Besides receptor binding, the proteolytic cleavage of coronavirus S proteins by host cell-derived proteases is essential to permit fusion 24 , These data support the evaluation of the TMPRSS2 inhibitors camostat mesylate and nafamostat mesylate in clinical trials, since in vitro studies have demonstrated their potent antiviral activity against emerging coronaviruses, including SARS-CoV-2 refs 29 , 31 , SARS-CoV primarily targets pneumocytes and lung macrophages in lower respiratory tract tissues, where ACE2 is predominantly expressed, consistent with the lower respiratory tract disease resulting from SARS-CoV infection and the limited viral spread 33 — Cleavage results in enhanced infection and has been proposed to be a key event in SARS-CoV-2 evolution as efficient S protein cleavage is required for successful infection and is a main determinant in overcoming species barriers 10 — 12 , 15 , 16 , 28 , 30 , 44 — This pre-processing of the SARS-CoV-2 S protein by furin may contribute to the expanded cell tropism and zoonotic potential and might increase transmissibility 16 , Importantly, such cleavage sites have not been identified in other members of the Sarbecovirus genus However, there are multiple instances of furin-like cleavage site acquisitions that occurred independently during coronavirus evolution and similar cleavage sites are present in other human coronaviruses such as HCoV-HKU1 ref.
Recently, an independent insertion of amino acids PAA at the same region of the S protein has been identified in the bat coronavirus RmYN02 ref.
Such independent insertion events highlight the zoonotic potential of bat severe acute respiratory syndrome-related coronaviruses and may increase the possibility of future outbreaks. The importance of coronavirus S protein-mediated receptor binding and temporally coordinated conformational rearrangements that result in membrane fusion make this process a prime target of innate and adaptive antiviral responses.
Notably, a screen involving several hundred interferon-stimulated genes identified lymphocyte antigen 6 family member E Ly6E as a potent inhibitor of coronavirus fusion Ly6E-mediated inhibition of coronavirus entry was demonstrated for various coronaviruses, including SARS-CoV-2, and seems to have pivotal importance in protecting the haematopoietic immune cell compartment in a mouse model of coronavirus infection. Moreover, the exposure of S protein on the surface of the virion results in the induction of specific neutralizing humoral immune responses Coronavirus S proteins are heavily glycosylated, which promotes immune evasion by shielding epitopes from neutralizing antibodies 16 , 53 , Several specific or cross-reactive antibodies that bind the SARS-CoV-2 S protein have been recently reported and their administration to infected patients could potentially provide immediate protection 55 — Taken together, the exploitation of a combination of multiple neutralizing antibodies that do not compete for overlapping epitopes may not only result in synergistic improvements but also impede the appearance of escape mutations.
Sequence identity differed highly upon comparison of individual genes and domains, indicating frequent recombination events in natural reservoir hosts 14 , 23 , Moreover, the environmental separation of bats and humans might favour the existence of an intermediate host, responsible for SARS-CoV-2 adaption and transmission into the human population, just like civet cats were suggested in the SARS-CoV outbreak The example of pangolin CoV MP, which shared five essential amino acids for ACE2 binding in the S with SARS-CoV-2 highlights the existence of a variety of unidentified betacoronaviruses in wild-life animals and their roles as possible intermediate hosts The release of the coronavirus genome into the host cell cytoplasm upon entry marks the onset of a complex programme of viral gene expression, which is highly regulated in space and time.
This determines the stoichiometry between pp1a and pp1ab, with pp1a being approximately 1. Sixteen non-structural proteins are co-translationally and post-translationally released from pp1a nsp1—11 and pp1ab nsp1—10, nsp12—16 upon proteolytic cleavage by two cysteine proteases that are located within nsp3 papain-like protease; PL pro and nsp5 chymotrypsin-like protease Fig.
