Biology subjects

Georgiev, G.

Publications and source records attributed to Georgiev, G..

3 recordsLinked to original sources

bioRxiv2023

Diffusion of activated ATM explains γH2AX and MDC1 spread beyond the DNA damage site

During DNA repair, ATM-induced H2AX histone phosphorylation and MDC1 recruitment spread megabases beyond the damage site. The mechanism underlying this spread remains unclear. To elucidate this step of the DNA damage response, we measured ATM and MDC1 recruitment kinetics at micro-irradiation-induced complex DNA lesions. While MDC1 spreads beyond the damage-induced focus of ATM accumulation, cohesin loader NIPBL and cohesin subunit RAD21 accumulate later than MDC1. Such delayed recruitment suggests that, in complex DNA lesions, loop extrusion cannot alone explain {gamma}H2AX and MDC1 spread. To determine if diffusion of activated ATM could account for the observed behavior, we measured the exchange rate and diffusion constants of ATM and MDC1 within damaged and unperturbed chromatin. Based on these measurements, we introduced a quantitative model that describes the dynamic behavior of ATM and subsequent MDC1 spread at complex DNA lesions. Altogether, we propose activated ATM diffusion as an underlying mechanism of MDC1 spread.

cell biology↗

bioRxiv2021

Mosquito saliva sialokinin-dependent enhancement of arbovirus infection through endothelial barrier leakage

Viruses transmitted by Aedes mosquitoes constitute an increasingly important global health burden. Defining common determinants of host susceptibility to this large group of heterogenous pathogens are key for informing the rational design of new pan-viral medicines. Infection of the vertebrate host with these viruses is enhanced by the presence of mosquito saliva, a complex mixture of salivary gland-derived factors and microbiota. We show that enhancement of infection by saliva was dependent on vascular function and was independent of most anti-saliva immune responses, including to salivary microbiota. Instead, the Aedes gene product sialokinin mediated enhancement of virus infection through a rapid reduction in endothelial barrier integrity. Sialokinin is unique within the insect world as having vertebrate-like tachykinin sequence and is absent from non-vector competent Anopheles mosquitoes, whose saliva was not pro-viral and did not induce similar vascular permeability. Therapeutic strategies targeting sialokinin have potential to limit disease severity following infection with Aedes mosquito-borne viruses.

microbiology↗

bioRxiv2020

A replication-competent vesicular stomatitis virus for studies of SARS-CoV-2 spike-mediated cell entry and its inhibition

There is an urgent need for vaccines and therapeutics to prevent and treat COVID-19. Rapid SARS-CoV-2 countermeasure development is contingent on the availability of robust, scalable, and readily deployable surrogate viral assays to screen antiviral humoral responses, and define correlates of immune protection, and to down-select candidate antivirals. Here, we describe a highly infectious recombinant vesicular stomatitis virus bearing the SARS-CoV-2 spike glycoprotein S as its sole entry glycoprotein that closely resembles the authentic agent in its entry-related properties. We show that the neutralizing activities of a large panel of COVID-19 convalescent sera can be assessed in high-throughput fluorescent reporter assay with rVSV-SARS-CoV-2 S and that neutralization of the rVSV and authentic SARS-CoV-2 by spike-specific antibodies in these antisera is highly correlated. Our findings underscore the utility of rVSV-SARS-CoV-2 S for the development of spike-specific vaccines and therapeutics and for mechanistic studies of viral entry and its inhibition.

microbiology↗