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• W2460440812 abstract "Urinary tract infections caused by uropathogenic Escherichia coli (UPEC) pathovars belong to the most frequent infections in humans. In men, pathogens can also spread to the genital tract via the continuous ductal system, eliciting bacterial prostatitis and/or epididymo-orchitis. Antibiotic treatment usually clears pathogens in acute epididymitis; however, the fertility of patients can be permanently impaired. Because a premature acrosome reaction was observed in an UPEC epididymitis mouse model, and sialidases on the sperm surface are considered to be activated via proteases of the acrosome, we aimed to investigate whether alterations of the sialome of epididymal spermatozoa and surrounding epithelial cells occur during UPEC infection. In UPEC-elicited acute epididymitis in mice, a substantial loss of N-acetylneuraminic acid residues was detected in epididymal spermatozoa and epithelial cells using combined laser microdissection/HPLC-ESI-MS analysis. In support, a substantial reduction of sialic acid residues bound to the surface of spermatozoa was documented in men with a recent history of E. coli-associated epididymitis. In vitro, such an UPEC induced N-acetylneuraminic acid release from human spermatozoa was effectively counteracted by a sialidase inhibitor. These findings strongly suggest a substantial remodeling of the glycocalyx of spermatozoa and epididymal epithelial cells by endogenous sialidases after a premature acrosome reaction during acute epididymitis. Urinary tract infections caused by uropathogenic Escherichia coli (UPEC) pathovars belong to the most frequent infections in humans. In men, pathogens can also spread to the genital tract via the continuous ductal system, eliciting bacterial prostatitis and/or epididymo-orchitis. Antibiotic treatment usually clears pathogens in acute epididymitis; however, the fertility of patients can be permanently impaired. Because a premature acrosome reaction was observed in an UPEC epididymitis mouse model, and sialidases on the sperm surface are considered to be activated via proteases of the acrosome, we aimed to investigate whether alterations of the sialome of epididymal spermatozoa and surrounding epithelial cells occur during UPEC infection. In UPEC-elicited acute epididymitis in mice, a substantial loss of N-acetylneuraminic acid residues was detected in epididymal spermatozoa and epithelial cells using combined laser microdissection/HPLC-ESI-MS analysis. In support, a substantial reduction of sialic acid residues bound to the surface of spermatozoa was documented in men with a recent history of E. coli-associated epididymitis. In vitro, such an UPEC induced N-acetylneuraminic acid release from human spermatozoa was effectively counteracted by a sialidase inhibitor. These findings strongly suggest a substantial remodeling of the glycocalyx of spermatozoa and epididymal epithelial cells by endogenous sialidases after a premature acrosome reaction during acute epididymitis. Acute epididymitis or a combined epididymo-orchitis in men represents a relevant entity in urological practice. Epididymitis is usually the result of an infection starting in the urethra that ultimately ascends to the epididymis and testis (1Berger R.E. Kessler D. Holmes K.K. Etiology and manifestations of epididymitis in young men: correlations with sexual orientation.J. Infect. Dis. 1987; 155: 1341-1343Crossref PubMed Scopus (43) Google Scholar). Uropathogenic Escherichia coli (UPEC) 4The abbreviations used are:UPECuropathogenic Escherichia coliNeu5AcN-acetylneuraminic acidNeu5GcN-glycolylneuraminic acidsiglecsialic acid-binding immunoglobulin-type lectinSNASambucus nigraLCMDlaser