The protease residing in nsp5 is frequently referred to as 3C-like protease 3CL pro , because of its similarities to the picornaviral 3C protease, or as main protease M pro , because it is responsible for proteolytic processing of the majority of polyprotein cleavage sites. Proteolytic release of nsp1 is known to occur rapidly 62 , which enables nsp1 to target the host cell translation machinery 63 — Nsp2—16 compose the viral RTC and are targeted to defined subcellular locations where interactions with host cell factors determine the course of the replication cycle 66 — Nsp2—11 are believed to provide the necessary supporting functions to accommodate the viral RTC, such as modulating intracellular membranes, host immune evasion and providing cofactors for replication, whereas nsp12—16 contain the core enzymatic functions involved in RNA synthesis, RNA proofreading and RNA modification 4 , Coronavirus polyprotein processing and domains of non-structural proteins nsp are illustrated for severe acute respiratory syndrome-related coronaviruses.
Proteolytic cleavage of the polyproteins pp1a and pp1ab is facilitated by viral proteases residing in nsp3 PL pro and nsp5 M pro. PL pro proteolytically releases nsp1, nsp2, nsp3 and the amino terminus of nsp4 from the polyproteins pp1a and pp1ab indicated by the blue arrows.
M pro proteolytically releases nsp5—16 and the carboxy terminus of nsp4 from the polyproteins pp1a and pp1ab indicated by the red arrows Conserved domains and known functions are schematically depicted for nsp1—16 refs 4 , 66 , 67 , One such target is M pro , which resides in nsp5. M pro releases the majority of nsps from the polyproteins and is essential for the viral life cycle.
Furthermore, as M pro is very sequence specific, compounds that structurally mimic those cleavage sites can specifically target the viral protease with little or no impact on host cellular proteases 75 — Based on structural analysis of the protein, multiple research groups have successfully developed lead compounds that block M pro function in cell culture assays, thus providing frameworks that could aid in rapid drug discovery 75 , Viral genomic replication is initiated by the synthesis of full-length negative-sense genomic copies, which function as templates for the generation of new positive-sense genomic RNA.
These newly synthesized genomes are used for translation to generate more nsps and RTCs or are packaged into new virions. The discontinuous step of negative strand RNA synthesis results in the production of a set of negative-strand sgRNAs that are then used as templates to synthesize a characteristic nested set of positive-sense sg mRNAs that are translated into structural and accessory proteins. Schematic depiction of coronaviral RNA synthesis. This process can take place at any TRS-B and will collectively result in the production of the characteristic nested set of coronaviral mRNAs.
However, it remains to be determined whether all of these non-canonical sgRNAs truly arise by discontinuous transcription or whether they represent RNAs that result from recombination.
Nevertheless, similar findings were previously reported for other coronaviruses, including MHV 61 and HCoVE 81 , which indicates an enhanced coding potential for coronaviruses Overall, these unexpected fusion events may drive coronavirus evolution through variant generation, and novel ORFs could encode additional accessory proteins that are involved in either viral replication or modulation of the host immune response 60 , The RdRP residing in nsp12 is the centrepiece of the coronavirus RTC and has been suggested as a promising drug target as it is a crucial enzyme in the virus life cycle both for replication of the viral genome but also for transcription of sgRNAs.
The structural similarities of the RdRP active site, including conserved key amino acid residues, with other positive-sense RNA viruses suggest the possibility to repurpose known drugs that are effective against other RNA viruses One of the most promising candidates is the phosphoramidate remdesivir RDV , which, in its triphosphate form, acts as a substrate for viral RdRPs and competes with ATP In contrast to classic nucleoside analogues that lead to immediate termination of the synthesis reaction after incorporation, the RdRP continues for three nucleotides after RDV has been incorporated before chain termination.
Nucleotide analogues like RDV may have limited efficacy owing to the proofreading function of the exonuclease domain contained in nsp14 ExoN The corrective function that is exerted by ExoN is not only responsible for maintaining the stability of the coronavirus genome but also enables the excision of erroneous mutagenic nucleotides 71 , The mode of action observed for RDV might be an explanation for its increased efficiency over other nucleoside analogues as the delayed-chain termination could lead to improved evasion from the proofreading function of nsp The current model suggests steric hindrance as a likely reason for termination, disturbing the positioning of the RNA and thus hampering the translocation to the next position 86 , However, a recent randomized, double-blind, placebo-controlled clinical trial in humans with severe COVID showed limited clinical efficacy of RDV treatment 92 and further studies will be necessary.
