cell transmission
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2021 ◽  
Vol 119 (1) ◽  
pp. e2111400119
Author(s):  
Cong Zeng ◽  
John P. Evans ◽  
Tiffany King ◽  
Yi-Min Zheng ◽  
Eugene M. Oltz ◽  
...  

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible coronavirus responsible for the global COVID-19 pandemic. Herein, we provide evidence that SARS-CoV-2 spreads through cell–cell contact in cultures, mediated by the spike glycoprotein. SARS-CoV-2 spike is more efficient in facilitating cell-to-cell transmission than is SARS-CoV spike, which reflects, in part, their differential cell–cell fusion activity. Interestingly, treatment of cocultured cells with endosomal entry inhibitors impairs cell-to-cell transmission, implicating endosomal membrane fusion as an underlying mechanism. Compared with cell-free infection, cell-to-cell transmission of SARS-CoV-2 is refractory to inhibition by neutralizing antibody or convalescent sera of COVID-19 patients. While angiotensin-converting enzyme 2 enhances cell-to-cell transmission, we find that it is not absolutely required. Notably, despite differences in cell-free infectivity, the authentic variants of concern (VOCs) B.1.1.7 (alpha) and B.1.351 (beta) have similar cell-to-cell transmission capability. Moreover, B.1.351 is more resistant to neutralization by vaccinee sera in cell-free infection, whereas B.1.1.7 is more resistant to inhibition by vaccinee sera in cell-to-cell transmission. Overall, our study reveals critical features of SARS-CoV-2 spike-mediated cell-to-cell transmission, with important implications for a better understanding of SARS-CoV-2 spread and pathogenesis.


2021 ◽  
Author(s):  
Rebecca T van Dorsten ◽  
Lucia Reh ◽  
Alexandra Trkola ◽  
Lynn Morris ◽  
Penny L Moore

Broadly neutralizing antibodies (bNAbs) are able to prevent HIV infection following passive administration. Single-chain variable fragments (scFv) may have advantages over IgG as their smaller size permits improved diffusion into mucosal tissues. We have previously shown that scFv of bNAbs retain significant breadth and potency against cell-free viral transmission in a TZM-bl assay. However, scFv have not been tested for their ability to block cell-cell transmission, a model in which full-sized bNAbs lose potency. We tested 4 scFv (CAP256.25, PGT121, 3BNC117 and 10E8v4) compared to IgG, in free-virus and cell-cell neutralization assays in A3.01 cells, against a panel of seven heterologous viruses. We show that free-virus neutralization titers in the TZM-bl and A3.01 assays were not significantly different, and confirm that scFv show a 1 to 32-fold reduction in activity in the cell-free model, compared to IgG. However, whereas IgG show 3.4 to 19-fold geometric mean potency loss in cell-cell neutralization compared to free-virus transmission, scFv had more comparable activity in the two assays, with only a 1.3 to 2.3-fold reduction. Geometric mean IC 50 of scFv for cell-cell transmission ranged from 0.65 μg/ml (10E8v4) to 2.3 μg/ml (3BNC117) with IgG and scFv neutralization showing similar potency against cell-associated transmission. Therefore, despite the reduced activity of scFv in cell-free assays, their retention of activity in the cell-cell format may make scFv useful for the prevention of both modes of transmission in HIV prevention studies. Importance Broadly neutralizing antibodies (bNAbs) are a major focus for passive immunization against HIV, with the recently concluded HVTN AMP (Antibody Mediated Protection) trial providing proof of concept. Most studies focus on cell-free HIV, however cell-associated virus may play a significant role in HIV infection, pathogenesis and latency. Single-chain variable fragments (scFv) of antibodies may have increased tissue penetration, and reduced immunogenicity. We previously demonstrated that scFv of four HIV-directed bNAbs (CAP256-VRC26.25, PGT121, 3BNC117 and 10E8v4) retain significant potency and breadth against cell-free HIV. As some bNAbs have been shown to lose potency against cell-associated virus, we investigated the ability of bNAb scFv to neutralize this mode of transmission. We demonstrate that unlike IgG, scFv of bNAbs are able to neutralize cell-free and cell-associated virus with similar potency. These scFv, which show functional activity in the therapeutic range, may therefore be suitable for further development as passive immunity for HIV prevention.


2021 ◽  
Author(s):  
Conrad En-Zuo Chan ◽  
Ching-Ging Ng ◽  
Angeline P. C. Lim ◽  
Shirley Gek-Kheng Seah ◽  
De Hoe Chye ◽  
...  