capture microdissectionKDO3-deoxy-d-manno-oct-2-ulosonic acidDANAN-acetyl-2,3-dehydro-2-deoxyneuraminic acidKDN2-keto-3-deoxynononic acidHTFhuman tubal fluidPSAPisum sativumDMB4,5-methylene dioxybenzene. belongs to the most common microbes associated with the condition, particularly in men over the age of 35 (2Pilatz A. Hossain H. Kaiser R. Mankertz A. Schüttler C.G. Domann E. Schuppe H.C. Chakraborty T. Weidner W. Wagenlehner F. Acute epididymitis revisited: impact of molecular diagnostics on etiology and contemporary guideline recommendations.Eur. Urol. 2015; 68: 428-435Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar). Although antibiotic treatment is usually successful in clearing the pathogens, about 40% of patients with UPEC epididymitis are subsequently diagnosed with impaired semen parameters causing sub- or infertility (3Rusz A. Pilatz A. Wagenlehner F. Linn T. Diemer T. Schuppe H.C. Lohmeyer J. Hossain H. Weidner W. Influence of urogenital infections and inflammation on semen quality and male fertility.World J. Urol. 2012; 30: 23-30Crossref PubMed Scopus (138) Google Scholar). Biopsies from patients with a past history of epididymitis showed drastic structural alterations such as epithelial cell damage, fibrosis, and absence of spermatozoa further distally (4Stammler A. Hau T. Bhushan S. Meinhardt A. Jonigk D. Lippmann T. Pilatz A. Schneider-Hüther I. Middendorff R. Epididymitis: ascending infection restricted by segmental boundaries.Hum. Reprod. 2015; 30: 1557-1565Crossref PubMed Scopus (21) Google Scholar). Rodent UPEC epididymitis models could replicate the damage seen in men and pointed to a role of the UPEC virulence factor α-hemolysin in an extensive premature acrosome reaction occurring in the epididymal duct, implying the untimely release of acrosomal enzymes in infected epididymis prior to reaching the female reproductive tract (5Lang T. Dechant M. Sanchez V. Wistuba J. Boiani M. Pilatz A. Stammler A. Middendorff R. Schuler G. Bhushan S. Tchatalbachev S. Wübbeling F. Burger M. Chakraborty T. Mallidis C. Meinhardt A. Structural and functional integrity of spermatozoa is compromised as a consequence of acute uropathogenic E. coli-associated epididymitis.Biol. Reprod. 2013; 89: 59Crossref PubMed Scopus (32) Google Scholar). uropathogenic Escherichia coli N-acetylneuraminic acid N-glycolylneuraminic acid sialic acid-binding immunoglobulin-type lectin Sambucus nigra laser capture microdissection 3-deoxy-d-manno-oct-2-ulosonic acid N-acetyl-2,3-dehydro-2-deoxyneuraminic acid 2-keto-3-deoxynononic acid human tubal fluid Pisum sativum 4,5-methylene dioxybenzene. The acrosome contains various digestive enzymes, among them proteases as well as various glycosidases, such as hyaluronidases and sialidases, that are essential for penetration of the zona pellucida and glycan remodeling of the gametes as a prerequisite for spermatozoa-oocyte binding (6Tambe A.S. Kaore S.B. Sawane M.V. Gosavi G.B. Acrosome intactness and seminal hyaluronidase activity: relationship with conventional seminal parameters.Indian J. Med. Sci. 2001; 55: 125-132PubMed Google Scholar, 7Talbot P. Franklin L.E. The release of hyaluronidase from guinea-pig spermatozoa during the course of the normal acrosome reaction in vitro.J. Reprod. Fertil. 1974; 39: 429-432Crossref PubMed Google Scholar, 8Srivastava P.N. Zaneveld L.J. Williams W.L. Mammalian sperm acrosomal neuraminidases.Biochem. Biophys. Res. Commun. 1970; 39: 575-582Crossref PubMed Scopus (31) Google Scholar, 9Pang P.C. Chiu P.C. Lee C.L. Chang L.Y. Panico M. Morris H.R. Haslam S.M. Khoo K.H. Clark G.F. Yeung W.S. Dell A. Human sperm binding is mediated by the sialyl-Lewisx oligosaccharide on the zona pellucida.Science. 