Leishmania lipophosphoglycan: how to establish structure-activity relationships for this highly complex and multifunctional glycoconjugate?

Forestier, Claire-Lise; Gao, Qi; Boons, Geert‐Jan

doi:10.3389/fcimb.2014.00193

Cited by 77 publications

(84 citation statements)

References 64 publications

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“…To initiate infection-induced intracellular signaling, surface molecules on both host and pathogens are involved (34). A variety of surface molecules on the Leishmania parasite have been identified, of which LPG, a constituent of the surface glycocalyx of the Leishmania parasite, plays a major role in host-parasite interactions (35). The predominant components of the glycocalyx of the infective promastigotes are the GPI-anchored phosphoglycosylated glycans and the LPG (35).…”

Section: Induction Of Autophagy In Hpmns Is Parasite Lpg Dependentmentioning

confidence: 99%

Leishmania donovaniInduces Autophagy in Human Blood–Derived Neutrophils

Pitale

Gendalur

Descoteaux

et al. 2019

The Journal of Immunology

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Neutrophils, the essential components of the innate immune system, are recruited in large numbers to the pathogen site of entry. Several pathogens induce neutrophil autophagy; however, function of autophagic events during Leishmania parasite infection remain unknown. In this article, we report a finding that is new, to our knowledge, of how Leishmania-induced human polymorphonuclear neutrophil (hPMN) autophagy regulates the silent mode of parasite transfer to macrophages by influencing the engulfment of infected cells. Leishmania infection induced a time-dependent autophagy increase responsive to block by 3-methyladenine but sensitive to ULK1/2 inhibition only after 3 h. This suggested the prevalence of canonical autophagy during later hours, ULK1/2 inhibition being able to block only canonical autophagy. Interaction of Rubicon and Beclin-1 at 1 h postinfection affirmed the prevalence of noncanonical autophagy during early infection. There was a reduction in macrophage uptake of parasite-exposed hPMNs treated with 3-methyladenine or ULK1/2 inhibitor, suggesting the involvement of both noncanonical and canonical autophagy in neutrophil engulfment. Autophagy inducer rapamycin augmented neutrophil engulfment by macrophages. Redistribution of hPMN surface CD47 encouraged neutrophil uptake. Activation of ERK, phosphoinositide 3-kinase, and NADPH oxidase–mediated reactive oxygen species generation were induced after parasite binding. The lpg1-knockout parasites expressing defective lipophosphoglycan did not induce autophagy, indicating that lipophosphoglycan is necessary for interaction with the neutrophils. Autophagy induction was TLR2/4 independent because the receptor blockade did not interfere with infection-induced autophagy. In summary, the engulfment of neutrophils by the macrophages was influenced by the escalation of hPMN autophagy, which is an important event during Leishmania infection.

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Section: Induction Of Autophagy In Hpmns Is Parasite Lpg Dependentmentioning

confidence: 99%

Leishmania donovaniInduces Autophagy in Human Blood–Derived Neutrophils

Pitale

Gendalur

Descoteaux

et al. 2019

The Journal of Immunology

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“…The hypersensitivity to acidic pH and heat likely compromised their ability to survive and replicate in the phagolysosome (37). Alteration in LPG structure may also contribute to the virulence attenuation (65). Overall, the fitness loss displayed by lso – is similar (in severity) to smt – and less dramatic than c14dm – mutants (18, 19).…”

Section: Discussionmentioning

confidence: 99%

Lathosterol oxidase (sterol C5-desaturase) deletion confers resistance to amphotericin B and sensitivity to acidic stress inLeishmania major

Frankfater²,

Hsu³

et al. 2020

Preprint

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8Lathosterol oxidase (LSO) catalyzes the formation of C5-C6 double bond in the synthesis 1 9 3 1 expression. Together, these findings suggest that the C5-C6 double bond is vital for the structure 3 2 of sterol core, and while the loss of LSO can lead to amphotericin B resistance, it also makes 3 3Leishmania parasites vulnerable to biologically relevant stress. 3 4 3 IMPORTANCE 3 5 Sterols are essential membrane components in eukaryotes and sterol synthesis inhibitors 3 6 can have potent effects against pathogenic fungi and trypanosomatids. Understanding the roles of 3 7 sterols will facilitate the development of new drugs and counter drug resistance. Lathosterol 3 8 oxidase (aka sterol C5-desaturase) is required for the formation of C5-C6 double bond in the 3 9 sterol core structure in mammals, fungi, protozoans, plants and algae. Functions of this C5-C6 4 0 double bond are not well understood. In this study, we generated and characterized a lathosterol 4 1 oxidase-null mutant in Leishmania major. Our data suggest that the C5-C6 double bond is vital 4 2 for the structure and membrane-stabilizing functions of leishmanial sterols. In addition, our 4 3 results imply that while mutations in lathosterol oxidase can confer resistance to amphotericin B, 4 4an important antifungal and antiprotozoal agent, the alteration in sterol structure leads to 4 5 significant defects in stress response that could be exploited for drug development. 4 6 4

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“…Indeed, LPG purified from L. major has already been used in vaccine trials against cutaneous leishmaniasis in the mice model at the end of the 1980s. 111 Furthermore, Seeberger's team proposed the synthesis of L. donovani terminal tetrasaccharides linked to a phospholipid or to an influenza protein. A decrease in both lesion size and parasite burden was observed.…”

Section: View Article Onlinementioning

confidence: 99%

Leishmania cell wall as a potent target for antiparasitic drugs. A focus on the glycoconjugates

et al. 2015

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Although leishmaniasis has been studied for over a century, the fight against cutaneous, mucocutaneous and visceral forms of the disease remains a hot topic. This review refers to the parasitic cell wall and more particularly to the constitutive glycoconjugates. The structures of the main glycolipids and glycoproteins, which are species-dependent, are described. The focus is on the disturbance of the lipid membrane by existing drugs and possible new ones, in order to develop future therapeutic agents.

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Leishmania lipophosphoglycan: how to establish structure-activity relationships for this highly complex and multifunctional glycoconjugate?

Cited by 77 publications

References 64 publications

Leishmania donovaniInduces Autophagy in Human Blood–Derived Neutrophils

Leishmania donovaniInduces Autophagy in Human Blood–Derived Neutrophils

Lathosterol oxidase (sterol C5-desaturase) deletion confers resistance to amphotericin B and sensitivity to acidic stress inLeishmania major

Leishmania cell wall as a potent target for antiparasitic drugs. A focus on the glycoconjugates

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