmania spp.-infected MP has extended to every IL-12 agonist that has been tested. Leishmania spp.-infected MP are unable to produce IL-12 even in response to strong inflammatory stimuli, including microbial stimuli, e.g., lipopolysacchar...

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Section: Discussionmentioning

confidence: 99%

Transcriptional Inhibition of Interleukin-12 Promoter Activity in Leishmania Spp.–Infected Macrophages

Jayakumar

Widenmaier

et al. 2008

Journal of Parasitology

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“…Como promastigotes metacíclicos, están listos para ser inoculados en el hospedero mamífero ante una nueva ingestión de sangre por el vector (7,19). estudiadas, caracterizadas y asociadas con la metaciclogénesis son el LPG (22,23) y la glicoproteína gp63 (24,25), expresadas abundantemente en la superficie de los promastigotes, principalmente en cepas del subgénero Leishmania, pero que sufren una considerable disminución o están ausentes, según la especie, en el estadio de amastigote (23). En el subgénero Leishmania, el LPG se expresa sobre toda la superficie del promastigote, incluido el flagelo, y está organizado como un filamento densamente empaquetado que forma un glicocálix.…”

Section: Cambios Morfológicos Genéticos Y Bioquímicos Asociados Con unclassified

“…Por su parte, el LPG, un factor de virulencia multifuncional al menos en L. major, se ha implicado en varios procesos que conllevan a la desactivación del macrófago, como es la inhibición de la proteína cinasa C (63,64), la cual está relacionada con la respuesta oxidativa del macrófago. Además, se ha visto que el LPG inhibe la fusión fagosoma-endosoma (65) y elimina eficientemente metabolitos tóxicos del oxígeno como el anión superóxido y radicales hidroxilos (23). La inhibición transitoria de la fusión fagosoma-endosoma puede entenderse como una estrategia del parásito para ganar tiempo hasta transformarse en amastigote, el cual es más resistente a enzimas hidrolíticas y al pH ácido encontrado en el fagolisosoma una vez ocurre la fusión fagosoma-endosoma.…”

Section: Implicaciones De La Metaciclogénesis En El Ciclo De Vida De unclassified

Metaciclogénesis: un proceso fundamental en la biología de Leishmania

Muskus¹,

Marín-Villa²

2002

biomedica

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La metaciclogénesis es un proceso que experimentan naturalmente los promastigotes de Leishmania en el tracto digestivo del insecto vector y cuya finalidad es transformar los promastigotes en formas altamente infectivas y capaces de sobrevivir en el hospedero vertebrado, donde es sometido a los ataques por parte del sistema inmune. Se ha demostrado que este fenómeno ocurre también en promastigotes en crecimiento en cultivos axénicos in vitro. El proceso de metaciclogénesis se asoció inicialmente con cambios morfológicos, observándose que los promastigotes cambiaban su forma y tamaño con incremento en la longitud del flagelo. Luego, se logró asociar con este fenómeno la expresión de ciertas moléculas implicadas en virulencia, como el lipofosfoglicano (LPG) y una proteasa de superficie, la gp63. Se demostró que estas moléculas experimentaban cambios tanto cuantitativos como cualitativos a medida que los promastigotes se diferencian de promastigotes procíclicos no infectivos a metacíclicos o infectivos. Hoy en día, mediante técnicas de hibridización substractiva con cADN o de amplificación diferencial, se han logrado identificar genes cuyo patrón de expresión está íntimamente ligado al proceso de metaciclogénesis. Se han identificado moléculas como el producto del gen B y una proteína asociada con la metaciclogénesis (Mat-1), las cuales se expresan exclusivamente en promastigotes metacíclicos, mientras que otras como las proteínas Meta-1, SHERP y HASP se sobrexpresan en los promastigotes metacíclicos. Sin embargo, la función y asociación de estas proteínas con este patrón particular de expresión y virulencia se está empezando a evaluar.Palabras clave: metaciclogénesis, Leishmania, promastigotes, LPG, gp63. Metacyclogenesis: a basic process in Leishmania biologyMetacyclogenesis is a process whereby Leishmania transforms from poorly infective procyclic promastigotes into highly infective metacyclic promastigotes. In nature, metacyclogenesis occurs in the insect vector. This transformation is accompanied by an increased ability to infect and survive in the vertebrate host, where the parasite is attacked by the host's immune system. Metacyclogenesis has also been shown to occur in axenic cultures of promastigotes. Morphological changes in size and shape, and length of flagellum were first associated with differentiation in the insect gut and in different phases of growth in culture. Later, the expression of molecules such as LPG and the surface protease gp63 were associated with this process. These two molecules were observed to undergo qualitative and quantitative modifications as the promastigotes differentiated from procyclic to metacyclic forms. Using cDNA subtractive hybridization-based methods or differential amplification, previously unknown genes tightly linked to metacyclogenesis have been identified. Gene products exclusively expresed in metacyclic promastigotes included a gene B product and Mat-1 -a gene associated with metacyclogenesis. Other proteins, Meta-1, SHERP and HASP, were up-regulated during the met...

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“…More recently the glycoinositolphospholipids (GIPLs) received great attention since it was demonstrated that they act as anchors of proteins on the eukaryotic cell membrane and, for instance, of a phosphosaccharide in Leishmania (Turco & Descoteaux 1992).…”

Section: Lppg and Galactofuranosementioning

confidence: 99%

“…It is interesting to note that in all GIPLs, furanoic galactose, when present, is bound to an α-D-mannose by a β1→3 bond, as a non reducing terminal sugar -as in LPPG (Lederkremer et al 1985b, Previato et al 1990, Carreira et al 1996) -or as an internal unit inside an oligosaccharide chain -as in Leishmania LPG (Turco & Descoteaux 1992). That specificity suggests the existence of a β(1-3) galactofuranosyltransferase for biosynthesis and a β(1-3) galactofuranosyl hydrolase for degradation.…”

Section: Lppg and Galactofuranosementioning

confidence: 99%