2011; 333: 1761-1764Crossref PubMed Scopus (250) Google Scholar, 10Ma F. Wu D. Deng L. Secrest P. Zhao J. Varki N. Lindheim S. Gagneux P. Sialidases on mammalian sperm mediate deciduous sialylation during capacitation.J. Biol. Chem. 2012; 287: 38073-38079Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar, 11Tecle E. Gagneux P. Sugar-coated sperm: Unraveling the functions of the mammalian sperm glycocalyx.Mol. Reprod. Dev. 2015; 82: 635-650Crossref PubMed Scopus (94) Google Scholar). Recent data revealed that, during capacitation, a biochemical process in the female reproductive tract in which spermatozoa accomplish full fertilizing “capacity,” two sialidases (the neuraminidases NEU1 and NEU3) are shed from the surface of spermatozoa, likely by the activity of proteases, which could be efficiently counteracted by protease inhibitors (10Ma F. Wu D. Deng L. Secrest P. Zhao J. Varki N. Lindheim S. Gagneux P. Sialidases on mammalian sperm mediate deciduous sialylation during capacitation.J. Biol. Chem. 2012; 287: 38073-38079Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar). This process led to the release of sialic acid residues from the surface of spermatozoa (10Ma F. Wu D. Deng L. Secrest P. Zhao J. Varki N. Lindheim S. Gagneux P. Sialidases on mammalian sperm mediate deciduous sialylation during capacitation.J. Biol. Chem. 2012; 287: 38073-38079Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar). The acrosome appears to contain a further reservoir of sialidases, which are released physiologically during the acrosome reaction prior to fertilization (8Srivastava P.N. Zaneveld L.J. Williams W.L. Mammalian sperm acrosomal neuraminidases.Biochem. Biophys. Res. Commun. 1970; 39: 575-582Crossref PubMed Scopus (31) Google Scholar, 12Srivastava P.N. Abou-Issa H. Purification and properties of rabbit spermatozoal acrosomal neuraminidase.Biochem. J. 1977; 161: 193-200Crossref PubMed Scopus (20) Google Scholar). Because NEU1 and NEU3 together are able to desialylate several different glycoconjugates (α2,3-, α2,6-, and α2,8-sialylated), a significant restructuring of the glycocalyx can be expected (13Sajo M. Sugiyama H. Yamamoto H. Tanii T. Matsuki N. Ikegaya Y. Koyama R. Neuraminidase-dependent degradation of polysialic acid is required for the lamination of newly generated neurons.PLoS ONE. 2016; 11: e0146398Crossref PubMed Scopus (12) Google Scholar, 14Takahashi K. Mitoma J. Hosono M. Shiozaki K. Sato C. Yamaguchi K. Kitajima K. Higashi H. Nitta K. Shima H. Miyagi T. Sialidase NEU4 hydrolyzes polysialic acids of neural cell adhesion molecules and negatively regulates neurite formation by hippocampal neurons.J. Biol. Chem. 2012; 287: 14816-14826Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 15Cairo C.W. Inhibitors of the human neuraminidase enzymes.MedChemComm. 2014; 5: 1067-1075Crossref Google Scholar). Sialic acids are acidic nine-carbon backbone α-keto sugars and represent one of the most important molecules of life (16Angata T. Varki A. Chemical diversity in the sialic acids and related α-keto acids: an evolutionary perspective.Chem. Rev. 2002; 102: 439-469Crossref PubMed Scopus (1038) Google Scholar, 17Varki A. Schauer R. Essentials of Glycobiology.in: Varki A. Cummings R.D. Esko J.D. Freeze H.H. Freeze P. Bertozzi C.R. Hart G.W. Etzler M.E. Cold Spring Harbor Laboratory Press, New York2009: 199-218Google Scholar). N-acetylneuraminic acid (Neu5Ac) as well as N-glycolylneuraminic acid (Neu5Gc) are the most abundant species in mammals. These sugar residues are commonly linked to the outermost position of the largest share of glycoproteins, which places them in an ideal position for their indispensable role in a diverse range of cellular processes such as intercellular adhesion and communication. However, sialic acids also play an important role during infection of many viruses, fungi, as well as bacteria (18Schauer R. Sialic acids: fascinating sugars in higher animals and man.Zoology. 