Bulletin of the American Physical Society
APS March Meeting 2022
Volume 67, Number 3
Monday–Friday, March 14–18, 2022; Chicago
Session M04: COVID I. Physics of COVID-19 and PandemicsFocus Recordings Available
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Sponsoring Units: DBIO GMED Chair: Ben Greenbaum, Memorial Sloan Kettering Cancer Center Room: McCormick Place W-176C |
Wednesday, March 16, 2022 8:00AM - 8:36AM |
M04.00001: Using molecular simulation to interpret weak cryo-EM density for the Spike protein post-fusion complex Invited Speaker: Karissa Sanbonmatsu The Spike protein plays a key role in viral entry during SARS-CoV-2 infection and is central to the Pfizer and Moderna COVID-19 vaccines. Understanding how the protein works in molecular detail is critical to further optimization of vaccines and therapies. While the structure of many regions of the Spike protein in several conformations has been solved via cryo-EM, the region of the Spike protein that anchors the virus to the host (fusion peptide region) remains elusive. For example, in the cryo-EM reconstruction of the fusion complex, this region has very weak cryo-EM density. Here, we use our cryo_fit method to produce structural ensembles of the spike protein complex, including the fusion peptide, highly consistent with the strong and weak density observed experimentally. Our simulated cryo-EM maps show agreement with the experimentally determined cryo-EM maps for full post-fusion complex (‘fusion state’), including the fusion peptide and fusion peptide proximal regions. |
Wednesday, March 16, 2022 8:36AM - 8:48AM |
M04.00002: Sterically confined rearrangements of SARS-CoV-2 Spike protein control cell invasion Esteban Dodero Rojas Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly contagious, and transmission involves a series of processes that may be targeted by vaccines and therapeutics. During transmission, host cell invasion is controlled by a large-scale (200–300 Å) conformational change of the Spike protein. This conformational rearrangement leads to membrane fusion, which creates transmembrane pores through which the viral genome is passed to the host. During Spike-protein-mediated fusion, the fusion peptides must be released from the core of the protein and associate with the host membrane. While infection relies on this transition between the prefusion and postfusion conformations, there has yet to be a biophysical characterization reported for this rearrangement. That is, structures are available for the endpoints, though the intermediate conformational processes have not been described. Interestingly, the Spike protein possesses many post-translational modifications, in the form of branched glycans that flank the surface of the assembly. With the current lack of data on the pre-to-post transition, the precise role of glycans during cell invasion has also remained unclear. To provide an initial mechanistic description of the pre-to-post rearrangement, an all-atom model with simplified energetics was used to perform thousands of simulations in which the protein transitions between the prefusion and postfusion conformations. These simulations indicate that the steric composition of the glycans can induce a pause during the Spike protein conformational change. We additionally show that this glycan-induced delay provides a critical opportunity for the fusion peptides to capture the host cell. In contrast, in the absence of glycans, the viral particle would likely fail to enter the host. This analysis reveals how the glycosylation state can regulate infectivity, while providing a much-needed structural framework for studying the dynamics of this pervasive pathogen. |
Wednesday, March 16, 2022 8:48AM - 9:00AM |
M04.00003: Helium-ion microscopy reveals an intra-cytoplasmic route for SARS-CoV-2 cell-cell transmission Antonio Merolli, Leila Kasaei, Santhamani Ramasamy, Afsal Kolloli, Ranjeet Kumar, Selvakumar Subbian, Leonard C Feldman The usual picture of SARS-CoV-2 transmission is extra-cytoplasmic, that is: virions (the basic virus complex) from outside enter the host cell by docking their spike glycoproteins to the Angiotensin Converting Enzyme 2 (ACE2) present on the host cell membrane. After intracellular entry, newly replicated virions are released outside the host cell to propagate the infection via the same ACE2 docking mechanism. Antibodies may attack the extra-cellular virions, thus providing immunity. We used scanning Helium-ion microscopy to study the virion propagation process in in-vitro culture of Vero E6 cells infected with mNeonGreen-SARS-CoV-2. The unprecedented resolution of HeIM and its capacity to scan a large number of samples, showed the presence of: 1)-long tunneling nanotubes that connect two or more cells over submillimeter distances; 2)-large scale multiple cell fusion events; and 3)-abundant extracellular vesicles of various sizes. Tunneling nanotubes and cell fusion events are not significanlty present in uninfected samples. Taken together, these three ultrastructural features reveal a new intra-cytoplasmic modality to connect SARS-CoV-2 infected cells; this modality may act as an alternative route of viral transmission, different from the extra-cytoplasmic ACE2 docking mechanism. Our findings may explain the ability of SARS-CoV-2 to survive the immune surveillance of the host organism and may explain clinical observations such as the breakthrough infections. |
