Biology subjects

Goekeri, C.

Publications and source records attributed to Goekeri, C..

4 recordsLinked to original sources

bioRxiv2024

Neutrophil-chemoattractant CXCL5 induces lung barrier permeability in acute lung injury

RationaleAcute lung injury is frequently caused by pneumonia, and severity correlates with inflammatory cell recruitment and lung barrier failure. Deciphering drug-targetable pathways is of clinical importance. ObjectivesInvestigation of paracrine and autocrine effects of epithelial-derived chemokine CXCL5 in acute lung injury. MethodsWe assessed the role of CXCL5 and related chemokines in patients with severe pneumonia and primary cells or cell lines challenged with Streptococcus pneumoniae or exposed to mechanical stretch. Furthermore, we evaluated the role of CXCL5 in in vivo models of acute lung injury through use of Cxcl5-deficient mice and in vitro human lung barrier models. ResultsPneumococcal infection and mechanical ventilation were associated with CXCL5 production in human subjects and in mice. CXCL5 was produced by bronchial and alveolar epithelial cells. The alveolar-epithelial barrier was protected in acute lung injury models in Cxcl5-deficient mice, independent of alveolar neutrophil recruitment. Single-cell transcriptomics revealed enhanced cell junctional transcripts in epithelial, but not endothelial cells in Cxcl5-deficient mice. Accordingly, CXCL5 exposure disrupted the barrier function of TNF-primed human primary alveolar epithelial cells, but not pulmonary microvascular endothelial cells. ConclusionsWe describe a novel function of CXCL5 in acute lung injury. Besides its recognized role in recruiting highly inflammatory cells such as neutrophils, CXCL5 increases alveolar-epithelial barrier permeability. Thus, in severe bacterial pneumonia, targeting of CXCL5 as adjunctive therapy to antibiotics may aid in reducing overshooting inflammation as well as stabilizing lung barrier function.

immunology↗

bioRxiv2024

Neural Network-Assisted Humanization of COVID-19 Hamster scRNAseq Data Reveals Matching Severity States in Human Disease

Translating findings from animal models to human disease is essential for dissecting disease mechanisms, developing and testing precise therapeutic strategies. The coronavirus disease 2019 (COVID-19) pandemic has highlighted this need, particularly for models showing disease severity-dependent immune responses. Single-cell transcriptomics (scRNAseq) is well poised to reveal similarities and differences between species at the molecular and cellular level with unprecedented resolution. However, computational methods enabling detailed matching are still scarce. Here, we provide a structured scRNAseq-based approach that we applied to scRNAseq from blood leukocytes originating from humans and hamsters affected with moderate or severe COVID-19. Integration of COVID-19 patient data with two hamster models that develop moderate (Syrian hamster, Mesocricetus auratus) or severe (Roborovski hamster, Phodopus roborovskii) disease revealed that most cellular states are shared across species. A neural network-based analysis using variational autoencoders quantified the overall transcriptomic similarity across species and severity levels, showing highest similarity between neutrophils of Roborovski hamsters and severe COVID-19 patients, while Syrian hamsters better matched patients with moderate disease, particularly in classical monocytes. We further used transcriptome-wide differential expression analysis to identify which disease stages and cell types display strongest transcriptional changes. Consistently, hamsters response to COVID-19 was most similar to humans in monocytes and neutrophils. Disease-linked pathways found in all species specifically related to interferon response or inhibition of viral replication. Analysis of candidate genes and signatures supported the results. Our structured neural network-supported workflow could be applied to other diseases, allowing better identification of suitable animal models with similar pathomechanisms across species. Key PointsO_LINeural networks can successfully match disease states between animal models and humans using single-cell data as shown for COVID-19 C_LIO_LIModerately diseased patients best matched Syrian hamster cells; severely diseased patients best matched Roborovski hamster neutrophils C_LI

immunology↗

bioRxiv2024

Enzymatic modulation of the pulmonary glycocalyx alters susceptibility to Streptococcus pneumoniae

The pulmonary epithelial glycocalyx is rich in glycosaminoglycans such as hyaluronan and heparan sulfate. Despite their presence, the precise role of these glycosaminoglycans in bacterial lung infections remains elusive. To address this, we intranasally inoculated mice with Streptococcus pneumoniae in the presence or absence of enzymes targeting pulmonary hyaluronan and heparan sulfate, followed by characterization of subsequent disease pathology, pulmonary inflammation, and lung barrier dysfunction. Enzymatic degradation of hyaluronan and heparan sulfate exacerbated pneumonia in mice, as evidenced by increased disease scores and alveolar neutrophil recruitment. However, targeting epithelial hyaluronan further exacerbated systemic disease, indicated by elevated splenic bacterial load and plasma levels of pro-inflammatory cytokines. In contrast, enzymatic cleavage of heparan sulfate resulted in increased bronchoalveolar bacterial burden, lung damage and pulmonary inflammation in mice infected with Streptococcus pneumoniae. Accordingly, heparinase-treated mice also exhibited disrupted lung barrier integrity as evidenced by higher alveolar edema scores and vascular protein leakage into the airways. This finding was corroborated in a human alveolus-on-a-chip platform, confirming that heparinase treatment also disrupts the human lung barrier. Notably, enzymatic pre-treatment with either hyaluronidase or heparinase also rendered human epithelial cells more sensitive to pneumococcal-induced barrier disruption, as determined by transepithelial electrical resistance measurements, consistent with our findings in murine pneumonia. Taken together, these findings demonstrate the importance of intact hyaluronan and heparan sulfate in controlling pneumococcal virulence, pulmonary inflammation, and epithelial barrier function.

molecular biology↗

bioRxiv2022

A live attenuated vaccine confers superior mucosal and systemic immunity to SARS-CoV-2 variants

Vaccines are a cornerstone in COVID-19 pandemic management. Here, we compare immune responses to and preclinical efficacy of the mRNA vaccine BNT162b2, an adenovirus-vectored spike vaccine, and the live-attenuated-virus vaccine candidate sCPD9 after single and double vaccination in Syrian hamsters. All regimens containing sCPD9 showed superior efficacy. The robust immunity elicited by sCPD9 was evident in a wide range of immune parameters after challenge with heterologous SARS-CoV-2 including rapid viral clearance, reduced tissue damage, fast differentiation of pre-plasmablasts, strong systemic and mucosal humoral responses, and rapid recall of memory T cells from lung tissue. Our results demonstrate that use of live-attenuated vaccines may offer advantages over available COVID-19 vaccines, specifically when applied as booster, and may provide a solution for containment of the COVID-19 pandemic.

immunology↗