Biology subjects

Gozal, D.

Publications and source records attributed to Gozal, D..

3 recordsLinked to original sources

bioRxiv2025

Thymidine Phosphorylase Drives SARS-CoV-2 Spike Protein-Induced Lung Tumorigenesis

Rationale and ObjectivesCOVID-19 survivors exhibit increased interstitial lung fibrosis, a known risk factor for lung cancer. We investigated whether SARS-CoV-2 Spike protein (SP)-induced lung injury and elevated thymidine phosphorylase (TYMP) promote lung tumorigenesis. MethodsA TriNetX retrospective cohort analysis was combined with mechanistic studies in K18-hACE2TG and K18-hACE2TG/Tymp-/- mice. Mice received intratracheal SP or control lysate followed by a urethane-induced lung cancer protocol. Lung injury, inflammation, thrombosis, fibrosis, STAT3 activation, cytokine profiles, and tumor burden were assessed. In vitro assays evaluated SP- and RBD-induced ACE2 processing. ResultsPropensity score-matched TriNetX cohorts demonstrated an increased lung cancer risk after COVID-19, particularly among current smokers (n = 166,807; RR 1.22; HR 1.50; P < .001). In mice, SP induced acute lung injury, neutrophil infiltration, and microthrombi, which were reduced in TYMP-deficient mice. SP markedly increased lung tumor incidence and aggressiveness, whereas TYMP deficiency reduced tumor formation from 50% to 18% of lung lobes. SP-induced STAT3 upregulation and collagen deposition were significantly attenuated in K18-hACE2TG/Tymp-/- mice. Cytokine profiling revealed a tumor-promoting, myeloid-dominant inflammatory milieu in K18-hACE2TG mice, in contrast to a T cell-inflamed, anti-tumor profile in K18-hACE2TG/Tymp-/- mice. SP and RBD altered ACE2 processing, generating lower-molecular-weight fragments consistent with enhanced turnover. ConclusionsSARS-CoV-2 SP drives lung injury, fibrosis, and tumorigenesis through a TYMP-dependent mechanism involving STAT3 signaling and inflammatory microenvironment remodeling. COVID-19 significantly increases lung cancer risk, especially in current smokers. TYMP represents a potential therapeutic target to mitigate long-term pulmonary consequences of COVID-19.

cell biology↗

bioRxiv2025

Poor sleep impairs immune responses and influenza vaccine protection

Disrrupted sleep, a common occurrence among shift workers, older adults, and individuals with sleep disorders, is increasingly recognized as a potential factor interfering with vaccine efficacy. Using a mouse model, we show that two weeks of chronic sleep fragmentation (CSF) before and during influenza vaccination significantly impair humoral immunity and reduce protection against lethal viral challenge. CSF-exposed mice exhibited lower neutralizing antibody titers, diminished IgG subclass responses, and reduced survival after viral challenge, despite preserved antibody binding avidity. Single-cell RNA sequencing and immune receptor profiling revealed altered B cell maturation, abnormal germinal center activation, and plasma cell stress, characterized by activation of unfolded protein response and oxidative stress pathways. CSF also reprogrammed B-cell signaling and disrupted coordination with T-cells. Together, this study showed that CSF compromises vaccine-induced immune responses by affecting multistage of B-cell differentiation, underscoring the importance of considering sleep health in vaccination strategies for vulnerable populations. One Sentence SummaryPoor sleep weakens both the magnitude and quality of immune responses, compromising the protective efficacy of influenza vaccination.

immunology↗

bioRxiv2020

Impact of sleep fragmentation, heart failure, and their combination, on the gut microbiome

Heart failure (HF) is a common condition associated with a high rate of hospitalizations and adverse outcomes. HF is characterized by impairments of the cardiac ventricular filling and/or ejection of blood capacity. Sleep fragmentation (SF) involves a series of short sleep interruptions that lead to fatigue and contribute to cognitive impairments and dementia. Both conditions are known to be associated with increased inflammation and dysbiosis of the gut microbiota. In the present study, male mice were distributed into four groups, and subjected for four weeks to either HF, SF, both HF and SF, or left unperturbed as controls. We used 16S metabarcoding to assess fecal microbiome composition before and after the experiments. Evidence for distinct alterations in several bacterial groups and an overall decrease in alpha diversity emerged in HF and SF treatment groups. Combined HF and SF conditions, however, showed no synergism, and observed changes were not always additive, suggesting that some of the individual effects of either HF or SF cancel each other out when applied concomitantly. IMPORTANCEThe study demonstrates the potential of the gut microbiome as a source of molecular markers for the diagnosis, prevention, and treatment of both heart failure and sleep fragmentation conditions in isolation. Our results provide the first evidence of an antagonistic effect of the presence of both conditions in the gut microbiome dysbiosis, showing an attenuation of the alterations that are observed when considering them separately.

microbiology↗