Wednesday, March 16, 2022 9:00AM - 9:12AM |
M04.00004: Extracellular vimentin as a target against SARS-CoV-2 host cell invasion Maxx Swoger, Łukasz Suprewicz, Sarthak Gupta, Danielle Germann, Paul Janmey, J. M Schwarz, Robert Bucki, Alison E Patteson Pathogens infect cells by targeting receptors on the surface of host cells. SARS-CoV-2 does this by specifically binding the viral spike protein to host cell's angiotensin-converting enzyme 2 (ACE2) receptors, however different cell types expressing ACE2 are shown to be infected at unequal rates, suggesting other factors are contributing to infection. Vimentin is a cytoskeletal polymer that gives the cell's interior its strength, however there is a growing body of evidence indicating presence and function of vimentin on the cell surface. Extracellular vimentin is a cell surface protein that may serve as a binding partner to ACE2, facilitating the interaction with the spike protein. Here we present results indicating that extracellular vimentin may serves as an important binding partner for the SARS-CoV-2 spike protein by showing that antibodies against vimentin reduced SARS-CoV-2 pseudoviral infection of ACE2-expressing cells. These results provide new strategies for therapeutic treatments for SARS-CoV-2 by focusing on targeting extracellular vimentin in host cells. |
Wednesday, March 16, 2022 9:12AM - 9:24AM |
M04.00005: Binding Mechanism of SARS-CoV(-2) into hACE2 Receptor Narayan P Adhikari, Bidhya Thapa, Rajendra P Koirala, Shyam P Khanal, Jhulan Powrel, Lokendra S Dhami, Lalit Dhami
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Wednesday, March 16, 2022 9:24AM - 10:00AM |
M04.00006: Modeling within-host SARS-CoV-2 dynamics and the relationship between viral load and a person's infectiousness Invited Speaker: Alan S Perelson The within-host viral kinetics of SARS-CoV-2 infection and how they relate to a person’s infectiousness are not well understood. This limits our ability to quantify the impact of interventions on viral transmission.We developed variety of viral dynamic models of SARS-CoV-2 infection in both the upper and lower respiratory tracts (URT and LRT) to gain a quantitative understanding of the infection dynamics of SARS-CoV-2. The models we studied compared the roles of target-cell limitation versus the roles of the innate and the adaptive immune response as well as the role of spatial infection in the LRT. We fit these models to clinical data to estimate key within-host parameters such as the infected cell half-life and the within-host reproductive number. We then develop a model linking viral load (VL) in the URT to infectiousness and showed a person’s infectiousness increases sub-linearly with VL and that the logarithm of the VL in the upper respiratory tract (URT) is a better surrogate of infectiousness than the VL itself. Overall, our models provide a quantitative framework for inferring the impact of therapeutics and vaccines that lower VL on the infectiousness of individuals and for evaluating rapid testing strategies. |
Wednesday, March 16, 2022 10:00AM - 10:12AM |
M04.00007: Effect of diurnal temperature range on SARS-CoV-2 lifetime Te Faye Yap, Colter J Decker, Daniel J Preston Epidemiological studies indicate that the daily mean temperature and the diurnal temperature range (DTR) are inversely correlated with the likelihood of SARS-CoV-2 transmission. These statistical studies rely on transmission data obtained after the disease has spread across various climates; the results do not provide a physical understanding of virus lifetime. On the other hand, reaction kinetics models have only been used to describe the effect of constant-temperature surroundings on virus lifetime and do not address the inverse correlation between virus lifetime and DTR. This study provides a framework, based on the rate law and Arrhenius equation, for modeling virus lifetime in an environment with a time-varying temperature profile. The virus inactivation rate has an exponential dependence on temperature, which causes temperature fluctuations above the mean temperature to increase the instantaneous rate of inactivation to a greater extent than identical fluctuations below the mean. This asymmetric behavior results in shorter virus lifetimes, offering an explanation for the inverse correlation between the number of COVID-19 cases and DTR, and indicating that regions with similar daily mean temperatures may have different virus transmission rates depending on DTR. |
Wednesday, March 16, 2022 10:12AM - 10:24AM |