Another promising candidate is the purine analogue favipiravir FPV , which has been shown to effectively target multiple RNA viruses Although the mechanism of action is not yet completely understood, a recent study of the in vitro mechanism of FPV suggested a combination of chain termination, slowed RNA synthesis and lethal mutagenesis as the mode of action against SARS-CoV-2, which indicates that FPV might be used to effectively restrict viral replication Indeed, results of an experimental pilot study showed that using FPV as treatment against COVID led to increased recovery and faster viral clearance times in treated patients compared to control treatments Clinical studies with both RDV and FPV are currently ongoing and will establish whether these compounds are effective antivirals to treat coronavirus infections The structural proteins of SARS-CoV-2 have not yet been assessed in terms of their role in virus assembly and budding.
In general, coronavirus structural proteins assemble and assist in the budding of new virions at the endoplasmic reticulum ER -to-Golgi compartment that are suggested to exit the infected cell by exocytosis 95 — During this process, viral interference with lysosomal acidification, lysosomal enzyme activity and antigen presentation was demonstrated. In addition, ORF10 has been postulated to be located downstream of the N gene. For example, in the case of ORF10, recent sequencing data questioned whether ORF10 is actually expressed, as the corresponding sgRNA could only be detected once in the entire dataset Furthermore, using proteomics approaches, the ORF10 protein has not been found in infected cells , , whereas ribosome profiling data suggested that ORF10 may be translated The accessory genes display a high variability among coronavirus groups and usually show no sequence similarity with other viral and cellular proteins.
Although they are not required for virus replication in cell culture 4 , 5 , they are, to some extent, conserved within the respective virus species and are suspected to have important roles in the natural host. Although there are indications that ORF3b could exhibit its interferon antagonistic function also in a truncated form 99 , it has not yet been found to be expressed at the protein level in virus-infected cells , Whereas the early isolates from human patients contained a full-length ORF8, a deletion of 29 nucleotides was observed in all SARS-CoV strains during the middle-to-late stages.
Furthermore, less frequent deletion events were also observed, including an nucleotide deletion and a nucleotide deletion, which led to a complete loss of ORF8 refs , , suggesting a possible benefit of SARS-CoV ORF8 deletions in vivo.
This may indicate a tendency towards host adaption and decreased pathogenicity or, alternatively, that the ORF8 protein is dispensable in humans, whereas it is required in the natural host. Primary interactions between nsps and host cell factors during the early coronavirus replication cycle initiate the biogenesis of replication organelles 66 , , Although mechanisms underlying replication organelle formation are not fully understood, the concerted role of the membrane-spanning nsp3, nsp4 and nsp6 has been implicated in diverting host endomembranes into replication organelles — Detailed electron microscopy investigations have described the phenotypic appearance and extent of membrane modifications induced by coronaviruses to accommodate viral replication.
Coronavirus infection, like many other positive-sense RNA viruses, manifests in the generation of ER-derived and interconnected perinuclear double-membrane structures such as double-membrane vesicles DMVs , convoluted membranes and the recently discovered double-membrane spherules , — Interestingly, these structures are highly dynamic and develop during the viral life cycle , Even though replicase subunits — notably SARS-CoV nsp3, nsp5 and nsp8 — have been shown to be anchored on convoluted membranes, to date, the specific location of viral RNA synthesis remains the most intriguing unanswered question , Although, until recently, no openings towards the cytosol have been observed 97 , , molecular pores involving nsp3 were demonstrated to span DMVs in MHV-infected cells These newly identified structures, which were also observed in SARS-CoVinfected cells, provide a connection between the dsRNA-containing DMV interior and the cytosol, thereby hypothetically rendering newly synthesized viral RNAs available for translation and encapsidation into nascent virions They also provide new opportunities to experimentally address the origin, fate and trafficking routes of viral RNAs contained in DMVs.