2004; 107: 49-64Crossref PubMed Scopus (349) Google Scholar, 19Schauer R. Sialic acids as regulators of molecular and cellular interactions.Curr. Opin. Struct. Biol. 2009; 19: 507-514Crossref PubMed Scopus (507) Google Scholar, 20Varki A. Gagneux P. Multifarious roles of sialic acids in immunity.Ann. N.Y. Acad. Sci. 2012; 1253: 16-36Crossref PubMed Scopus (403) Google Scholar). For instance, during invasion, pathogenic bacteria use sialic acid residues on the surface of epithelial cells for the initiation of infection by mediating bacterial adherence. On the other hand, detachment of sialic acid residues from host cells represents a further powerful means of bacteria to manipulate the immune response, e.g. by influencing the recognition of specific sugar moieties by sialic acid-binding immunoglobulin-type lectins (siglecs) on immune cells (21Lewis A.L. Lewis W.G. Host sialoglycans and bacterial sialidases: a mucosal perspective.Cell Microbiol. 2012; 14: 1174-1182Crossref PubMed Scopus (132) Google Scholar, 22Macauley M.S. Crocker P.R. Paulson J.C. Siglec-mediated regulation of immune cell function in disease.Nat. Rev. Immunol. 2014; 14: 653-666Crossref PubMed Scopus (625) Google Scholar). For example, several pathogenic bacteria secrete sialidases as a virulence factor, leading to sepsis as a consequence of an uncontrolled stimulation of the immune system. In this regard, bacterial sialidase inhibitors can efficiently counteract the dramatic progression of the disease in a mouse model, demonstrating their clinical potential during infection (23Paulson J.C. Kawasaki N. Sialidase inhibitors DAMPen sepsis.Nat. Biotechnol. 2011; 29: 406-407Crossref PubMed Scopus (23) Google Scholar, 24Chen G.Y. Chen X. King S. Cavassani K.A. Cheng J. Zheng X. Cao H. Yu H. Qu J. Fang D. Wu W. Bai X.F. Liu J.Q. Woodiga S.A. Chen C. et al.Amelioration of sepsis by inhibiting sialidase-mediated disruption of the CD24-SiglecG interaction.Nat. Biotechnol. 2011; 29: 428-435Crossref PubMed Scopus (130) Google Scholar). In consideration that UPEC infection of the epididymis results in a premature release of acrosomal content (5Lang T. Dechant M. Sanchez V. Wistuba J. Boiani M. Pilatz A. Stammler A. Middendorff R. Schuler G. Bhushan S. Tchatalbachev S. Wübbeling F. Burger M. Chakraborty T. Mallidis C. Meinhardt A. Structural and functional integrity of spermatozoa is compromised as a consequence of acute uropathogenic E. coli-associated epididymitis.Biol. Reprod. 2013; 89: 59Crossref PubMed Scopus (32) Google Scholar), we aimed to investigate whether this affects the sialome of spermatozoa and surrounding epididymal epithelial cells using a mouse epididymitis model and ejaculates of men with a recent history of the disease. To elucidate whether the UPEC-induced acrosome reaction leads to an activation of endogenous sialidases, initiating a subsequent desialylation of spermatozoa, an established epididymitis mouse model was utilized (25Lang T. Hudemann C. Tchatalbachev S. Stammler A. Michel V. Aslani F. Bhushan S. Chakraborty T. Renz H. Meinhardt A. Uropathogenic Escherichia coli modulates innate immunity to suppress Th1-mediated inflammatory responses during infectious epididymitis.Infect. Immun. 2014; 82: 1104-1111Crossref PubMed Scopus (16) Google Scholar). Histopathology in Masson-Goldner-stained epididymis demonstrated fibrotic remodeling and interstitial leukocytic infiltration as the most obvious consequences 3 days post-UPEC infection, as shown previously (Fig. 1A) (4Stammler A. Hau T. Bhushan S. Meinhardt A. Jonigk D. Lippmann T. Pilatz A. Schneider-Hüther I. Middendorff R. Epididymitis: ascending infection restricted by segmental boundaries.Hum. Reprod. 