M04.00008: A model based on mobility data explains localization-delocalization properties in the spread of diseases among communities Guillaume Le Treut We investigate the modes of propagation of an epidemic across a network of communities. Specifically, we consider a spatial variant of the famous SIR model. We first show that the infectivity matrix, characterizing the spread of the infection, can be related to the matrix of fluxes between communities, which we obtained from cell phone mobility data recorded in the USA between March 2020 and February 2021. We applied this model to the 2020 pandemic of SARS-CoV-2, and compared its predictions to empirical data. By fitting just one global parameter representing the frequency of interaction between individuals, we found that the number of susceptible and infected individuals predicted by the model agreed with the empirical reports locally, in each community, thus validating our model. The effect of "shelter-in-place" policies instated throughout the USA at the onset of the pandemic is clearly seen in our results. We then consider the effect an alternative policy would have had, namely restricting long-range travels. We find that this policy is successful in decreasing the epidemic size, but it requires a substantial restriction on the distance traveled. Due to the mode of propagation to nearest-neighbors, this policy leads to infection waves. On a simplified two-dimensional rectangular lattice, we show that there is a regime in which an infection wave exists. We give the differential equation satisfied by the wave profile, and show it is in agreement with numerical simulations. We hope this type of approach, integrating real-time measurements into epidemiological models, will lead to accurate short-term predictions about the spread of infectious agents. |
Wednesday, March 16, 2022 10:24AM - 10:36AM |
M04.00009: Inferring the effects of mutations on SARS-CoV-2 transmission from genomic surveillance data John P Barton, Brian Lee, Syed Ahmed, Elizabeth Finney, Ahmed Quadeer, Muhammad Sohail, Matthew McKay Pathogens can acquire mutations that affect how easily they are transmitted to others. Rapidly identifying more transmissible variants could aid in public health decisions. However, it is challenging to disentangle the effects of individual mutations from complex data, and the popular phylogenetic approaches for analyzing viral sequences are computationally intractable for large data sets. Here we describe a Bayesian inference method to infer the effects of mutations on viral transmission. Our model extends the standard susceptible-infected-recovered (SIR) epidemiological model by including features such as superspreading and the spread of infection through travel, which are relevant for SARS-CoV-2. Using a path integral approach originally applied in population genetics [1], we obtain analytical estimates for the transmission effects of mutations that best explain genomic surveillance data. Our analysis reveals hotspots for transmission-affecting mutations throughout the SARS-CoV-2 genome, highlighting well-known Spike mutations as well as less-studied mutations in other proteins. Crucially, we also show that our model is capable of rapidly detecting new variants with enhanced transmissibility, which we demonstrate through an analysis of the rise of the Alpha variant in the UK. |
Wednesday, March 16, 2022 10:36AM - 10:48AM |
M04.00010: Back projection methods for the refinement of SARS-Cov-2 sequence data Elizabeth Finney, John P Barton, Brian Lee, Syed Faraz Ahmed, Ahmed Abdul Quadeer, Muhammad Saqib Sohail, Matthew McKay
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Wednesday, March 16, 2022 10:48AM - 11:00AM |
M04.00011: Critical behavior of the diffusive susceptible-infected-recovered model Shengfeng Deng, Geza Odor The critical behavior of the classical non-diffusive susceptible-infected-recovered model on lattices, where at least the recovered individuals stay immobile, had been immensely studied and well understood. By performing numerical simulations on a square lattice, we show that diffusion for all agents in the susceptible-infected-recovered model constitutes a singular perturbation, which induces asymptotically novel dynamical and stationary critical behavior distinct from the non-diffusive model. Dynamical simulations starting from a single infected seed yield diffusion-rate independent exponents that still render the hyperscaling relation held. Moreover, data collapse results for the number of active agents reveal that there exists an asymptotic universal scaling function independent of the implemented diffusion rate. Stationary critical properties obtained from finite-size scaling analysis further corroborate the dynamical critical properties through conventional scaling relations. In particular, the diffusive model exhibits a crossover from the classical model before the asymptotic long-time, large-scale regime is approached. |
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