9-O-Acetylated Sialoglycoproteins Are Important Immunomodulators in Indian Visceral Leishmaniasis

Ghoshal, Angana; Mukhopadhyay, Sumi; Saha, Bibhuti; Mandal, Chitra

doi:10.1128/cvi.00453-08

Cited by 12 publications

(9 citation statements)

References 48 publications

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“…Studies reported by our group initially demonstrated the presence of 9- O -AcSGPs and anti-9- O -AcSGP antibodies in VL [22], [29]. Earlier we have reported the presence of only two 9- O -AcSGPs of molecular weight 36 kDa and 144 kDa on PBMC N respectively [41]–[43].…”

Section: Discussionmentioning

confidence: 65%

“…amastigotes in splenic aspirates [28]. Blood was sent to the Indian Institute of Chemical Biology where it was processed immediately and the diagnosis validated by two in-house techniques in which the increased presence of linkage-specific 9- O -AcSGPs on erythrocytes was quantified by an erythrocyte binding assay [9] and anti-9- O -AcSGP antibodies in serum or plasma were detected by ELISA [18], [29]. The serum was also checked for the level of parasite-specific antibodies by ELISA with parasite lysates as coating antigen [22].…”

Section: Methodsmentioning

confidence: 99%

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Sialoglycosylation of RBC in Visceral Leishmaniasis Leads to Enhanced Oxidative Stress, Calpain-Induced Fragmentation of Spectrin and Hemolysis

et al. 2012

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Visceral leishmaniasis (VL) caused by the intracellular parasite Leishmania donovani accounts for an estimated 12 million cases of human infection. It is almost always associated with anemia, which severely complicates the disease course. However, the pathological processes leading to anemia in VL have thus far not been adequately characterized to date. In studying the glycosylation patterns of peripheral blood cells we found that the red blood cells (RBC) of VL patients (RBCVL) express eight 9-O-acetylated sialoglycoproteins (9-O-AcSGPs) that are not detected in the RBC of healthy individuals (RBCN). At the same time, the patients had high titers of anti-9-O-AcSGP IgG antibodies in their sera. These two conditions appear to be linked and related to the anemic state of the patients, as exposure of RBCVL but not RBCN to anti-9-O-AcSGPs antibodies purified from patient sera triggered a series of responses. These included calcium influx via the P/Q-type but not L-type channels, activation of calpain I, proteolysis of spectrin, enhanced oxidative stress, lipid peroxidation, externalization of phosphatidyl serine with enhanced erythrophagocytosis, enhanced membrane fragility and, finally, hemolysis. Taken together, this study suggests that the enhanced hemolysis is linked to an impairment of membrane integrity in RBCVL which is mediated by ligand-specific interaction of surface 9-O-AcSGPs. This affords a potential explanation for the structural and functional features of RBCVL which are involved in the hemolysis related to the anemia which develops in VL patients.

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Section: Discussionmentioning

confidence: 65%

Section: Methodsmentioning

confidence: 99%

Sialoglycosylation of RBC in Visceral Leishmaniasis Leads to Enhanced Oxidative Stress, Calpain-Induced Fragmentation of Spectrin and Hemolysis

et al. 2012

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“…The presence of different derivatives of SA on Leishmania donovani [9]–[13], different immune cells [14], [15] and RBC [16]–[18] of patients with visceral leishmaniasis (VL) (RBC VL ) and their role [19]–[26] have been demonstrated.…”

Section: Introductionmentioning

confidence: 99%

Glycosylation of Erythrocyte Spectrin and Its Modification in Visceral Leishmaniasis