2015; 30: 1557-1565Crossref PubMed Scopus (21) Google Scholar, 26Michel V. Duan Y. Stoschek E. Bhushan S. Middendorff R. Young J.M. Loveland K.A. Kretser D.M. Hedger M.P. Meinhardt A. Uropathogenic Escherichia coli cause fibrotic remodelling of the epididymis.J. Pathol. 2016; Crossref PubMed Scopus (29) Google Scholar). Acrosomal staining with FITC-labeled peanut agglutinin lectin indicated a premature acrosome reaction in the majority of spermatozoa in the lumen of the epididymis following UPEC infection (Fig. 1B), similar to previous findings (5Lang T. Dechant M. Sanchez V. Wistuba J. Boiani M. Pilatz A. Stammler A. Middendorff R. Schuler G. Bhushan S. Tchatalbachev S. Wübbeling F. Burger M. Chakraborty T. Mallidis C. Meinhardt A. Structural and functional integrity of spermatozoa is compromised as a consequence of acute uropathogenic E. coli-associated epididymitis.Biol. Reprod. 2013; 89: 59Crossref PubMed Scopus (32) Google Scholar). In contrast, the acrosome was visible in most spermatozoa in untreated and sham controls. To gain a first insight into the sialylation status, sialic acid residues were visualized on epididymal sections using FITC-conjugated SNA lectin (Fig. 2). SNA prevalently binds α2,6-linked sialic acid residues; however, α2,3-linked sialic acid residues will also be bound by this lectin but to a lesser degree. Fluorescence microscopy revealed diffusely distributed and weaker SNA labeling in spermatozoa of UPEC-infected mice, whereas in controls, prominent staining of sialic acid residues was evident in the acrosome and sperm tail (Fig. 2). The reduced SNA staining in UPEC-treated mice suggested that Neu5Ac residues were cleaved during infection. Because qualitative as well as quantitative lectin analyses of sialic acids are often misleading, and SNA lectin visualize only a proportion of all sialic acid residues on glycoconjugates (27Galuska S.P. Sialobiology: Structure, Biosynthesis, and Function.in: Tiralongo J. Martinez-Duncker I. Betham eBooks, 2013: 448-475Google Scholar), a recently developed combination of LCMD and DMB-HPLC-ESI-MS analyses was applied (Fig. 3) (28Bartel J. Feuerstacke C. Galuska C.E. Weinhold B. Gerardy-Schahn R. Geyer R. Münster-Kühnel A. Middendorff R. Galuska S.P. Laser microdissection of paraffin embedded tissue as a tool to estimate the sialylation status of selected cell populations.Anal. Chem. 2014; 86: 2326-2331Crossref PubMed Scopus (4) Google Scholar). Starting from murine paraffin-embedded tissue samples, epididymal spermatozoa were isolated via LCMD after nuclear staining using Mayer's hematoxylin (Fig. 3, A and B). Thereafter, sialic acids were released under acidic conditions, fluorescently labeled, and subjected to a HPLC-ESI-MS system. The obtained chromatograms showed smaller peaks of DMB-labeled Neu5Ac in infected material (Fig. 3C). The respective DMB-Neu5Ac mass at m/z 448 [M + Na]+ in the ESI-MS spectrum verified the presence of DMB-Neu5Ac during the corresponding retention time of an DMB-Neu5Ac standard (Fig. 3C). Calculation of corresponding peak areas demonstrated a significant reduction of Neu5Ac (∼19%) in spermatozoa in UPEC epididymitis (Fig. 3D). Although, in UPEC-treated samples, a peak for DMB-Neu5Gc was apparent in the HPLC chromatogram, in the sham control, hardly any signal was detectable. However, no mass corresponding to DMB-Neu5Gc was obtained by ESI-MS in untreated as well as infected mice (data not shown). Because of the fact that DMB reacts with all α-keto acids, possible contamination in infected mice by α-keto acids originating from the pathogen was