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Virol Sin ; 35(3): 280-289, 2020 Jun.
Article in English | MEDLINE | ID: covidwho-1384632


Cancer cell lines have been used widely in cancer biology, and as biological or functional cell systems in many biomedical research fields. These cells are usually defective for many normal activities or functions due to significant genetic and epigenetic changes. Normal primary cell yields and viability from any original tissue specimens are usually relatively low or highly variable. These normal cells cease after a few passages or population doublings due to very limited proliferative capacity. Animal models (ferret, mouse, etc.) are often used to study virus-host interaction. However, viruses usually need to be adapted to the animals by several passages due to tropism restrictions including viral receptors and intracellular restrictions. Here we summarize applications of conditionally reprogrammed cells (CRCs), long-term cultures of normal airway epithelial cells from human nose to lung generated by conditional cell reprogramming (CR) technology, as an ex vivo model in studies of emerging viruses. CR allows to robustly propagate cells from non-invasive or minimally invasive specimens, for example, nasal or endobronchial brushing. This process is rapid (2 days) and conditional. The CRCs maintain their differentiation potential and lineage functions, and have been used for studies of adenovirus, rhinovirus, respiratory syncytial virus, influenza viruses, parvovirus, and SARS-CoV. The CRCs can be easily used for air-liquid interface (ALI) polarized 3D cultures, and these coupled CRC/ALI cultures mimic physiological conditions and are suitable for studies of viral entry including receptor binding and internalization, innate immune responses, viral replications, and drug discovery as an ex vivo model for emerging viruses.

Cellular Reprogramming Techniques , Models, Biological , Respiratory Mucosa/cytology , Respiratory Mucosa/virology , Betacoronavirus/physiology , COVID-19 , Cell Differentiation , Cell Lineage , Cells, Cultured , Coronavirus Infections/immunology , Coronavirus Infections/virology , Epithelial Cells/cytology , Epithelial Cells/virology , Humans , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , SARS-CoV-2
PLoS One ; 15(9): e0238412, 2020.
Article in English | MEDLINE | ID: covidwho-1388884


We investigate phase transitions associated with three control methods for epidemics on small world networks. Motivated by the behavior of SARS-CoV-2, we construct a theoretical SIR model of a virus that exhibits presymptomatic, asymptomatic, and symptomatic stages in two possible pathways. Using agent-based simulations on small world networks, we observe phase transitions for epidemic spread related to: 1) Global social distancing with a fixed probability of adherence. 2) Individually initiated social isolation when a threshold number of contacts are infected. 3) Viral shedding rate. The primary driver of total number of infections is the viral shedding rate, with probability of social distancing being the next critical factor. Individually initiated social isolation was effective when initiated in response to a single infected contact. For each of these control measures, the total number of infections exhibits a sharp phase transition as the strength of the measure is varied.

Coronavirus Infections/transmission , Models, Theoretical , Pneumonia, Viral/transmission , Asymptomatic Diseases , Betacoronavirus/isolation & purification , Betacoronavirus/physiology , COVID-19 , Coronavirus Infections/epidemiology , Coronavirus Infections/pathology , Coronavirus Infections/virology , Epidemics , Humans , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , SARS-CoV-2 , Virus Shedding
Nat Commun ; 11(1): 5874, 2020 11 18.
Article in English | MEDLINE | ID: covidwho-1387320


Non-structural proteins (nsp) constitute the SARS-CoV-2 replication and transcription complex (RTC) to play a pivotal role in the virus life cycle. Here we determine the atomic structure of a SARS-CoV-2 mini RTC, assembled by viral RNA-dependent RNA polymerase (RdRp, nsp12) with a template-primer RNA, nsp7 and nsp8, and two helicase molecules (nsp13-1 and nsp13-2), by cryo-electron microscopy. Two groups of mini RTCs with different conformations of nsp13-1 are identified. In both of them, nsp13-1 stabilizes overall architecture of the mini RTC by contacting with nsp13-2, which anchors the 5'-extension of RNA template, as well as interacting with nsp7-nsp8-nsp12-RNA. Orientation shifts of nsp13-1 results in its variable interactions with other components in two forms of mini RTC. The mutations on nsp13-1:nsp12 and nsp13-1:nsp13-2 interfaces prohibit the enhancement of helicase activity achieved by mini RTCs. These results provide an insight into how helicase couples with polymerase to facilitate its function in virus replication and transcription.