Replication organelles are a conserved and characteristic feature of coronavirus replication and, consistent with suggested roles of rewired intracellular membranes in the context of other positive-sense RNA virus infections, they provide a propitious niche with adequate concentrations of macromolecules necessary for RNA synthesis while preventing the exposure of viral replication intermediates to cytosolic innate immune sensors 95 , The functional dissection of coronavirus replication organelles has proven challenging as their contributions to viral fitness and pathogenesis are indistinguishable from functions provided by enzymes of the RTC, which are anchored on the membranes of the replication organelle — Nevertheless, recent studies revealed the overall composition of the coronavirus RTC, with nsp2—nsp16 and the nucleocapsid protein comprising the viral components 68 , Moreover, several genetic and proteomic screening approaches aimed at deciphering essential coronavirus—host interactions and the RTC microenvironment identified supportive roles of the ER and the early secretory system as well as related vesicular trafficking pathways for efficient replication 68 , — and provided a comprehensive list of cellular proteins that are in close proximity to the coronaviral RTC 68 , — Collectively, these studies, in combination with advanced electron microscopy, provide ground for future studies to dissect the microarchitecture of the coronaviral RTC in relation to remodelled ER-derived membranes and to functionally link those structures to processes taking place in close proximity to the RTC such as translation, replication and transcription of viral RNA.
A successful intracellular coronavirus life cycle invariably relies on critical molecular interactions with host proteins that are repurposed to support the requirements of the virus. This includes host factors required for virus entry such as the entry receptor and host cell proteases , factors required for viral RNA synthesis and virus assembly such as ER and Golgi components and associated vesicular trafficking pathways and factors required for the translation of viral mRNAs such as critical translational initiation factors 68 , — A first systematic expression study of SARS-CoV-2 proteins and subsequent affinity purification followed by mass spectrometry identified more than potential coronavirus—host protein interactions.
These systematic screening approaches of large compound libraries that target host proteins provide means of rapidly identifying antiviral repurposed drugs and accelerated clinical availability However, a detailed functional characterization of conserved host pathways that promote coronavirus replication will guide the development of efficacious targeted therapeutics against coronavirus infections.
In addition, coronaviruses efficiently evade innate immune responses. Virus—host interactions in this context are multifaceted and include strategies to hide viral pathogen-associated molecular patterns, such as replication intermediates dsRNA , that may be sensed by cytosolic pattern recognition receptors , The coronaviral RTC also contributes to innate immune evasion through several nsp-encoded functions.
Although these mechanisms have been elucidated in considerable detail for several prototype coronaviruses, data for SARS-CoV-2 are not yet available. Besides the well-conserved functions residing in the nsps that comprise the RTC, additional mechanisms to counteract innate immune responses are known for coronaviruses. For example, nsp1 is rapidly proteolytically released from pp1a and pp1ab and affects cellular translation in the cytoplasm to favour viral mRNAs over cellular mRNA, and thereby also decreases the expression of type I and III interferons and of other host proteins of the innate immune response.
Indeed, a first structural and functional analysis of SARS-CoV-2 nsp1 showed binding of nsp1 to ribosomes and nsp1-mediated impairment of translation Although this property remains to be demonstrated in the context of viral infection, these results suggest that SARS-CoV-2 shares some preserved accessory protein activities with SARS-CoV that interfere with antiviral host responses. Thus, there is a need to establish experimental systems, such as representative animal models to study the transmission and pathogenicity of SARS-CoV-2, primary airway epithelial cultures and organoids to study SARS-CoV-2 replication and host responses to infection in relevant cell types, and reverse genetics systems to study the specific gene functions of SARS-CoV-2 Table 1.
As we currently understand, SARS and COVID are a consequence of virus-encoded functions and delayed interferon responses and, in severe cases, they are associated with dysregulated immune responses and immunopathologies , Indeed, rapid and uncontrolled viral replication of SARS-CoV has been demonstrated to evade the host innate immune activation during its initial steps.
