Biology subjects

Pylaeva, E.

Publications and source records attributed to Pylaeva, E..

3 recordsLinked to original sources

bioRxiv2026

Integrated kidney and urine proteomics define encrypted antimicrobial peptides as effectors of host defence in human pyelonephritis

Antimicrobial peptides (AMPs) are key effectors of host defence, however, their functional deployment across renal tissue and urine in pyelonephritis (PN) remains incompletely understood. Here, we integrate kidney and urine proteomics with urinary peptidomics and computational prediction to define AMP organisation and function. Proteomic analysis indicated coordinated induction of multiple AMPs in infected kidneys. These patterns were recapitulated in the urinary proteome, where AMP abundance correlated with leukocyte counts. Multiplex immunofluorescence microscopy localised these AMPs to myeloid cells, identifying them as central effector sources. Importantly, analysis of the urine peptidome revealed multiple encrypted AMPs (EPs), which arise from proteolytic processing of precursor proteins. To systematically assess their relevance for host defence, we applied an ensemble of machine learning-based predictors to prioritise candidates with activity in the urinary environment. This approach identified several potential EPs, among which the S100A12-derived peptide Calcitermin was confirmed in patient urine. Furthermore, it exerts antibacterial activity against uropathogenic E. coli (UPEC) and modulates myeloid cell responses. Together, these findings define a coordinated and compartmentalised AMP defence programme in human PN that extends beyond increased peptide expression, highlighting EPs as functionally relevant effectors with therapeutic potential.

immunology↗

bioRxiv2026

Histone neutralization protects the ischemic brain against stroke-associated pneumonia

Bacterial pneumonia aggravates ischemic stroke via mechanisms that still remain to be determined. In ischemic stroke patients and mice exposed to middle cerebral artery occlusion, we show that stroke-associated pneumonia markedly worsens clinical stroke outcome. In mice, pneumonia induced 3 days after stroke impaired neurological recovery and increased brain neutrophil infiltrates, blood-brain barrier breakdown, cerebral microvascular thrombosis, and progressive brain atrophy. The antibiotic amoxicillin only partially ameliorated pneumonia-associated neurological deficits and neutrophil infiltrates. Neutrophils were critical mediators of pneumonia-induced blood-brain barrier breakdown and microvascular thrombosis. Notably, administration of a neutralizing anti-histone antibody during pneumonia--unlike degradation or blockade of neutrophil extracellular trap formation or myeloperoxidase inhibition--restored long-term neurological recovery and prevented brain atrophy in stroke-associated pneumonia mice. This study identifies extracellular histones as key drivers of secondary inflammatory brain injury and establishes histone neutralization as a therapeutic strategy with an extended treatment window in the post-acute stroke phase. One Sentence SummaryNeutralizing extracellular histones reverses pneumonia-driven secondary brain injury and restores long-term recovery after ischemic stroke.

neuroscience↗

bioRxiv2025

Serpins A1/A3 within tumor-derived extracellular vesicles support pro-tumoral bias of neutrophils in cancer

Neutrophils are known to play an important regulatory role during tumor progression in several types of cancer. However, the mechanisms responsible for their tumorigenic bias and extended lifespan in cancer are not clear to date. This study uncovers a previously unknown mechanism by which tumor-derived small extracellular vesicles (sEVs), via their serpin cargo, reprogram neutrophils to adopt a tumor-supporting phenotype. We demonstrated here an elevated content of plasma sEVs during head and neck cancer progression, and their significant cargo enrichment with inhibitors of neutrophil serine proteases: serpins A1 and A3. Mechanistically, neutrophils educated with serpin-rich tumor-derived sEVs displayed typical pro-tumoral characteristics, including prolonged lifespan and activated CD62Llow CD11bhigh PDL1high phenotype. Functionally, such neutrophils demonstrated a strong ability to promote the epithelial-to-mesenchymal transition of tumor cells. Moreover, such neutrophils induced remarkable suppression of cytotoxic CD8 T cells, significantly reducing their tumor cell-killing capacity. Importantly, serpin cargo was essential for this activity, as serpin-depleted sEVs failed to reprogram neutrophils. These findings again highlight the clinical significance of sEVs and suggest their serpin content as important mediators of pro-tumoral functionality. Targeting the biogenesis or uptake of such immunosuppressive sEVs, or modifying their cargo, could potentially serve as a potent adjuvant anti-cancer therapy.

cancer biology↗