Efficacy of Antigonococcal CMP-Nonulosonate Therapeutics Require Cathelicidins
In: The Journal of infectious diseases, Jg. 222 (2020-06-10), Heft 10
Online
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Zugriff:
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.
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Efficacy of Antigonococcal CMP-Nonulosonate Therapeutics Require Cathelicidins
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Autor/in / Beteiligte Person: | Lewis, Lisa A. ; Varki, Ajit ; Rice, Peter A. ; Schoenhofen, Ian C. ; Iesha Y Moustafa ; Gulati, Sunita ; Ram, Sanjay ; Lindhout-Djukic, Theresa ; Zheng, Bo ; Saha, Sudeshna ; Nowak, Nancy A. |
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Zeitschrift: | The Journal of infectious diseases, Jg. 222 (2020-06-10), Heft 10 |
Veröffentlichung: | 2020 |
Medientyp: | unknown |
ISSN: | 1537-6613 (print) |
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