As a consequence, the increase in aberrant pro-inflammatory responses and immune cell infiltration in the lungs provoke tissue damage and contribute to the clinical manifestation of SARS Consistently, host responses, such as cytokine expression, that are known to drive inflammation and immunopathologies have been assessed in studies that revealed that SARS-CoV-2 considerably affects the transcriptional landscape of infected cells by inducing inflammatory cytokine and chemokine signatures 38 , , Although interferon responses have been shown to potently impair SARS-CoV-2 replication, only moderate induction of type I interferon, type II interferon and interferon-stimulated genes was reported 38 , Together, these effects may translate into strong and dysregulated pro-inflammatory responses, while cells display low innate antiviral defence activation as revealed by single-cell transcriptomic studies of nasopharyngeal and bronchial patient samples 38 , , , In severe COVID cases, as opposed to mild cases, aberrant recruitment of inflammatory macrophages and infiltration of T lymphocytes, including cytotoxic T cells, as well as of neutrophils have been measured in the lung , The accumulating evidence of dysregulated pro-inflammatory responses during SARS-CoV-2 infections has led to the use of immune modulators to inhibit hyperactivated pathogenic immune responses , , , In contrast to the SARS-CoV epidemic of almost 20 years ago, improved technologies, such as transcriptomics, proteomics, single-cell RNA sequencing, global single-cell profiling of patient samples, advanced primary 3D cell cultures and rapid reverse genetics, have been valuable tools to understand and tackle SARS-CoV-2 infections.
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Volker Thiel, Email: hc. Corresponding author. Accepted Sep This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source.
This article has been cited by other articles in PMC. Abstract The SARS-CoV-2 pandemic and its unprecedented global societal and economic disruptive impact has marked the third zoonotic introduction of a highly pathogenic coronavirus into the human population. Open in a separate window. The coronavirus virion and life cycle. Box 1 Milestones in coronavirus discovery and research Coronaviruses CoVs are a large family of viruses long known to infect a wide variety of mammalian and avian species, including livestock and companion animals.
However, current NGS technologies fail to capture spatial relationships and dynamic phenotypic changes in cells within tissues. Image analysis techniques powered by machine learning allows capturing spatial relationships among cells and evaluating cellular crosstalk. Imaging data are also translatable to multiscale in silico tissue simulations to estimate dynamics of cell movements and molecular crosstalk.
We have developed an open-source platform, the endothelial cells profiling tool EC-PT , to measure individual EC phenotype within endothelia. ECPT includes tools to measure spatial autocorrelation of features such as NOTCH signalling at single cell level allowing to estimate dynamic molecular crosstalk between neighbouring EC and across the whole endothelium.
We will present data demonstrating previously unappreciated degrees of EC heterogeneity within the same EC monolayer suggesting a high degree of plasticity. Furthermore, we have developed simulations of NOTCH signalling in cell monolayers using Compucell3D and suggesting that such heterogeneity can result from dynamic and relatively fast phenotypic adjustments at the single cell level.
These results provide possible molecular explanations of how EC within the same vascular bed can exert different functions such as proliferation self-renewal , maintenance of endothelial barrier as well as differential responses to drugs and potentially to pathogens. November 4, Meeting Slides: Are here these are the WG's slides, the presentation's slides are linked with the speakers below. Presentations Ulrich Schwarz, Univ.
Heidelberg, Germany. Title: Multiscale modeling of malaria parasites. Abstract: Malaria has been called the most devastating disease every experienced by mankind. Although today we have efficient drugs and even a first vaccine, it still kills around Because the malaria parasite goes through so many different stages during its journey through the mosquito and human hosts, modeling efforts have to focus on specific aspects of high biological and medical relevance.
Here we focus on the skin stage, when the parasite has the form of slender and crescent sporozoites. After release into the host skin during a mosquito blood meal, the malaria sporozoite quickly moves through the connective tissue in search of blood vessels. On a flat substrate, single cells follow circular trajectories with stick-and-slip motion. Using pillar arrays and agent-based computer simulations, we show how this circular motion is converted into different motion patterns that depend on the geometrical properties of the environment.
We also study sporozoite movement in the context of large rotating collectives extracted from mosquito salivary glands. Quantitative image processing and agent-based modeling reveal that sporozoites are sorted in these vortices according to their curvatures and speeds, and that this phenomenon strongly depends on its mechanical flexibility. We conclude that this flexibility is an essential element for malaria sporozoites to move in mechanically challenging environments.
The success of this strategy relies on the rate of vaccine deployment and acceptance across the globe. As these efforts are being conducted, the severe acute respiratory syndrome coronavirus 2 SARS-CoV-2 virus is continuously mutating, which leads to the emergence of variants with increased transmissibility, virulence, and lower response to vaccines.
