Natural Compound-Mediated SUMOylation Rewires Host Immunity Against Klebsiella pneumoniae
- 1Amrita Vishwa Vidyapeetham - Amritapuri Campus
Abstract
Klebsiella pneumoniae is a major cause of multidrug-resistant and hypervirulent infections worldwide, highlighting the urgent need for host-directed therapeutic strategies that complement conventional antibiotics. Emerging evidence suggests that K. pneumoniae promotes intracellular persistence by suppressing host SUMOylation, a reversible post-translational modification that regulates protein stability, cellular signaling, and innate immune response. This decrease in SUMOylation perturbs NF-{kappa}B signaling, leading to dysregulation of inflammation that promotes bacterial survival, rather than effective immune clearance. Clove Bud Oil (CBO), a natural product derived from Syzygium aromaticum, has previously been shown to possess anti-virulence as well as immunomodulatory properties. In this regard, we investigated the capability of CBO to restore host SUMOylation and enhance innate immune response during infection with classical as well as hypervirulent K. pneumoniae. In macrophages, classical and hypervirulent K. pneumoniae impaired global host SUMOylation, disrupting IKK{beta}-RelA/NF-{kappa}B signalling and uncoupling inflammatory regulation from effective antimicrobial defense to facilitate intracellular persistence. CBO restored SUMOylation-dependent immune homeostasis by attenuating sustained IKK{beta} phosphorylation and degradation, thereby constraining aberrant RelA nuclear translocation, rebalancing pro-inflammatory cytokine responses, and restricting intracellular bacterial survival. These findings demonstrate that restoration of host SUMOylation acts as a key driver of the immunomodulatory activity of CBO, leading to coordinated innate immune responses and enhanced intracellular bacterial clearance. Collectively, our study identifies host SUMOylation as a critical pathway targeted during K. pneumoniae infection and highlights restoration of SUMOylation-mediated immune homeostasis as a promising host-directed therapeutic strategy against multidrug-resistant and hypervirulent K. pneumoniae.
Related
- Follistatin-like 1 Promotes Neutrophil-mediated Host Defense against Klebsiella pneumoniae
- An OmpX mRNA-LNP vaccine induces protective humoral and cellular immunity against Klebsiella pneumoniae in a C57BL/6 mouse model
- Genomic Insights into Multi-Drug-Resistant, Klebsiella pneumoniae Isolated from an Infertile Woman: A Comprehensive Analysis of Antibiotic Resistance and Virulence Factors
- Defining nutrient dependencies of intestinal Klebsiella pneumoniae guides rational probiotic engineering
- Layered phage therapy exploits capsule-loss escape and altered antibiotic susceptibility in CG23 hypervirulent Klebsiella pneumoniae
BibTeX
@misc{padmakumar2026natural,
title = {{Natural Compound-Mediated SUMOylation Rewires Host Immunity Against Klebsiella pneumoniae}},
author = {S. Padmakumar and A. Kuniyil and A. P. Jaykumar and A. Gopakumar and M. Soorej and P. Babu and B. G. Nair and A. Madhavan and G. Kumar},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.12.751131},
url = {https://www.biorxiv.org/content/10.64898/2026.09.12.751131v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Natural Compound-Mediated SUMOylation Rewires Host Immunity Against Klebsiella pneumoniae
AU - S. Padmakumar
AU - A. Kuniyil
AU - A. P. Jaykumar
AU - A. Gopakumar
AU - M. Soorej
AU - P. Babu
AU - B. G. Nair
AU - A. Madhavan
AU - G. Kumar
PY - 2026
DA - 2026/09/12
PB - bioRxiv
DO - 10.64898/2026.09.12.751131
UR - https://www.biorxiv.org/content/10.64898/2026.09.12.751131v1
AB - Klebsiella pneumoniae is a major cause of multidrug-resistant and hypervirulent infections worldwide, highlighting the urgent need for host-directed therapeutic strategies that complement conventional antibiotics. Emerging evidence suggests that K. pneumoniae promotes intracellular persistence by suppressing host SUMOylation, a reversible post-translational modification that regulates protein stability, cellular signaling, and innate immune response. This decrease in SUMOylation perturbs NF-{kappa}B signaling, leading to dysregulation of inflammation that promotes bacterial survival, rather than effective immune clearance. Clove Bud Oil (CBO), a natural product derived from Syzygium aromaticum, has previously been shown to possess anti-virulence as well as immunomodulatory properties. In this regard, we investigated the capability of CBO to restore host SUMOylation and enhance innate immune response during infection with classical as well as hypervirulent K. pneumoniae. In macrophages, classical and hypervirulent K. pneumoniae impaired global host SUMOylation, disrupting IKK{beta}-RelA/NF-{kappa}B signalling and uncoupling inflammatory regulation from effective antimicrobial defense to facilitate intracellular persistence. CBO restored SUMOylation-dependent immune homeostasis by attenuating sustained IKK{beta} phosphorylation and degradation, thereby constraining aberrant RelA nuclear translocation, rebalancing pro-inflammatory cytokine responses, and restricting intracellular bacterial survival. These findings demonstrate that restoration of host SUMOylation acts as a key driver of the immunomodulatory activity of CBO, leading to coordinated innate immune responses and enhanced intracellular bacterial clearance. Collectively, our study identifies host SUMOylation as a critical pathway targeted during K. pneumoniae infection and highlights restoration of SUMOylation-mediated immune homeostasis as a promising host-directed therapeutic strategy against multidrug-resistant and hypervirulent K. pneumoniae.
ER -