examined by separate analysis of bacteria only. In UPEC, the presence of DMB-labeled KDO, a well known bacterial α-keto acid (16Angata T. Varki A. Chemical diversity in the sialic acids and related α-keto acids: an evolutionary perspective.Chem. Rev. 2002; 102: 439-469Crossref PubMed Scopus (1038) Google Scholar), was measurable as a prominent peak at the retention time of DMB-Neu5Gc (Fig. 4A). In addition, KDO-related monoisotopic pseudomolecular masses of DMB-KDO at m/z 337 ([M + H]+ − H2O), 355 ([M + H]+), and 377 ([M + Na]+) were monitored in the ESI-MS spectrum at this particular time (Fig. 4B). To verify this finding, KDO was applied to the DMB-HPLC analysis, demonstrating that Neu5Gc and KDO show overlapping peak areas (Fig. 4C). Thus, in UPEC-treated mice, bacterial KDO was obviously recorded at the retention time of DMB-Neu5Gc. Release of sialic acids from the spermatozoa to the luminal fluid following UPEC infection could be enzymatically mediated by soluble sialidases, a hypothesis supported by an observation of Gagneux and co-workers (10Ma F. Wu D. Deng L. Secrest P. Zhao J. Varki N. Lindheim S. Gagneux P. Sialidases on mammalian sperm mediate deciduous sialylation during capacitation.J. Biol. Chem. 2012; 287: 38073-38079Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar), who described that the sialidases NEU1 and NEU3 are released from the cell surface of spermatozoa after proteolytic activation. Consequently, soluble neuraminidases would be also able to reach the cell surface of surrounding cells. To test this hypothesis, the sialylation status of epididymal epithelial cells (whose apical surface borders on the luminal fluid) was analyzed using the abovementioned combined LCMD/DMB-HPLC-ESI-MS strategy (Fig. 5). In support, epididymal epithelial cells showed a reduction of sialic acid residues (∼49%) 3 days post-infection with UPEC (Fig. 5, C and D). Reduction of Neu5Ac from epithelial cells is substantially stronger in comparison with spermatozoa (Fig. 3). Thus, the obtained results demonstrate that the sialylation status of epididymal spermatozoa in the lumen as well as that of the lumen lining epithelial cells decreases in the epididymis after bacterial infection. To investigate whether UPEC can also induce hyposialylation in human spermatozoa, motile spermatozoa of healthy donors collected after swim-up were subsequently infected with UPEC (Fig. 6). DMB-HPLC analysis pointed to a reduction of Neu5Ac to approximately half the amount measured in an untreated control (Fig. 6A). Correspondingly, PSA-FITC lectin staining detected a substantially higher number of acrosomally reacted spermatozoa compared with controls (Fig. 6B). To examine whether the investigated hyposialylation of spermatozoa is mostly the consequence of a general loss of glycoconjugates, e.g. because of the degradation of the glycoprotein backbone or the activation of neuraminidases during the acrosome reaction, motile human spermatozoa were treated with UPEC in the presence of the sialidase inhibitor DANA (Fig. 6A). Here, co-incubation of DANA with UPEC completely prevented hyposialylation of human spermatozoa (Fig. 6A). Bacterial sialidase activity could be excluded by in silico analysis of the UPEC genome. Consequently, the decreased sialylation status in infected spermatozoa is likely based on the enzymatic activity of released sialidases. In addition, semen samples of patients suffering from E. coli epididymitis were included in our study. For this purpose, spermatozoa were obtained by swim-up from ejaculates of men 14 days after diagnosis and treatment of E. coli-based unilateral epididymitis. The analyzed samples showed malformation (sperm head, acrosome visualized by PSA-FITC staining, Fig. 