Biology subjects

Can, F.

Publications and source records attributed to Can, F..

5 recordsLinked to original sources

bioRxiv2025

PM2.5 Exposure Facilitates SARS-CoV-2 Infection through ACE2/TMPRSS2 Regulation and Suppression of Anti-Viral Response

BackgroundEpidemiological studies suggest an interaction between air pollution including particulate matter <2.5 {micro}m (PM2.5) and coronavirus disease 2019 (COVID-19) mortality and morbidity; however, the underlying mechanisms are not clear. The aim of our study was to investigate effects of PM2.5 on viability, epithelial integrity, and cellular entry of SARS-CoV-2 into airway epithelial cells, and the mechanisms involved. MethodsWe exposed Calu-3 airway epithelial cell cultures to PM2.5 (10, 50, and100 {micro}g/ml) and SARS-CoV-2 (MOI 0.01) for 24 h. The viability of Calu-3 cells and epithelial barrier integrity were determined using MTT assay and immunofluorescence staining for Zonula Occludens-1, respectively. mRNA expression for viral entry-related genes such as angiotensin converting enzyme (ACE)2 and transmembrane protease, serine (TMPRSS)2, and inflammatory and inflammasomal genes, including interleukin (IL)-8,IL-6, nuclear factor (NF)-{kappa}B p65 (RELA), JNK, c-JUN, Caspase-1, IL-1{beta}, NLRP3, was analyzed by qRT-PCR. Intracellular viral spike protein intensity and RNA-dependent RNA polymerase (RdRP) expression were determined using immunofluorescence staining and qRT-PCR, respectively. ELISA was used to analyze the release of inflammatory cytokines (IL-8, IL-6, and GM-CSF). ResultsHigher concentrations of 100{micro}g/ml PM2.5 decreased Calu-3 cell viability (p=0.02) and deteriorated epithelial barrier integrity, while 50 {micro}g/ml of PM2.5 (p<0.01) induced mRNA expression for ACE2 and TMPRSS2. Although PM2.5 alone decreased c-JUN, it did not alter the expression of mRNA for JNK and RELA. In contrast, a combination of SARS-CoV-2 and PM2.5 led to a significant increase in mRNA for both JNK and RELA (p < 0.05 and p < 0.01, respectively) and attenuated c-JUN expression. Moreover, our results indicated an increase in the expression of IL-1{beta}, IL-6, and GM-CSF following exposure to PM2.5 and PM2.5 + SARS-CoV-2, whereas IL-8 was induced only by SARS-CoV-2 exposure. Co-incubation of Calu-3 cells with PM2.5 and SARS-CoV-2 leads to a decrease in IL-8, IL-1{beta}, Caspase-1 (CASP-1), and Interferon gamma (IFNG) expression. Finally, the viral load (RdRP) also increased in the presence of both PM2.5 and the SARS-CoV-2 group. ConclusionOur findings have demonstrated that PM2.5 impaired epithelial integrity and cell viability, whereas it increased the mRNA expression for ACE2 and TMPRSS2, and induced inflammatory changes in Calu-3 cells incubated with SARS-CoV-2. These findings suggest that PM2.5 can facilitate the entry of SARS-CoV-2 into airway epithelial cells, and that both PM2.5 and SARS-CoV-2 can decrease the inflammatory and antiviral responses of the host cell.

cell biology↗

bioRxiv2024

FABP4 as a Therapeutic Host Target Controlling SARS-CoV2 Infection

Host metabolic fitness is a critical determinant of infectious disease outcomes. Obesity, aging, and other related metabolic disorders are recognized as high-risk disease modifiers for respiratory infections, including coronavirus infections, though the underlying mechanisms remain unknown. Our study highlights fatty acid-binding protein 4 (FABP4), a key regulator of metabolic dysfunction and inflammation, as a modulator of SARS-CoV-2 pathogenesis, correlating strongly with disease severity in COVID-19 patients. We demonstrate that loss of FABP4 function, by genetic or pharmacological means, reduces SARS-CoV2 replication and disrupts the formation of viral replication organelles in adipocytes and airway epithelial cells. Importantly, FABP4 inhibitor treatment of infected hamsters diminished lung viral titers, alleviated lung damage and reduced collagen deposition. These findings highlight the therapeutic potential of targeting host metabolism in limiting coronavirus replication and mitigating the pathogenesis of infection.

