Interferon-epsilon, an estrogen-induced type I interferon, is uniquely exploited by Neisseria gonorrhoeae via effects on sialic acid metabolism

  • Cell Host Microbe. 2025 Jul 9;33(7):1133-1145.e4. doi: 10.1016/j.chom.2025.05.015.
Evelyn A Kurt-Jones  1 ,  Sunita Gulati  1 ,  Michael King  1 ,  Rosane B de Oliveira  1 ,  Peter A Rice  1 ,  Bo Zheng  1 ,  Jutamas Shaughnessy  1 ,  Jennifer L Edwards  2 ,  Paul J Hertzog  3 ,  Sanjay Ram  1 ,  Douglas T Golenbock  4
Affiliations
  • 1. Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA.
  • 2. Department of Pediatrics, The Research Institute at Nationwide Children's Hospital and The Ohio State University, Columbus, OH, USA.
  • 3. Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia; Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia.
  • 4. Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA. Electronic address: [email protected].
PMID: 40494348 DOI: 10.1016/j.chom.2025.05.015
Abstract

The female genital mucosa expresses the hormone-dependent type I interferon (IFN), IFN-epsilon (IFN-ε), which protects against chlamydia and herpes Infection. Surprisingly, we found that IFN-ε knockout (Ifnε-/-) mice and type I IFN receptor knockout (IFNAR1-/-) mice exhibited enhanced clearance of Neisseria gonorrhoeae (Ng). This result was phenocopied using blocking anti-IFNAR monoclonal antibody (mAb). Ng colonization of the Ifnε-/- urogenital tract was restored by exogenous recombinant IFN-ε or IFN-β. Clearance of Ng in anti-IFNAR-treated mice required the expression of the cathelicidin mCRAMP. Ng deploys a unique mechanism to evade cathelicidins and Other innate defenses by sialylating its lipooligosaccharide (LOS) using host-derived cytidine-5'-monophospho-N-acetylneuraminic acid (CMP-Neu5Ac or CMP-sialic acid). Ifnε-/- mice expressed reduced levels of CMP-sialic acid synthetase mRNA in genital tissues. Accordingly, Ng recovered from IFN-deficient mice were hyposialylated. In conclusion, Ng exploits type I IFNs to obtain CMP-sialic acid for LOS sialylation, resulting in innate immune evasion and enhanced colonization.

Keywords
IFNAR; Neisseria gonorrhoeae; cathelicidin; cytidine-5'-monophospho-N-acetylneuraminic acid; interferon-epsilon; lipooligosaccharide; sialylation; type I interferon.
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