7A) and much lower levels of Neu5Ac (∼75% reduction) compared with healthy control spermatozoa (Fig. 7B). Thus, in agreement with the determined loss of sialic acid residues in the epididymitis mouse model as well as in the in vitro experiments, spermatozoa of epididymitis patients are hyposialylated. Glycans play an essential role in fertilization, particularly in mediating the species-specific interaction between spermatozoa and the zona pellucida of the egg (9Pang P.C. Chiu P.C. Lee C.L. Chang L.Y. Panico M. Morris H.R. Haslam S.M. Khoo K.H. Clark G.F. Yeung W.S. Dell A. Human sperm binding is mediated by the sialyl-Lewisx oligosaccharide on the zona pellucida.Science. 2011; 333: 1761-1764Crossref PubMed Scopus (250) Google Scholar, 11Tecle E. Gagneux P. Sugar-coated sperm: Unraveling the functions of the mammalian sperm glycocalyx.Mol. Reprod. Dev. 2015; 82: 635-650Crossref PubMed Scopus (94) Google Scholar). Binding of spermatozoa to the zona pellucida is thereby strongly induced by terminal Neu5Ac residues of sialyl-LewisX oligosaccharides on the surface of the zona pellucida. In addition, successful interaction of both gametes requires previous desialylation of the spermatozoal surface (10Ma F. Wu D. Deng L. Secrest P. Zhao J. Varki N. Lindheim S. Gagneux P. Sialidases on mammalian sperm mediate deciduous sialylation during capacitation.J. Biol. Chem. 2012; 287: 38073-38079Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar) (Fig. 8). For this purpose, spermatozoa are equipped with sialidases (8Srivastava P.N. Zaneveld L.J. Williams W.L. Mammalian sperm acrosomal neuraminidases.Biochem. Biophys. Res. Commun. 1970; 39: 575-582Crossref PubMed Scopus (31) Google Scholar, 10Ma F. Wu D. Deng L. Secrest P. Zhao J. Varki N. Lindheim S. Gagneux P. Sialidases on mammalian sperm mediate deciduous sialylation during capacitation.J. Biol. Chem. 2012; 287: 38073-38079Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar, 12Srivastava P.N. Abou-Issa H. Purification and properties of rabbit spermatozoal acrosomal neuraminidase.Biochem. J. 1977; 161: 193-200Crossref PubMed Scopus (20) Google Scholar, 29Srivastava P.N. Kumar V.M. Arbtan K.D. Neuraminidase induces capacitation and acrosome reaction in mammalian spermatozoa.J. Exp. Zool. 1988; 245: 106-110Crossref PubMed Scopus (10) Google Scholar). Under normal conditions, neuraminidases are only activated in the female reproductive tract as a consequence of capacitation and/or acrosome reaction (8Srivastava P.N. Zaneveld L.J. Williams W.L. Mammalian sperm acrosomal neuraminidases.Biochem. Biophys. Res. Commun. 1970; 39: 575-582Crossref PubMed Scopus (31) Google Scholar, 10Ma F. Wu D. Deng L. Secrest P. Zhao J. Varki N. Lindheim S. Gagneux P. Sialidases on mammalian sperm mediate deciduous sialylation during capacitation.J. Biol. Chem. 2012; 287: 38073-38079Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar, 12Srivastava P.N. Abou-Issa H. Purification and properties of rabbit spermatozoal acrosomal neuraminidase.Biochem. J. 1977; 161: 193-200Crossref PubMed Scopus (20) Google Scholar, 29Srivastava P.N. Kumar V.M. Arbtan K.D. Neuraminidase induces capacitation and acrosome reaction in mammalian spermatozoa.J. Exp. Zool. 1988; 245: 106-110Crossref PubMed Scopus (10) Google Scholar). Premature release of neuraminidases prior ejaculation is usually avoided, as untimely desialylation could result in elimination of spermatozoa by phagocytic cells (30Toshimori K. Araki S. Oura C. Eddy E.M. Loss of sperm surface sialic acid induces phagocytosis: an assay with a monoclonal antibody T21, which recognizes a 54K sialoglycoprotein.Arch. Androl. 