One important question is whether surveillance testing is still needed in order to limit SARS-CoV-2 transmission in an increasingly vaccinated population. In this talk, I will present multi-scale mathematical models of SARS-CoV-2 transmission, and use them to determine the effects of vaccine uptake; surveillance testing with tests of different sensitivity, cost, testing frequency, and delay in test return; and testing strategies in limiting an outbreak with alpha and delta variants.
October 28, Meeting Slides: Are here these are the WG's slides, the presentation's slides are linked with the speakers below. Title: Robotics for the ICU.
We had technical difficulties and we will try to reschedule Dr. Taylor for a future meeting. David Forgacs , University of Georgia. One year after its launch, we have amassed nearly 9, visits by close to 2, participants from several locations throughout Georgia and California.
During monthly visits, saliva is obtained for virological testing and sequencing, serum is collected for the detection of SARS-CoVspecific antibodies, and PBMCs are banked for blood cell analysis.
The focus of my talk is going to be what serological analyses have taught us about infection, vaccination, and a combination of the two. I will show antibody binding, as well as viral neutralization data to show how effective immunization with an mRNA vaccine is at eliciting a large antibody response, while infection is of much smaller magnitude but stays stable for a much longer period after infection.
Presentations Jason Shoemake r, University of Pittsburgh. October 14, Meeting Slides: Are here these are the WG's slides, the presentation's slides are linked with the speakers below. October 7, Meeting Slides: Are here these are the WG's slides, the presentation's slides are linked with the speakers below. September 30, Meeting Slides: Are here these are the WG's slides, the presentation's slides are linked with the speakers below.
Title: Models and indicators for the evolution of the epidemic in Mexico. In Mexico there are limited testing and contact tracing of cases.
We have, therefore, limited information for disease surveillance. Nevertheless, the need to have indicators of the state of the epidemic is a pressing need.
We have developed some ideas to overcome these limitations that incorporate the traditional social behaviour of the Mexican people into our models. September 16, Meeting Slides: Are here these are the WG's slides, the presentation's slides are linked with the speakers below.
Presentations Daniel Becker , University of Oklahoma. Title: Optimizing predictive models to prioritize viral discovery in zoonotic reservoirs. Abstract: Identifying and monitoring the wildlife reservoirs of novel zoonotic viruses remains logistically challenging and costly. Statistical models can be used to guide sampling prioritization, but predictions from any given model may be highly uncertain; moreover, systematic model validation is rare, and the drivers of model performance are consequently under-documented.
Here, we use bat hosts of betacoronaviruses as a case study for the data-driven process of comparing and validating predictive models of likely reservoir hosts.
In the first quarter of , we generated an ensemble of eight statistical models that predict host-virus associations and developed priority sampling recommendations for potential bat reservoirs. Over a year, we tracked the discovery of 40 new bat hosts of betacoronaviruses, validated initial predictions, and dynamically updated our analytic pipeline.
We find that ecological trait-based models perform extremely well at predicting these novel hosts, whereas network methods consistently perform roughly as well or worse than expected at random. These findings illustrate the importance of ensembling as a buffer against variation in model quality and highlight the value of including host ecology in predictive models. Our revised models show improved performance and predict over bat species globally that could be undetected hosts of betacoronaviruses.
Although 20 species of rhinolophid bats are known to be the primary reservoir of SARS-like viruses, we find at least three-fourths of plausible betacoronavirus reservoirs in this bat genus might still be undetected.
Our study is the first to show via systematic validation that machine learning models can help optimize wildlife sampling for undiscovered viruses and illustrates how such approaches are best implemented through a dynamic process of prediction, data collection, validation, and updating. Lastly, we discuss next steps to systematically integrate within-host data streams into future modeling efforts.
September 9, Meeting Slides: Are here these are the WG's slides, the presentation's slides are linked with the speakers below. Abstract: The basic reproduction number R0 of the coronavirus disease has been estimated to range between 2 and 4.
Here, we used an SEIR model that properly accounts for the distribution of the latent period and, based on empirical estimates of the doubling time in the near-exponential phases of epidemic progression in China, Italy, Spain, France, UK, Germany, Switzerland and New York State, we estimated that R0 lies in the range 4.
We explained this discrepancy by performing stochastic simulations of model dynamics in a population with a small proportion of super-spreaders. The simulations revealed two-phase dynamics, in which an initial phase of relatively slow epidemic progression diverts to a faster phase upon appearance of infectious super-spreaders.
