Epidemiology and clinical features of SARS-CoV-2 infection in hospitalized children across four waves in Hungary: A retrospective, comparative study from March 2020 to December 2021

Background and AimsFrom 2019 till the present, infections induced by the novel coronavirus and its mutations have posed a new challenge for healthcare. However, comparative studies on pediatric infections throughout waves are few. During four different pandemic waves, we intended to investigate the clinical and epidemiological characteristic of the pediatric population hospitalized for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus infection. MethodsBetween March 2020 and December 2021, we performed our retrospective research on children infected with the SARS-CoV-2 virus at the University of Szeged. We analyzed the data of all patients who required hospitalization due to positive results of SARS-CoV-2 tests (Nucleic Acid Amplification Test or rapid antigen test). Data analysis included demographic data, medical history, clinical findings, length of hospitalization, and complications, using medical records. ResultsIn this study, data from 358 coronavirus-infected children were analyzed. The most affected age group was children over 1 month and under 1 year (30.2%). The highest number of cases was recorded in the fourth wave (53.6%). Fever (65.6%), cough (51.4%), nasal discharge (35.3%), nausea and vomiting (31.3%), and decreased oral intake (28.9%) were the most common symptoms. The most common complications were dehydration (50.5%), pneumonia (14.9%), and bronchitis/bronchiolitis (14.5%). Based on RR values, there are considerable differences in the prevalence of the symptoms and complications between the different age groups and waves. Cox proportional hazard model analyzes showed that fever and tachypnoea had a relevant effect on days to recovery. ConclusionsWe found trends similar to those previously published, overall statistics. The proportion of children requiring hospitalization varied from wave to wave, with the fourth wave affecting the Hungarian child population the most. Our findings suggest that hospitalization time is unrelated to age, but that certain symptoms (fever and tachypnoea) are associated with longer hospitalization. The onset of certain symptoms may differ by age group

Central role of the exchange factor GEF-H1 in TNF-α–induced sequential activation of Rac, ADAM17/TACE, and RhoA in tubular epithelial cells

Transactivation of the epidermal growth factor receptor (EGFR) by tumor necrosis factor-α (TNF-α) is a key step in mediating RhoA activation and cytoskeleton and junction remodeling in the tubular epithelium. In this study we explore the mechanisms underlying TNF-α-induced EGFR activation. We show that TNF-α stimulates the TNF-α convertase enzyme (TACE/a disintegrin and metalloproteinase-17), leading to activation of the EGFR/ERK pathway. TACE activation requires the mitogen-activated protein kinase p38, which is activated through the small GTPase Rac. TNF-α stimulates both Rac and RhoA through the guanine nucleotide exchange factor (GEF)-H1 but by different mechanisms. EGFR- and ERK-dependent phosphorylation at the T678 site of GEF-H1 is a prerequisite for RhoA activation only, whereas both Rac and RhoA activation require GEF-H1 phosphorylation on S885. Of interest, GEF-H1-mediated Rac activation is upstream from the TACE/EGFR/ERK pathway and regulates T678 phosphorylation. We also show that TNF-α enhances epithelial wound healing through TACE, ERK, and GEF-H1. Taken together, our findings can explain the mechanisms leading to hierarchical activation of Rac and RhoA by TNF-α through a single GEF. This mechanism could coordinate GEF functions and fine-tune Rac and RhoA activation in epithelial cells, thereby promoting complex functions such as sheet migration

Profibrotic epithelial phenotype:a central role for MRTF and TAZ

Abstract Epithelial injury is a key initiator of fibrosis but - in contrast to the previous paradigm - the epithelium in situ does not undergo wide-spread epithelial-mesenchymal/myofibroblast transition (EMT/EMyT). Instead, it assumes a Profibrotic Epithelial Phenotype (PEP) characterized by fibrogenic cytokine production. The transcriptional mechanisms underlying PEP are undefined. As we have shown that two RhoA/cytoskeleton-regulated transcriptional coactivators, Myocardin-related transcription factor (MRTF) and TAZ, are indispensable for EMyT, we asked if they might mediate PEP as well. Here we show that mechanical stress (cyclic stretch) increased the expression of transforming growth factor-β1 (TGFβ1), connective tissue growth factor (CTGF), platelet-derived growth factor and Indian Hedgehog mRNA in LLC-PK1 tubular cells. These responses were mitigated by siRNA-mediated silencing or pharmacological inhibition of MRTF (CCG-1423) or TAZ (verteporfin). RhoA inhibition exerted similar effects. Unilateral ureteral obstruction, a murine model of mechanically-triggered kidney fibrosis, induced tubular RhoA activation along with overexpression/nuclear accumulation of MRTF and TAZ, and increased transcription of the above-mentioned cytokines. Laser capture microdissection revealed TAZ, TGFβ1 and CTGF induction specifically in the tubular epithelium. CCG-1423 suppressed total renal and tubular expression of these proteins. Thus, MRTF regulates epithelial TAZ expression, and both MRTF and TAZ are critical mediators of PEP-related epithelial cytokine production

MRTF: Basic Biology and Role in Kidney Disease

A lesser known but crucially important downstream effect of Rho family GTPases is the regulation of gene expression. This major role is mediated via the cytoskeleton, the organization of which dictates the nucleocytoplasmic shuttling of a set of transcription factors. Central among these is myocardin-related transcription factor (MRTF), which upon actin polymerization translocates to the nucleus and binds to its cognate partner, serum response factor (SRF). The MRTF/SRF complex then drives a large cohort of genes involved in cytoskeleton remodeling, contractility, extracellular matrix organization and many other processes. Accordingly, MRTF, activated by a variety of mechanical and chemical stimuli, affects a plethora of functions with physiological and pathological relevance. These include cell motility, development, metabolism and thus metastasis formation, inflammatory responses and—predominantly-organ fibrosis. The aim of this review is twofold: to provide an up-to-date summary about the basic biology and regulation of this versatile transcriptional coactivator; and to highlight its principal involvement in the pathobiology of kidney disease. Acting through both direct transcriptional and epigenetic mechanisms, MRTF plays a key (yet not fully appreciated) role in the induction of a profibrotic epithelial phenotype (PEP) as well as in fibroblast-myofibroblast transition, prime pathomechanisms in chronic kidney disease and renal fibrosis