Biology subjects

Ritvos, O.

Publications and source records attributed to Ritvos, O..

4 recordsLinked to original sources

bioRxiv2025

American mink as an animal model to study SARS-CoV-2 and vaccine response

Selecting a suitable animal model is crucial in understanding infectious diseases and developing vaccines. Here, we developed a receptor-binding domain -based SARS-CoV-2 vaccine with mouse Fc an immunopotentiator in a mink model. Four different variations of the vaccine were tested in groups of 30-31 American mink and followed for IgG and neutralizing antibodies (nAb) up to 27 weeks. Subcutaneous version induced a strong IgG and nAb response within two weeks and was still detectable at 27 weeks. Intranasal version also caused a detectable, although weaker, immune response. A simultaneously given subcutaneous vaccine against virus enteritis, botulism and hemorrhagic pneumonia potentially caused a lower SARS-CoV-2 antibody response, highlighting the need for further studies on co-effects of vaccines. In virus challenge with Alpha variant (B.1.1.7), vaccinated mink had a stronger antibody response than unvaccinated mink. Despite not preventing the infection, vaccinated mink had milder clinical signs and less virus in saliva. Another challenge of unvaccinated mink with Omicron variant showed similar results to alpha (BA.1) variant. Virus RNA was detected in the brain of unvaccinated mink but not vaccinated mink by in situ hybridization, indicating a suitability of mink to study neurological effects of SARS-CoV-2 and potentially long COVID as well. Author summaryFinding a good animal model is very important in studying infectious diseases and their treatment. The recent SARS-CoV2 pandemic highlighted this dilemma. We have developed an animal model based on mink due to their close match to humans in the symptomology of this disease. Such model will enable the study of relative susceptibility, transmission, tissue tropism, complex pathogenesis and long COVID, as well as prophylaxis and vaccines. This model will also help reduce the use of primates in this research. We have further developed a new vaccine for SARS-CoV2 based on the receptor binding domain of the S-protein with an inbuilt immune-enhancer. This vaccine underwent extensive testing in mink to determine response, long term protection, and safety. The vaccine was found to provide excellent titers of neutralizing antibodies with wide range in target variants. It also reduced the severity and duration of visible symptoms in the animals significantly. We propose this vaccine candidate for further study and future commercialization.

microbiology↗

bioRxiv2021

Intranasal inhibitor blocks Omicron and other variants of SARS-CoV-2

The recent emergence of novel SARS-CoV-2 variants capable of efficiently escaping neutralizing antibodies emphasizes the need for prophylactic strategies to complement vaccination in fighting the COVID-19 pandemic. Nasal epithelium is rich in the ACE2 receptor and important for SARS-CoV-2 transmission by supporting early viral replication before seeding to the lung1. Intranasal administration of SARS-CoV-2 neutralizing antibodies or antibody fragments has shown encouraging potential as a protective measure in animal models2-5. However, there remains a dire need for SARS-CoV-2 blocking agents that are less vulnerable to mutational variation in the neutralization epitopes of the viral spike glycoprotein and more economical to produce in large scale. Here we describe TriSb92, a highly manufacturable and extremely stable trimeric human SH3 domain-derived antibody mimetic targeted against a conserved region in the receptor-binding domain of spike. TriSb92 potently neutralizes SARS-CoV-2 and its variants of concern, including Omicron BA.5 as well as the latest and most immunoevasive variants like BF.7, XBB, and BQ.1.1. Intranasal administration of a modest dose of TriSb92 (5 or 50 micrograms) as early as eight hours before a challenge with SARS-CoV-2 efficiently protected mice from infection, and was still effective even when given 4 h after the viral challenge. The target epitope of TriSb92 was defined by cryo-EM, which revealed triggering of a conformational shift in the spike trimer rather than competition for ACE2 binding as the molecular basis of its strong inhibitory action. The high potency and robust biochemical properties of TriSb92 together with the remarkable resistance of its inhibitory action against viral sequence evolution suggest that TriSb92 could be useful as a nasal spray for protecting susceptible individuals from SARS-CoV-2 infection.

microbiology↗

bioRxiv2021

Coordinated activation of both TGFβ and BMP canonical pathways regulates autophagy and tissue regeneration in acetaminophen induced liver injury

Transforming Growth Factor-{beta}s (TGF{beta}s)/Activins and Bone Morphogenetic Proteins (BMPs) have been implicated in numerous aspects of hepatic pathophysiology. However, the way by which hepatocytes integrate and decode the interplay between the TGF{beta}/Activin and BMP branches in health and disease is still not fully understood. To address this, TGF{beta}/BMP Smad- responsive double transgenic reporter mice were generated and utilized to map patterns of TGF{beta}- and/or BMP-pathway activation during acetaminophen- induced liver injury. TGF{beta} signaling was blocked either pharmacologically or by Smad7 over-expression and the transcriptomes of canonical TGF{beta}- and/or BMP4-treated hepatospheres and Smad7-treated livers were analyzed to highlight TGF{beta}-superfamily-regulated pathways and processes. Acetaminophen administration led to dynamically evolving, stage- and context-specific, patterns of hepatic TGF{beta}/Activin and BMP-reporter expression. TGF{beta}-superfamily signaling was activated in an autophagy prone zone at the borders between healthy and injured tissue. Inhibition of TGF{beta}-superfamily signaling attenuated autophagy, exacerbated liver histopathology, and finally led to accelerated tissue-recovery. Hallmarks of this process were the paraptosis-like cell death and the attenuation of immune and reparatory cell responses. Transcriptomic analysis highlighted autophagy as a prominent TGF{beta}1- and BMP4-regulated process and recognized Trp53inp2 as the top TGF{beta}-superfamily-regulated autophagy-related gene. Collectively, these findings implicate the coordinated activation of both canonical TGF{beta}-superfamily signalling branches in balancing autophagic response and tissue-reparatory and -regenerative processes upon acetaminophen-induced hepatotoxicity, highlighting opportunities and putative risks associated with their targeting for treatment of hepatic diseases.

physiology↗

bioRxiv2019

Dysregulated cell signalling and reduced satellite cell potential in ageing muscle

Aberrant activation of signalling pathways has been postulated to promote age related changes in skeletal muscle. Cell signalling activation requires not only the expression of ligands and receptors but also an appropriate environment that facilitates their interaction. Here we first examined the expression of SULF1/SULF2 and members of RTK and the Wnt family in skeletal muscle of normal and a mouse model of accelerated ageing. We show that SULF1/SULF2 and these signalling components, a feature of early muscle development are barely detectable in early postnatal muscle. Real time qPCR and immunocytochemical analysis showed gradual but progressive up-regulation of SULF1/SULF2 and RTK/Wnt proteins not only in the activated satellite cells but also on muscle fibres that gradually increased with age. Satellite cells on isolated muscle fibres showed spontaneous in vivo satellite cell activation and progressive reduction in proliferative potential and responsiveness to HGF and dysregulated myogenic differentiation with age. Finally, we show that SULF1/SULF2 and RTK/Wnt signalling components are expressed in progeric mouse muscles at earlier stage but their expression is attenuated by an intervention that promotes muscle repair and growth.

cell biology↗