Early estimates obtained for this initial phase may suggest lower R0. September 2, Meeting Slides: Are here these are the WG's slides, the presentation's slides are linked with the speakers below.
August 19, Meeting Slides: Are here these are the WG's slides, the presentation's slides are linked with the speakers below. Presentations Dean Bottino, Takeda.
Title: Discrete state modeling and knowledge acquisition to investigate human immune response. Abstract: Human immune response is complex interplay of molecular and cellular responses to signals. The wide range of signals such as viruses and vaccines elicit cascades of signaling events, which can be measured using highly advanced high-throughput assays.
We have developed tools to construct mechanistic models of these signaling cascades using omics datasets. The mechanistic models are developed using parameter-free discrete-state methods and reveal multiple different states of cellular phenotype driven by molecular pathways. However, one caveat is in retrieving high-quality frequently updated topological maps of molecular and cellular information.
This talk will briefly introduce the mechanistic modeling methodology and will drive discussion on knowledge acquisition in context to molecular and cellular pathways. August 12, Meeting Slides: Are here these are the WG's slides, the presentation's slides are linked with the speakers below. Abstract: Fungal infections of the respiratory system are a life-threatening complication for immunocompromised patients.
The lack of neutrophils, a common immunodeficiency caused by, e. This paper shows that a key reason why macrophages are unable to control the infection in the absence of neutrophils is the onset of hemorrhaging, as the fungus punctures the alveolar wall. The result is that the fungus gains access to heme-bound iron. At the same time, the macrophage response to the fungus is impaired. We show that these two phenomena together enable the infection to be successful.
A key technology used in this work is a novel dynamic computational model used as a virtual laboratory to guide the discovery process. Sego, Indiana University. Abstract: The biophysics of an organism span multiple scales from subcellular to organismal, and include processes characterized by spatial properties, such as the diffusion of molecules, cell migration, and flow of intravenous fluids.
While non-spatial, ordinary differential equation ODE models are often used and readily calibrated to experimental data, they do not explicitly represent the spatial and stochastic features of a biological system, limiting their insights and applications. However, spatial models describing biological systems with spatial information are mathematically complex and computationally expensive, which limits the ability to calibrate and deploy them, and highlights the need for simpler methods able to model the spatial features of biological systems.
This work develops a formal method for deriving cell-based, spatial, multicellular models from ODE models of population dynamics in biological systems, and vice-versa. The method is demonstrated by generating spatiotemporal, multicellular models from ODE models of viral infection and immune response.
In these models the determinants of agreement of spatial and non-spatial models are the degree of spatial heterogeneity in viral production and rates of extracellular viral diffusion and decay. These generated spatial models show how ODE model parameters can implicitly represent spatial parameters, and cell-based spatial models can generate uncertain predictions through sensitivity to stochastic cellular events, which is not a feature of ODE models.
Using the method, we can test ODE models in a multicellular, spatial context and translate information to and from non-spatial and spatial models, which help to employ spatiotemporal multicellular models using calibrated ODE model parameters.
The method may be useful for generating new ODE model terms from spatiotemporal, multicellular models, recasting popular ODE models on a cellular basis, and generating better models for critical applications where spatial and stochastic features affect outcomes. Abstract: The goal of the paper is to define the domain of medical digital twins as well as the major benefits, opportunities, and challenges.
There are a range of understandings, definitions, and applications. Is it a giant computing infrastructure that will cost billions to develop? Or can usable examples be developed on a much smaller financial scale?
Is it AI based, or mechanism based? How does it relate to "Personalized Medicine"? What data is readily available and what data will require technological development to measure? How is data shared and communicated? Where is data stored? How is the data converted into actionable insights in patient care? Here we attempt to enumerate the domains and range for Medical Digital Twins, outline the challenges, opportunities and benefits and provide a definition of the components.
July 29, Meeting Slides: Are here these are the WG's slides, the presentation's slides are linked with the speakers below. Abstract: Given the importance and impact of pandemic viruses of bat origin, there is potential significant benefit in the comparative investigation into the differences in bat and human immune responses to viruses in terms of providing insight into what form future pandemics might manifest, and what types of potential therapies might be implemented.
