Gopakumar, A. | bioRxiv Science

bioRxiv2026

Natural Compound-Mediated SUMOylation Rewires Host Immunity Against Klebsiella pneumoniae

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.

immunology↗

bioRxiv2025

Structural Effects of Low Social Status and Obesogenic Diet on Social and Emotional Neurocircuits in Female Macaques: A Longitudinal Study from Infancy to Adulthood

A substantial body of literature has demonstrated a consistent link between psychosocial stress and obesity in children, particularly in those from low socioeconomic backgrounds. Despite evidence indicating a complex interplay between stress, diet and obesity, there is a limited understanding of the specific versus potentially synergistic effects of obesity and stress on brain structural and functional development. This study investigates the developmental and long-term brain structural alterations resulting from exposure to chronic social stress due to low (subordinate -SUB-) social status and postnatal obesogenic diets. Forty-one female rhesus macaques (Dominants -DOM-, n=21; Subordinates -SUB-, n=20) were assigned to either only low-calorie diet (LCD) or to both high-calorie diet (HCD) and LCD (Choice diet) from birth through the juvenile period. After menarche, all subjects were maintained on a LCD-only diet through adulthood. Twenty-seven animals (DOM: n=13, SUB: n=14) were studied again in adulthood to investigate the long-term effects of early diet and social rank on brain structure. Cumulative Kcal consumption was measured from birth through 16 months and body weights were measured at all time points. Overall, the findings show specific effects of obesogenic diet and psychosocial stress on cortical and corticolimbic brain regions. Animals with access to the obesogenic diet had larger overall brain size (measured as intracranial volume -ICV-) and larger overall volumes of prefrontal cortex, insula, superior temporal sulcus (defined as temporo-parieto-occipital area rostral and caudal regions (TPOr and TPOc)) than those in the low-calorie diet. Most of these regional diet effects, except for the insula, were driven by general effects of the diet on brain size. The diet effects were lost when adding the adult data to the longitudinal analysis, suggesting transient effects of obesogenic diets while the animals were consuming it, but not long-term, persistent effects. These findings highlight the potential of brain rescue mechanisms that could offset lasting developmental effects of early-life obesogenic diet consumption. With respect to social rank, SUB exhibited larger volumes in brain regions related to social cognition and emotional processing than DOM animals. When the adult data was added to the longitudinal analysis, the effects of social rank were prominent in the hippocampus, superior temporal sulcus, temporo-parieto-occipital rostral region, and the temporal auditory cortices after ICV data correction, suggesting long-term, persistent and cumulative effects of these social experiences, in contrast to the transient diet effects.

neuroscience↗