Biology subjects

Pawlowski, A.

Publications and source records attributed to Pawlowski, A..

3 recordsLinked to original sources

bioRxiv2026

Functional Characterization of RSV Clades Associated with Prophylactic Breakthrough Infections in Pediatric Transmission Clusters

The recent development of new respiratory syncytial virus (RSV) prophylactics for the prevention of severe lower respiratory tract infections in infants and older adults promises in lowering disease burden in these vulnerable populations. However, it remains unclear if periodic breakthrough infections in these populations may drive the emergence of resistant isolates or clades and what factors might contribute to these breakthroughs. In this retrospective cohort study, we performed whole-genome sequencing of RSV isolates from infants and adults during the past two RSV seasons (2023-2025) to assess viral and clinical correlates of nirsevimab breakthrough. RSV infections from nirsevimab breakthrough cases were associated with less severe clinical outcomes in the first, but not second, season after administration. While breakthrough isolates did not share any Fusion glycoprotein mutations in predicted antigenic sites, they largely belonged to only a few circulating clades that were responsible for driving temporally distinct pediatric transmission clusters. To determine if these transmission clusters and breakthrough infections were in part driven by differences in the Fusion proteins of these clades, we compared the relative fusogenicity and neutralization susceptibility of Fusion proteins from contemporary circulating clades. Notably, RSV-A clade A.D.3 exhibited modestly reduced susceptibility to nirsevimab neutralization, though it wasnt associated with any transmission clusters or breakthrough infections. Collectively, these data suggest that clade associations with prophylactic breakthrough are driven by pediatric transmission clusters rather than clade-associated resistance, though continued surveillance will be vital as prophylactic coverage continues to rise.

microbiology↗

bioRxiv2026

Pathogen-specific host responses define distinct pneumonia endotypes in the human lung

Pneumonia is the leading cause of death from infectious disease worldwide. The diagnosis and treatment of patients with pneumonia lag behind other major conditions, relying on syndromic definitions that lack molecular resolution and ignore underlying endotypes. We sought to test the hypothesis that dynamic pathogen-specific host responses in the alveolar space represent distinct pneumonia endotypes linked to different clinical features and outcomes. We prospectively enrolled a cohort of 690 patients (including immunocompromised patients) with known or suspected pneumonia receiving mechanical ventilation in whom the etiology of pneumonia was determined by gold-standard analysis of distal lung fluid obtained by bronchoalveolar lavage (BAL) combined with clinical adjudication. From these patients, we analyzed 792 BAL fluid samples, including 310 serial samples, using flow cytometry (482 patients) and single-cell RNA-sequencing (170 patients; 263 samples, complemented by 9 healthy controls and 25 post-COVID-19 patients, yielding [~]2.4 million single cells across 28 cell types), and extracted daily clinical data from the electronic health record (>15,000 patient-days). We used machine learning models to identify pathogen-specific host responses in the transcriptome of alveolar immune cells that were associated with changes in alveolar cell abundance and clinical features. Our results suggest that therapeutic strategies for pneumonia should be individualized to specific host-pathogen interactions.

immunology↗

bioRxiv2021

A chimeric KaiA-like regulator extends the nonstandard KaiB3-KaiC3 clock system in bacteria

Organisms from all kingdoms of life have evolved diverse mechanisms to address the predictable environmental changes resulting from the Earths rotation. The circadian clock of cyanobacteria is a particularly simple and elegant example of a biological timing mechanism for predicting daily changes in the light environment. The three proteins KaiA, KaiB, and KaiC constitute the central timing mechanism that drives circadian oscillations in the cyanobacterium Synechococcus elongatus PCC 7942. In addition to the standard oscillator, Synechocystis sp. PCC 6803, another model organism for cyanobacterial research, harbors several divergent clock homologs. Here, we describe a potential new chimeric KaiA homolog that we named KaiA3. At the N-terminus, KaiA3 is similar to the NarL-type response regulator receiver domain. However, its similarity to canonical NarL transcription factors drastically decreases in the C-terminal domain, which resembles the circadian clock protein, KaiA. In line with this, we detected KaiA3-mediated stimulation of KaiC3 phosphorylation. Phosphorylation of KaiC3 was rhythmic over 48 h in vitro in the presence of KaiA3 and KaiB3 as well as in Synechocystis cells under free-running conditions after light/dark entrainment. This results in the presence of two different oscillators in a single-celled prokaryotic organism. Deletion of the kaiA3 gene leads to KaiC3 dephosphorylation and results in growth defects during mixotrophic growth and in the dark. In summary, we suggest that KaiA3 is a nonstandard KaiA homolog, thereby extending the KaiB3-KaiC3 system in Cyanobacteria and potentially other prokaryotes.

microbiology↗