Betacoronavirus/chemistry , Betacoronavirus/physiology , Virus Replication , Betacoronavirus/genetics , Betacoronavirus/metabolism , Binding Sites , Cryoelectron Microscopy , Humans , Methyltransferases/chemistry , Methyltransferases/genetics , Methyltransferases/metabolism , Models, Molecular , Mutation , Protein Binding , Protein Conformation , RNA Helicases/chemistry , RNA Helicases/genetics , RNA Helicases/metabolism , RNA, Viral/metabolism , SARS-CoV-2 , Structure-Activity Relationship , Transcription, Genetic , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/genetics , Viral Nonstructural Proteins/metabolism
ACS Nano ; 14(8): 9364-9388, 2020 08 25.
Article in English | MEDLINE | ID: covidwho-1387150


The SARS-Cov-2 pandemic has spread worldwide during 2020, setting up an uncertain start of this decade. The measures to contain infection taken by many governments have been extremely severe by imposing home lockdown and industrial production shutdown, making this the biggest crisis since the second world war. Additionally, the continuous colonization of wild natural lands may touch unknown virus reservoirs, causing the spread of epidemics. Apart from SARS-Cov-2, the recent history has seen the spread of several viral pandemics such as H2N2 and H3N3 flu, HIV, and SARS, while MERS and Ebola viruses are considered still in a prepandemic phase. Hard nanomaterials (HNMs) have been recently used as antimicrobial agents, potentially being next-generation drugs to fight viral infections. HNMs can block infection at early (disinfection, entrance inhibition) and middle (inside the host cells) stages and are also able to mitigate the immune response. This review is focused on the application of HNMs as antiviral agents. In particular, mechanisms of actions, biological outputs, and limitations for each HNM will be systematically presented and analyzed from a material chemistry point-of-view. The antiviral activity will be discussed in the context of the different pandemic viruses. We acknowledge that HNM antiviral research is still at its early stage, however, we believe that this field will rapidly blossom in the next period.

Antiviral Agents/therapeutic use , Betacoronavirus , Coronavirus Infections/therapy , Nanostructures/therapeutic use , Pandemics , Pneumonia, Viral/therapy , Adaptive Immunity , Betacoronavirus/drug effects , Betacoronavirus/physiology , Betacoronavirus/ultrastructure , COVID-19 , Coronavirus Infections/epidemiology , Coronavirus Infections/virology , Drug Delivery Systems , Fullerenes/therapeutic use , Host Microbial Interactions/drug effects , Humans , Immunity, Innate , Metal Nanoparticles/therapeutic use , Models, Biological , Nanotechnology , Pneumonia, Viral/epidemiology , Pneumonia, Viral/virology , Reactive Oxygen Species/therapeutic use , SARS-CoV-2 , Virus Internalization/drug effects
Microbes Infect ; 22(4-5): 226-229, 2020.
Article in English | MEDLINE | ID: covidwho-1386324


During virus infection, host toll-like receptors (TLRs) can recognize different pathogen-associated molecular patterns and trigger the innate immune response. TLR7/8 can identify the single-stranded RNA (ssRNA) of the virus. This study aimed to search ssRNA sequences recognized by TLR7/8 from the SARS-CoV-2, SARS-CoV, and MERS-CoV whole genomes by a bioinformatic technique. The immunoinformatic approach showed that the SARS-CoV-2 genome has more ssRNA fragments that could be recognized by TLR7/8 than the SARS-CoV genome. These findings suggest innate immune hyperactivation by SARS-CoV-2. This activity is possibly able to provoke a robust proinflammatory response via TLR7/8 recognition and cause acute lung injury.

Betacoronavirus/physiology , Coronavirus Infections/virology , Middle East Respiratory Syndrome Coronavirus/physiology , Pneumonia, Viral/virology , SARS Virus/physiology , Toll-Like Receptor 7/physiology , Toll-Like Receptor 8/physiology , COVID-19 , Computational Biology , Genome, Viral , Humans , Immunity, Innate , Pandemics , SARS-CoV-2 , Virus Attachment