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Microbes & Immunity PTMs in Sepsis: Mechanisms and therapy

explores their potential as biomarkers and therapeutic products that further damage the endothelium and
targets to enhance sepsis treatment enhance. enhance platelet aggregation. The resulting disseminated
intravascular coagulation disrupts organ microcirculation,
2. Host response dysregulation in sepsis causing ischemic injury and worsening multi-organ

Sepsis arises from a dysregulated host immune response, failure. 14
characterized by a vicious cycle of hyperinflammation, Metabolic reprogramming is a hallmark of sepsis, driven
immunosuppression, coagulation abnormalities, and by inflammatory signals that shift immune cell metabolism
metabolic dysregulation. This cascade disrupts immune toward glycolysis, leading to lactate accumulation and
homeostasis, driving complex molecular interactions that metabolic acidosis. Excessive reactive oxygen species
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culminate in multi-organ dysfunction. (ROS) induces mitochondrial dysfunction, while lipid
In the early phase of sepsis, pathogen-associated peroxidation promotes ferroptosis, a form of programmed
molecular patterns and damage-associated molecular cell death. These processes impair immune cell function
patterns engage pattern recognition receptors, such as toll- and contribute to multi-organ metabolic failure. 16,17
like receptors (TLRs), on immune cells. This interaction Together, these metabolic disruptions exacerbate the
activates signaling cascades, including nuclear factor- systemic effects of sepsis and hinder recovery.
kappa B (NF-κB) and mitogen-activated protein kinase PTMs intricately regulate these dysregulated host
(MAPK) pathways, triggering a surge of pro-inflammatory responses, serving as critical molecular switches in
cytokines, such as tumor necrosis factor alpha (TNF- sepsis pathogenesis. For instance, phosphorylation
α), interleukin 6 (IL-6), and interleukin 1 beta (IL-1β). of NF-κB modulates excessive inflammation, while
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Concurrently, excessive activation of the complement phosphorylation of lymphocyte-specific protein-1 (Lsp1)
system (e.g., C3a, C5a) and the formation of neutrophil triggers B cell apoptosis. In addition, the E3 ubiquitin
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extracellular traps further amplify inflammation, damaging ligase TRIM47 promotes TNF-α-induced endothelial cell
vascular endothelium, causing capillary leakage and tissue activation through ubiquitination, and lactate-mediated
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edema. These processes exacerbate tissue injury and set lactylation of mitochondrial fission protein 1 (Fis1) drives
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the stage for systemic complications. mitochondrial dysfunction. These PTM-mediated
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Following the initial inflammatory storm, the host mechanisms, detailed in subsequent sections, highlight
immune system often transitions into a compensatory potential therapeutic targets for mitigating sepsis-induced
anti-inflammatory response syndrome. During this phase, organ damage.
pro-inflammatory cytokine production declines, while 3. Phosphorylation and sepsis
anti-inflammatory mediators (e.g., IL-10, transforming
growth factor beta) are overexpressed, suppressing immune Protein phosphorylation, the earliest discovered PTM,
cell function. This shift is accompanied by widespread is a well-studied mechanism in sepsis. It involves the
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apoptosis of T cells and B cells, impaired antigen- kinase-mediated transfer of a phosphate group from
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presenting capacity of dendritic cells, and expansion of ATP to specific amino acid residues, regulating cellular
myeloid-derived suppressor cells. In addition, upregulation signaling, metabolism, and inflammation. In sepsis,
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of immune checkpoint molecules (e.g., programmed cell phosphorylation modulates key pathways – such as NF-κB,
death protein 1 [PD-1], cytotoxic T-lymphocyte-associated MAPK, STAT3, and PI3K/ATK – affecting inflammation,
protein 4 [CTLA-4]) on T cell surfaces induces T cell immunity, and apoptosis, and thus influencing disease
exhaustion. This immunosuppressive state increases progression and outcomes.
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susceptibility to secondary infections, impairs pathogen
clearance, and significantly increases mortality risk. 3.1. NF-κB signaling pathway

Dysregulated coagulation forms a positive feedback NF-κB, a pivotal transcription factor in immune and
loop with inflammation, exacerbating sepsis pathology. inflammatory responses, comprises five subunits: p50,
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Inflammatory cytokines inhibit the thrombomodulin- p52, RelA (p65), c-Rel, and RelB. In resting cells, NF-κB
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protein C system, impairing anticoagulation while is sequestered in the cytoplasm by its inhibitor, IκB.
upregulating tissue factor expression to activate the Activation proceeds through two distinct pathways:
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extrinsic coagulation pathway. Simultaneously, increased classical and non-classical.
levels of plasminogen activator inhibitor-1 suppress The classical pathway, initiated by inflammatory
fibrinolysis, promoting platelet activation and fibrin cytokines, involves IKK complex-mediated
deposition. 12,13 These changes lead to microthrombi phosphorylation and subsequent degradation of IκB,
formation, compounded by complement activation releasing NF-κB dimers (e.g., p50/p65), which translocate

Volume 2 Issue 3 (2025) 2 doi: 10.36922/MI025090016