1991; 27: 79-86Crossref PubMed Scopus (38) Google Scholar). Under pathophysiological conditions such as bacterial epididymitis, considerable premature exocytosis of the acrosome has been observed in vivo and in vitro, which contributes substantially to the loss of fertilizing capacity, as shown by subsequent in vitro fertilization experiments in mice (5Lang T. Dechant M. Sanchez V. Wistuba J. Boiani M. Pilatz A. Stammler A. Middendorff R. Schuler G. Bhushan S. Tchatalbachev S. Wübbeling F. Burger M. Chakraborty T. Mallidis C. Meinhardt A. Structural and functional integrity of spermatozoa is compromised as a consequence of acute uropathogenic E. coli-associated epididymitis.Biol. Reprod. 2013; 89: 59Crossref PubMed Scopus (32) Google Scholar). This prompted us to examine whether an undue acrosome reaction could affect the sialome of epididymal spermatozoa and surrounding epithelial cells by applying an established acute mouse bacterial infectious epididymitis model and ejaculates of men with a recent history of the disease. Both in murine epididymitis as well as in in vitro-treated human spermatozoa, UPEC stimulates a premature acrosome reaction, leading to a significant desialylation of spermatozoa as well as adjacent cells (illustrated in Fig. 8). Surprisingly, the investigated desialylation was much more pronounced in epididymitis patients. The desialylation could be efficiently blocked with a neuraminidase inhibitor in vitro, indicating that the loss of sialic acid residues is particularly a consequence of endogenous neuraminidases (Fig. 8). A limitation in the analysis of human samples in this study is the relatively small number of semen samples from patients/controls suitable for glycoanalysis because of the need to clean ejaculates by the swim-up method. Because semen samples of patients with acute epididymitis are usually characterized by a largely reduced semen quality and leukocytospermia, the swim-up technique was employed to select the viable and motile sperm, thereby removing contaminating non-sperm cells (e.g. leukocytes) to avoid bias between patient and control samples. Because sialic acids have multifactorial roles in the host response to infection, the massive release of sialic acid residues from the cell surface of epithelial cells and spermatozoa may contribute to the observed tissue damage in epididymitis (Fig. 8). This view is supported by the fact that bacterial lipopolysaccharide triggers complement activation and that hyposialylation promotes the perforation of host cell membranes by the membrane attack complex by counteracting a protective mechanism conveyed by complement factor H (31Pangburn M.K. Müller-Eberhard H.J. Complement C3 convertase: cell surface restriction of β1H control and generation of restriction on neuraminidase-treated cells.Proc. Natl. Acad. Sci. U.S.A. 1978; 75: 2416-2420Crossref PubMed Scopus (264) Google Scholar). Complement factor H exhibits sialic acid-specific binding domains that are necessary for efficient cell surface binding (32Blaum B.S. Hannan J.P. Herbert A.P. Kavanagh D. Uhrín D. Stehle T. Structural basis for sialic acid-mediated self-recognition by complement factor H.Nat. Chem. Biol. 2015; 11: 77-82Crossref PubMed Scopus (192) Google Scholar). Factor H on cell membranes is essential to remove activated complement factor 3b from cellular surfaces to prevent perforation of host cell membranes and limit tissue damage. As shown recently, complement factor H is an important component of seminal plasma, as it protects spermatozoa against such a complement attack in the female reproductive tract (33Sakaue T. Takeuchi K. Maeda T. Yamamoto Y. Nishi K. Ohkubo I. Factor H in porcine seminal plasma protects sperm against complement attack in genital tracts.J. Biol." @default.
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