microbiology↗

bioRxiv2021

Protein scaffold-based multimerization of soluble ACE2 efficiently blocks SARS-CoV-2 infection in vitro

Soluble ACE2 (sACE2) decoy receptors are promising agents to inhibit SARS-CoV-2, as their efficiency is less likely to be affected by common escape mutations in viral proteins. However, their success may be limited by their relatively poor potency. To address this challenge, we developed a large decoy library of sACE2 fusion proteins, generated with several protease inhibitors or multimerization tags. Among these decoys, multimeric sACE2 consisting of SunTag or MoonTag systems, which were originally utilized for signal amplification or gene activation systems, were extremely effective in neutralizing SARS-CoV-2 in pseudoviral systems and in clinical isolates. These novel sACE2 fusion proteins exhibited greater than 100-fold SARS-CoV-2 neutralization efficiency, compared to monomeric sACE2. SunTag or MoonTag in combination with a more potent version of sACE2, which has multiple point mutations for greater binding (v1), achieved near complete neutralization at a sub-nanomolar range, comparable with clinical monoclonal antibodies. Pseudoviruses bearing mutant versions of Spike, alpha, beta, gamma or delta variants, were also neutralized efficiently with SunTag or MoonTag fused sACE2(v1). Finally, therapeutic treatment of sACE2(v1)-MoonTag provided protection against SARS-CoV-2 infection in an in vivo mouse model. Overall, we suggest that the superior activity of the sACE2-SunTag or sACE2-MoonTag fusions is due to the greater occupancy of the multimeric sACE2 receptors on Spike protein as compared to monomeric sACE2. Therefore, these highly potent multimeric sACE2 decoy receptors may offer a promising treatment approach against SARS-CoV-2 infections. One Sentence SummaryMultimerization of sACE2 markedly enhanced the neutralization of SARS-CoV-2 by blocking multiple viral spike proteins simultaneously.

molecular biology↗

bioRxiv2019

The role of iron uptake systems in the pathogenesis of colistin-resistant hypervirulent K. pneumoniae infections

Here we proposed the hypothesis that hypervirulent colistin resistant K.pneumoniae (ColR-Kp) exhibit high number of virulence factors and have enhanced survival capacity against neutrophil activity.\n\nWe studied virulence genes of ColR-Kp isolates and neutrophil response in 142 patients with invasive infections.\n\nThe patients infected with hypervirulent ST101 and ST395 ColR-Kp had higher 30-day mortality (58%, p=0.005 and 75%, p=0.003, respectively. The yersiniabactin biosynthesis gene (ybtS) and ferric uptake operon associated gene (kfu) were significantly higher in ST101 (99%, p=<0.001) and in ST395 (94%, p<0.012). Being in ICU (OR: 7.9; CI: 1.43-55.98; p=0.024), kfu (OR:27.0; CI:5.67-179.65; p<0.001) and ST101 (OR: 17.2; CI: 2.45-350.40; p=0.01) were found to be predictors of 30-day mortality. The uptake of kfu+-ybtS+ ColR-Kp by neutrophils was significantly higher than kfu--ybtS- ColR-Kp (78% vs 65%, p<0.001). However, kfu+-ybtS+ ColR-Kp were more resistant to the killing activity of neutrophils than negative ones (7.90 vs 4.22; p=0.001). The kfu+-ybtS+ ColR-Kp stimulated excessive NET formation while the NETs against kfu--ybtS- ColR-Kp were weak and rare.\n\nIron uptake systems enhance successful survival of K.pneumoniae against neutrophil phagocytic defense, and stimulate excessive NET formation. The drugs targeted to iron uptake systems would be a promising approach for treatment of hypervirulent K.pneumoniae infections.

microbiology↗

bioRxiv2018

Adaptation of Acinetobacter baumannii to colistin exposure: Laboratory mimicking of a clinical case

Adaptation of Acinetobacter baumannii to colistin use on a disease course of a patient was described. Effects of colistin was mimicked in the laboratory conditions. The colistin resistant isolate was identified from the patient after 25 days of colistin treatment. In the laboratory, the expressions of pmrCAB were the highest at the generation which was corresponded to the duration of therapy. A. baumannii can develop a stable colistin-resistant phenotype after three weeks of colistin exposure.

microbiology↗