A human monoclonal antibody panel (PD4, PD5, PD7, SC23 and SC29) was isolated from the B cells of convalescent patients and used to examine the S protein in SARS-CoV-2-infected cells. While all five antibodies bound conformational-specific epitopes within SARS-CoV-2 Spike (S) protein, only PD5, PD7, and SC23 were able to bind to the Receptor Binding Domain (RBD). Immunofluorescence microscopy was used to examine the S protein RBD in cells infected with the Singapore isolates SARS-CoV-2/0334 and SARS-CoV-2/1302. The RBD-binders exhibited a distinct cytoplasmic staining pattern that was primarily localised within the Golgi complex and was distinct from the diffuse cytoplasmic staining pattern exhibited by the non-RBD binders (PD4 and SC29). These data indicated that the S protein adopted a conformation in the Golgi complex that enabled the RBD recognition by the RBD-binders. The RBD-binders also recognised the uncleaved S protein indicating that S protein cleavage was not required for RBD recognition. Electron microscopy indicated high levels of cell-associated virus particles, and multiple cycle virus infection using RBD-binder staining provided evidence for direct cell-to-cell transmission for both isolates. Although similar levels of RBD-binder staining was demonstrated for each isolate, the SARS-CoV-2/1302 exhibited slower rates of cell-to-cell transmission. These data suggest that a conformational change in the S protein occurs during its transit through the Golgi complex that enables RBD recognition by the RBD-binders, and suggests that these antibodies can be used to monitor S protein RBD formation during the early stages of infection.


Author(s):  
Zeyu Shi ◽  
Yangzhou Chen ◽  
Jingyuan Zhan ◽  
Xiangyu Guo ◽  
Shuke An

To describe the dynamics of traffic flow in the urban link accurately, the waves which generate at intersections are adopted as the influencing factors of traffic flow. Based on the urban traffic waves, a wave-oriented variable cell transmission model (WVCTM) is proposed to illustrate the urban traffic flow. In this model, the average density and length are the state variables. The cells are divided by traffic waves. The upstream cell is the influence area of the waves at the upstream intersection, the downstream cell is the influence area of the waves at the downstream intersection, and the rest is the mediate cell. Consistent with the fundamental diagram and the cell division, the traffic states of urban links are divided into six modes. The variation of modes is explained by hybrid automata. Finally, an experiment is designed to verify the feasibility of WVCTM. The data in the experiment come from the actual scene. Compared with the cell transmission model (CTM) and variable-length CTM (VCTM), WVCTM possesses the valuable performance to predict the traffic states. Likewise, it is rational that WVCTM can correctly illustrate the urban traffic flow.


2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Facundo Storani ◽  
Roberta Di Pace ◽  
Francesca Bruno ◽  
Chiara Fiori

Abstract Background This paper compares a hybrid traffic flow model with benchmark macroscopic and microscopic models. The proposed hybrid traffic flow model may be applied considering a mixed traffic flow and is based on the combination of the macroscopic cell transmission model and the microscopic cellular automata. Modelled variables The hybrid model is compared against three microscopic models, namely the Krauß model, the intelligent driver model and the cellular automata, and against two macroscopic models, the Cell Transmission Model and the Cell Transmission Model with dispersion, respectively. To this end, three main applications were considered: (i) a link with a signalised junction at the end, (ii) a signalised artery, and (iii) a grid network with signalised junctions. Results The numerical simulations show that the model provides acceptable results. Especially in terms of travel times, it has similar behaviour to the microscopic model. By contrast, it produces lower values of queue propagation than microscopic models (intrinsically dominated by stochastic phenomena), which are closer to the values shown by the enhanced macroscopic cell transmission model and the cell transmission model with dispersion. The validation of the model regards the analysis of the wave propagation at the boundary region.


Author(s):  
Wei Gao ◽  
Man Liang

Air traffic congestion is caused by the unbalance between increasing traffic demand and saturating capacity. Flight delay not only causes huge economical lost, but also has very negative environmental impact in the whole air transportation system. In order to identify the impact of extended TMA on airport capacity, an airspace capacity assessment method based on augmented cell transmission model was proposed. Firstly, the airspace structure was modeled with points, segments, layers, and cells. Secondly, mixed integer linear programming model was built up with maximum throughput or capacity as the objective function. Finally, genetic algorithm was used to find the optimal result, and the results were validated by comparing with the fast-time simulation results generated by total airspace and airport modeler (TAAM) software. It is found that the proposed method could achieve a relatively accurate result in a much affordable and fast way. The numerical results could be very helpful for air traffic controllers to analyze the dynamic traffic flow entering and exiting TMA, so as to make decisions via reasonable analysis and do planning in advance by referring to the airport capacity.


Author(s):  
Qing Ge ◽  
Xia Wang ◽  
Libin Rong

In this paper, we propose a reaction–diffusion viral infection model with nonlinear incidences, cell-to-cell transmission, and a time delay. We impose the homogeneous Neumann boundary condition. For the case where the domain is bounded, we first study the well-posedness. Then we analyze the local stability of homogeneous steady states. We establish a threshold dynamics which is completely characterized by the basic reproduction number. For the case where the domain is the whole Euclidean space, we consider the existence of traveling wave solutions by using the cross-iteration method and Schauder’s fixed point theorem. Finally, we study how the speed of spread in space affects the spread of cells and viruses. We obtain the existence of the wave speed, which is dependent on the diffusion coefficient.


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