The practice of comparative biology can be potentially enhanced by the addition of mathematical and computational methods that can provide a means of dynamic knowledge representation to visualize and interrogate the putative differences between the two systems. Towards this end, we present an agent-based model of components of the immune system that encompasses and bridges the differences between bat and human responses to viral infection; we term this model the Comparative Biology Immune Agent-based Model, or CBIABM.
Simulation experiments with the CBIABM demonstrate the efficacy of bat-related changes of impaired inflammasome activation and constitutive production of Type 1 Interferons in conferring viral resistance.
Furthermore, simulation studies suggest a crucial role of endothelial inflammasome activity as a mechanism for systemic bat viral resistance and the clinical manifestations and severity of disease in human viral infections. Future work will involve the additional of adaptive immune features to this initial version of the CBIABM and the incorporation of features and properties of specific viruses.
We hope that this initial study will help inspire additional comparative modeling projects that use computational dynamic knowledge representation to link, compare, and contrast immunological functions shared across different species, and in so doing, provide insight and preparation for responses to future viral pandemics of zoonotic origin. Keisuke Ejima , Indiana University Bloomington.
Abstract: Viral dynamics models have extensively been used in mathematical biology. The models helped us understand quantitative and qualitative characteristics of temporal dynamics of viral load. Recently, the models are used in epidemiological and clinical studies. Since COVID pandemic started, our group has been exploring the utility of the models in providing implication for public health practice. Particularly, the model was used to estimate the following two key epidemiological parameters: incubation period and false-negative rate of PCR tests.
Additionally, we demonstrated the utility of the model in distinguishing imported cases and locally infected cases at early phase of the pandemic. The model was also used to compute the sample size for clinical trials of antiviral treatment and design guideline to determine when to end isolation of COVID patients.
I would like to argue the possibility of collecting longitudinal viral load data and further application of the models to epidemiological and clinical studies. July 22, Meeting Slides: Are here these are the WG's slides, the presentation's slides are linked with the speakers below.
Title: A modular computational framework for medical digital twins Abstract: This paper presents a modular software design for the construction of computational modeling technology that will help implement precision medicine. In analogy to a common industrial strategy used for preventive maintenance of engineered products, medical digital twins are computational models of disease processes calibrated to individual patients using multiple heterogeneous data streams.
They have the potential to help improve diagnosis, prognosis, and personalized treatment for a wide range of medical conditions. Their large-scale development relies on both mechanistic and data driven techniques and requires the integration and ongoing update of multiple component models developed across many different laboratories.
Distributed model building and integration requires an open-source modular software platform for the integration and simulation of models that is scalable and supports a decentralized, community-based model building process. This paper presents such a platform, including a case study in an animal model of a respiratory fungal infection.
July 15, Meeting Slides: Are here these are the WG's slides, the presentation's slides are linked with the speakers below. Presentations Martha Mendoza , Associated Press.
Both want to engage, both want to inform. He also served as innovation lead at the Co-Laboratory for Data Impact within Northeastern while teaching courses in journalism, coding and data visualization. Abstract: 1 How do we better communicate models and with models, drawing on my work collaborating with researchers and building my own. July 8, Meeting Slides: Are here these are the WG's slides, the presentation's slides are linked with the speakers below. The Jupyter Notebook used in the presentation is here and it can be run from your browser.
July 1, Meeting Slides: Are here. Email: jsp7 cornell. Project Period: July to June The Center involves researchers from both the River Campus and the Medical Center, combining expertise in biology, chemistry, engineering, neurology, and pharmacology. A graphic created by the New York Times illustrates how the coronavirus that causes COVID enters the body through the nose, mouth, or eyes and attaches to our cells. Once the virus is inside our cells, it releases its RNA. The virus assembles new copies of itself and spreads to more parts of the body and—by way of saliva, sweat, and other bodily fluids—to other humans.
One of the reasons viruses are such a challenge is that they change and mutate in response to drugs. That means novel virus treatments and vaccines have to be created each time a new strain of virus presents itself. Traditional vaccines against viruses like influenza inject inactivated virus proteins called antigens. This mRNA provides cells with instructions to produce the virus antigen themselves.
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