Efficacy of Antigonococcal CMP-Nonulosonate Therapeutics Require Cathelicidins

Overview

Journal J Infect Dis

Publisher Oxford University Press

Specialty Infectious Diseases

Date 2020 Jul 22

PMID 32692363

Citations 11

Authors

Sunita Gulati

Ian C Schoenhofen

Theresa Lindhout-Djukic

Lisa A Lewis

Iesha Y Moustafa

Sudeshna Saha

Bo Zheng

Nancy Nowak

Peter A Rice

Ajit Varki

Sanjay Ram

Affiliations

Soon will be listed here.

Abstract

Novel therapies to counteract multidrug-resistant gonorrhea are urgently needed. A unique gonococcal immune evasion strategy involves capping of lipooligosaccharide (LOS) with sialic acid by gonococcal sialyltransferase (Lst), utilizing host-derived CMP-sialic acid (CMP-Neu5Ac in humans). LOS sialylation renders gonococci resistant to complement and cationic peptides, and down-regulates the inflammatory response by engaging siglecs. CMP-sialic acid analogs (CMP-nonulosonates [CMP-NulOs]) such as CMP-Leg5,7Ac2 and CMP-Kdn are also utilized by Lst. Incorporation of these NulO analogs into LOS maintains gonococci susceptible to complement. Intravaginal administration of CMP-Kdn or CMP-Leg5,7Ac2 attenuates gonococcal colonization of mouse vaginas. Here, we identify a key mechanism of action for the efficacy of CMP-NulOs. Surprisingly, CMP-NulOs remained effective in complement C1q-/- and C3-/- mice. LOS Neu5Ac, but not Leg5,7Ac2 or Kdn, conferred resistance to the cathelicidins LL-37 (human) and mouse cathelicidin-related antimicrobial peptide in vitro. CMP-NulOs were ineffective in Camp-/- mice, revealing that cathelicidins largely mediate the efficacy of therapeutic CMP-NulOs.

Citing Articles

Broad-Spectrum Legionaminic Acid-Specific Antibodies in Pooled Human IgGs Revealed by Glycan Microarrays with Chemoenzymatically Synthesized Nonulosonosides.

Kooner A, Yu H, Leviatan Ben-Arye S, Padler-Karavani V, Chen X Molecules. 2024; 29(16).

PMID: 39203058 PMC: 11356810. DOI: 10.3390/molecules29163980.

Addressing Sexually Transmitted Infections Due to in the Present and Future.

Colon Perez J, Villarino Fernandez R, Dominguez Lago A, Trevino Castellano M, Perez Del Molino Bernal M, Sanchez Poza S Microorganisms. 2024; 12(5).

PMID: 38792714 PMC: 11124187. DOI: 10.3390/microorganisms12050884.

scavenges host sialic acid for Siglec-mediated, complement-independent suppression of neutrophil activation.

Cardenas A, Thomas K, Broden M, Ferraro N, Pires M, John C mBio. 2024; 15(5):e0011924.

PMID: 38587424 PMC: 11078009. DOI: 10.1128/mbio.00119-24.

scavenges host sialic acid for Siglec-mediated, complement-independent suppression of neutrophil activation.

Cardenas A, Thomas K, Broden M, Ferraro N, John C, Pires M bioRxiv. 2024; .

PMID: 38293026 PMC: 10827150. DOI: 10.1101/2024.01.17.576097.

Gardnerella Vaginolysin Potentiates Glycan Molecular Mimicry by Neisseria gonorrhoeae.

Morrill S, Saha S, Varki A, Lewis W, Ram S, Lewis A J Infect Dis. 2023; 228(11):1610-1620.

PMID: 37722688 PMC: 10681867. DOI: 10.1093/infdis/jiad391.

References

Schneider H, Cross A, Kuschner R, Taylor D, Sadoff J, Boslego J . Experimental human gonococcal urethritis: 250 Neisseria gonorrhoeae MS11mkC are infective. J Infect Dis. 1995; 172(1):180-5. DOI: 10.1093/infdis/172.1.180. View

Rowley J, Vander Hoorn S, Korenromp E, Low N, Unemo M, Abu-Raddad L . Chlamydia, gonorrhoea, trichomoniasis and syphilis: global prevalence and incidence estimates, 2016. Bull World Health Organ. 2019; 97(8):548-562P. PMC: 6653813. DOI: 10.2471/BLT.18.228486. View

Gulati S, Rice P, Ram S . Complement-Dependent Serum Bactericidal Assays for Neisseria gonorrhoeae. Methods Mol Biol. 2019; 1997:267-280. DOI: 10.1007/978-1-4939-9496-0_16. View

van Harten R, van Woudenbergh E, van Dijk A, Haagsman H . Cathelicidins: Immunomodulatory Antimicrobials. Vaccines (Basel). 2018; 6(3). PMC: 6161271. DOI: 10.3390/vaccines6030063. View