et al. 2011

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Using a lectin, Achatinin-H, having preferential specificity for glycoproteins with terminal 9-O-acetyl sialic acid derivatives linked in α2-6 linkages to subterminal N-acetylgalactosamine, eight distinct disease-associated 9-O-acetylated sialoglycoproteins was purified from erythrocytes of visceral leishmaniaisis (VL) patients (RBCVL). Analyses of tryptic fragments by mass spectrometry led to the identification of two high-molecular weight 9-O-acetylated sialoglycoproteins as human erythrocytic α- and β-spectrin. Total spectrin purified from erythrocytes of VL patients (spectrinVL) was reactive with Achatinin-H. Interestingly, along with two high molecular weight bands corresponding to α- and β-spectrin another low molecular weight 60 kDa band was observed. Total spectrin was also purified from normal human erythrocytes (spectrinN) and insignificant binding with Achatinin-H was demonstrated. Additionally, this 60 kDa fragment was totally absent in spectrinN. Although the presence of both N- and O-glycosylations was found both in spectrinN and spectrinVL, enhanced sialylation was predominantly induced in spectrinVL. Sialic acids accounted for approximately 1.25 kDa mass of the 60 kDa polypeptide. The demonstration of a few identified sialylated tryptic fragments of α- and β-spectrinVL confirmed the presence of terminal sialic acids. Molecular modelling studies of spectrin suggest that a sugar moiety can fit into the potential glycosylation sites. Interestingly, highly sialylated spectrinVL showed decreased binding with spectrin-depleted inside-out membrane vesicles of normal erythrocytes compared to spectrinN suggesting functional abnormality. Taken together this is the first report of glycosylated eythrocytic spectrin in normal erythrocytes and its enhanced sialylation in RBCVL. The enhanced sialylation of this cytoskeleton protein is possibly related to the fragmentation of spectrinVL as evidenced by the presence of an additional 60 kDa fragment, absent in spectrinN which possibly affects the biology of RBCVL linked to both severe distortion of erythrocyte development and impairment of erythrocyte membrane integrity and may provide an explanation for their sensitivity to hemolysis and anemia in VL patients.

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“…The predominantly occurring forms are the O -acetylated SA (at C-7/8/9) forming O -acetylated sialoglycoconjugates [12–15, 49, 50]. It is usually present at the terminal end of glycoconjugates and affects different cell-mediated physiological processes.…”

Section: Sialic Acids and Parasitementioning

confidence: 99%

“…Sialic acids or N -acetylneuraminic acid (Neu5Ac or SA) are nine carbon sugar molecules comprising of more than 50 forms based on modifications of the amino and hydroxyl group [ 11 , 16 , 17 , 49 ]. The predominantly occurring forms are the O -acetylated SA (at C-7/8/9) forming O -acetylated sialoglycoconjugates [ 12 – 15 , 49 , 50 ]. It is usually present at the terminal end of glycoconjugates and affects different cell-mediated physiological processes.…”

Section: Sialic Acids and Parasitementioning

confidence: 99%

A Perspective on the Emergence of Sialic Acids as Potent Determinants AffectingLeishmaniaBiology

Ghoshal

Mandal

2011

Molecular Biology International

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Leishmaniasis caused by Leishmania sp. has a wide range of manifestations from cutaneous to the deadly visceral form. They shuttle between the invertebrate and vertebrate hosts as promastigotes and amastigotes having adaptations for subverting host immune responses. Parasite-specific glycoconjugates have served as important determinants influencing parasite recognition, internalization, differentiation, multiplication, and virulence. Despite the steady progress in the field of parasite glycobiology, sialobiology has been a less traversed domain of research in leishmaniasis. The present paper focuses on identification, characterization, and differential distribution of sialoglycotope having the linkage-specific 9-O-acetylated sialic acid in promastigotes of different Leishmania sp. causing different clinical ramifications emphasizing possible role of these sialoglycotopes in infectivity, virulence, nitric oxide resistance, and host modulation in Leishmania spp. asserting them to be important molecules influencing parasite biology.

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9-O-Acetylated Sialoglycoproteins Are Important Immunomodulators in Indian Visceral Leishmaniasis

Abstract: Overexpression of disease-associated 9-O-acetylated sialoglycoproteins (9-O-AcSGPs) on peripheral blood mononuclear cells (PBMC) of visceral leishmaniasis (VL) patients (PBMC

Cited by 12 publications

References 48 publications

Sialoglycosylation of RBC in Visceral Leishmaniasis Leads to Enhanced Oxidative Stress, Calpain-Induced Fragmentation of Spectrin and Hemolysis

Sialoglycosylation of RBC in Visceral Leishmaniasis Leads to Enhanced Oxidative Stress, Calpain-Induced Fragmentation of Spectrin and Hemolysis

Glycosylation of Erythrocyte Spectrin and Its Modification in Visceral Leishmaniasis

A Perspective on the Emergence of Sialic Acids as Potent Determinants AffectingLeishmaniaBiology

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