Matthies S, Stallforth P, Seeberger P . Total synthesis of legionaminic acid as basis for serological studies. J Am Chem Soc. 2015; 137(8):2848-51. DOI: 10.1021/jacs.5b00455. View

Greiner L, Edwards J, Shao J, Rabinak C, Entz D, Apicella M . Biofilm Formation by Neisseria gonorrhoeae. Infect Immun. 2005; 73(4):1964-70. PMC: 1087446. DOI: 10.1128/IAI.73.4.1964-1970.2005. View

Wu H, Jerse A . Alpha-2,3-sialyltransferase enhances Neisseria gonorrhoeae survival during experimental murine genital tract infection. Infect Immun. 2006; 74(7):4094-103. PMC: 1489707. DOI: 10.1128/IAI.00433-06. View

Warner D, Shafer W, Jerse A . Clinically relevant mutations that cause derepression of the Neisseria gonorrhoeae MtrC-MtrD-MtrE Efflux pump system confer different levels of antimicrobial resistance and in vivo fitness. Mol Microbiol. 2008; 70(2):462-78. PMC: 2602950. DOI: 10.1111/j.1365-2958.2008.06424.x. View

Lewis D . New treatment options for Neisseria gonorrhoeae in the era of emerging antimicrobial resistance. Sex Health. 2019; 16(5):449-456. DOI: 10.1071/SH19034. View

10.

Unemo M, Seifert H, Hook 3rd E, Hawkes S, Ndowa F, Dillon J . Gonorrhoea. Nat Rev Dis Primers. 2019; 5(1):79. DOI: 10.1038/s41572-019-0128-6. View

11.

Eyre D, Town K, Street T, Barker L, Sanderson N, Cole M . Detection in the United Kingdom of the FC428 clone, with ceftriaxone resistance and intermediate resistance to azithromycin, October to December 2018. Euro Surveill. 2019; 24(10). PMC: 6415501. DOI: 10.2807/1560-7917.ES.2019.24.10.1900147. View

12.

Ram S, Shaughnessy J, de Oliveira R, Lewis L, Gulati S, Rice P . Gonococcal lipooligosaccharide sialylation: virulence factor and target for novel immunotherapeutics. Pathog Dis. 2017; 75(4). PMC: 5449626. DOI: 10.1093/femspd/ftx049. View

13.

Lewis L, Gulati S, Burrowes E, Zheng B, Ram S, Rice P . α-2,3-sialyltransferase expression level impacts the kinetics of lipooligosaccharide sialylation, complement resistance, and the ability of Neisseria gonorrhoeae to colonize the murine genital tract. mBio. 2015; 6(1). PMC: 4324315. DOI: 10.1128/mBio.02465-14. View

14.

Trombley M, Post D, Rinker S, Reinders L, Fortney K, Zwickl B . Phosphoethanolamine Transferase LptA in Haemophilus ducreyi Modifies Lipid A and Contributes to Human Defensin Resistance In Vitro. PLoS One. 2015; 10(4):e0124373. PMC: 4406763. DOI: 10.1371/journal.pone.0124373. View

15.

Zughaier S, Rouquette-Loughlin C, Shafer W . Identification of a Histone Deacetylase: Epigenetic Impact on Host Gene Expression. Pathogens. 2020; 9(2). PMC: 7168274. DOI: 10.3390/pathogens9020132. View

16.

Botto M, DellAgnola C, Bygrave A, Thompson E, Cook H, Petry F . Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies. Nat Genet. 1998; 19(1):56-9. DOI: 10.1038/ng0598-56. View

17.

Jerse A . Experimental gonococcal genital tract infection and opacity protein expression in estradiol-treated mice. Infect Immun. 1999; 67(11):5699-708. PMC: 96944. DOI: 10.1128/IAI.67.11.5699-5708.1999. View

18.

Balthazar J, Gusa A, Martin L, Choudhury B, Carlson R, Shafer W . Lipooligosaccharide Structure is an Important Determinant in the Resistance of Neisseria Gonorrhoeae to Antimicrobial Agents of Innate Host Defense. Front Microbiol. 2011; 2:30. PMC: 3128933. DOI: 10.3389/fmicb.2011.00030. View

19.

Morioka Y, Yamasaki K, Leung D, Gallo R . Cathelicidin antimicrobial peptides inhibit hyaluronan-induced cytokine release and modulate chronic allergic dermatitis. J Immunol. 2008; 181(6):3915-22. PMC: 2655305. DOI: 10.4049/jimmunol.181.6.3915. View

20.

Exley R, Wu H, Shaw J, Schneider M, Smith H, Jerse A . Lactate acquisition promotes successful colonization of the murine genital tract by Neisseria gonorrhoeae. Infect Immun. 2006; 75(3):1318-24. PMC: 1828543. DOI: 10.1128/IAI.01530-06. View