ترغب بنشر مسار تعليمي؟ اضغط هنا

Model-based cellular kinetic analysis of SARS-CoV-2 infection: different immune response modes and treatment strategies

158   0   0.0 ( 0 )
 نشر من قبل Fangting Li
 تاريخ النشر 2021
  مجال البحث علم الأحياء
والبحث باللغة English




اسأل ChatGPT حول البحث

Increasing number in global COVID-19 cases demands for mathematical model to analyze the interaction between the virus dynamics and the response of innate and adaptive immunity. Here, based on the assumption of a weak and delayed response of the innate and adaptive immunity in SARS-CoV-2 infection, we constructed a mathematical model to describe the dynamic processes of immune system. Integrating theoretical results with clinical COVID-19 patients data, we classified the COVID-19 development processes into three typical modes of immune responses, correlated with the clinical classification of mild & moderate, severe and critical patients. We found that the immune efficacy (the ability of host to clear virus and kill infected cells) and the lymphocyte supply (the abundance and pool of naive T and B cell) play important roles in the dynamic process and determine the clinical outcome, especially for the severe and critical patients. Furthermore, we put forward possible treatment strategies for the three typical modes of immune response. We hope our results can help to understand the dynamical mechanism of the immune response against SARS-CoV-2 infection, and to be useful for the treatment strategies and vaccine design.



قيم البحث

اقرأ أيضاً

The transmission and evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are of paramount importance to the controlling and combating of coronavirus disease 2019 (COVID-19) pandemic. Currently, near 15,000 SARS-CoV-2 single muta tions have been recorded, having a great ramification to the development of diagnostics, vaccines, antibody therapies, and drugs. However, little is known about SARS-CoV-2 evolutionary characteristics and general trend. In this work, we present a comprehensive genotyping analysis of existing SARS-CoV-2 mutations. We reveal that host immune response via APOBEC and ADAR gene editing gives rise to near 65% of recorded mutations. Additionally, we show that children under age five and the elderly may be at high risk from COVID-19 because of their overreacting to the viral infection. Moreover, we uncover that populations of Oceania and Africa react significantly more intensively to SARS-CoV-2 infection than those of Europe and Asia, which may explain why African Americans were shown to be at increased risk of dying from COVID-19, in addition to their high risk of getting sick from COVID-19 caused by systemic health and social inequities. Finally, our study indicates that for two viral genome sequences of the same origin, their evolution order may be determined from the ratio of mutation type C$>$T over T$>$C.
A recent experimental study found that the binding affinity between the cellular receptor human angiotensin converting enzyme 2 (ACE2) and receptor-binding domain (RBD) in spike (S) protein of novel severe acute respiratory syndrome coronavirus 2 (SA RS-CoV-2) is more than 10-fold higher than that of the original severe acute respiratory syndrome coronavirus (SARS-CoV). However, main-chain structures of the SARS-CoV-2 RBD are almost the same with that of the SARS-CoV RBD. Understanding physical mechanism responsible for the outstanding affinity between the SARS-CoV-2 S and ACE2 is the urgent challenge for developing blockers, vaccines and therapeutic antibodies against the coronavirus disease 2019 (COVID-19) pandemic. Considering the mechanisms of hydrophobic interaction, hydration shell, surface tension, and the shielding effect of water molecules, this study reveals a hydrophobic-interaction-based mechanism by means of which SARS-CoV-2 S and ACE2 bind together in an aqueous environment. The hydrophobic interaction between the SARS-CoV-2 S and ACE2 protein is found to be significantly greater than that between SARS-CoV S and ACE2. At the docking site, the hydrophobic portions of the hydrophilic side chains of SARS-CoV-2 S are found to be involved in the hydrophobic interaction between SARS-CoV-2 S and ACE2. We propose a method to design live attenuated viruses by mutating several key amino acid residues of the spike protein to decrease the hydrophobic surface areas at the docking site. Mutation of a small amount of residues can greatly reduce the hydrophobic binding of the coronavirus to the receptor, which may be significant reduce infectivity and transmissibility of the virus.
In the current COVID19 crisis many national healthcare systems are confronted with an acute shortage of tests for confirming SARS-CoV-2 infections. For low overall infection levels in the population, pooling of samples can drastically amplify the tes ting efficiency. Here we present a formula to estimate the optimal pooling size, the efficiency gain (tested persons per test), and the expected upper bound of missed infections in the pooled testing, all as a function of the populationwide infection levels and the false negative/positive rates of the currently used PCR tests. Assuming an infection level of 0.1 % and a false negative rate of 2 %, the optimal pool size is about 32, the efficiency gain is about 15 tested persons per test. For an infection level of 1 % the optimal pool size is 11, the efficiency gain is 5.1 tested persons per test. For an infection level of 10 % the optimal pool size reduces to about 4, the efficiency gain is about 1.7 tested persons per test. For infection levels of 30 % and higher there is no more benefit from pooling. To see to what extent replicates of the pooled tests improve the estimate of the maximal number of missed infections, we present all results for 1, 3, and 5 replicates.
204 - Yoshihisa Tanaka 2020
The current pandemic of SARS-CoV-2 has caused extensive damage to society. The characterization of SARS-CoV-2 profiles has been addressed by researchers globally with the aim of resolving this disruptive crisis. This investigation process is indispen sable for an understanding of how SARS-CoV-2 behaves in human host cells. However, little is known about the systematic molecular mechanisms involved in the effect of SARS-CoV-2 infection on human host cells. Here, we have presented gene-to-gene regulatory networks in response to SARS-CoV-2 using a Bayesian network. We examined the dynamic changes of the SARS-CoV-2-purturbated networks established by our proposed framework for gene network analysis, revealing that interferon signaling gradually switches to the subsequent inflammatory-cytokine signaling cascades. Furthermore, we have succeeded in capturing a COVID-19 patient-specific network in which transduction of these signalings is coincidently induced. This enabled us to explore local regulatory systems influenced by SARS-CoV-2 in host cells more precisely at an individual level. Our panel of network analyses has provided new insight into SARS-CoV-2 research from the perspective of cellular systems.
SARS-CoV-2, like any other virus, continues to mutate as it spreads, according to an evolutionary process. Unlike any other virus, the number of currently available sequences of SARS-CoV-2 in public databases such as GISAID is already several million . This amount of data has the potential to uncover the evolutionary dynamics of a virus like never before. However, a million is already several orders of magnitude beyond what can be processed by the traditional methods designed to reconstruct a viruss evolutionary history, such as those that build a phylogenetic tree. Hence, new and scalable methods will need to be devised in order to make use of the ever increasing number of viral sequences being collected. Since identifying variants is an important part of understanding the evolution of a virus, in this paper, we propose an approach based on clustering sequences to identify the current major SARS-CoV-2 variants. Using a $k$-mer based feature vector generation and efficient feature selection methods, our approach is effective in identifying variants, as well as being efficient and scalable to millions of sequences. Such a clustering method allows us to show the relative proportion of each variant over time, giving the rate of spread of each variant in different locations -- something which is important for vaccine development and distribution. We also compute the importance of each amino acid position of the spike protein in identifying a given variant in terms of information gain. Positions of high variant-specific importance tend to agree with those reported by the USAs Centers for Disease Control and Prevention (CDC), further demonstrating our approach.
التعليقات
جاري جلب التعليقات جاري جلب التعليقات
سجل دخول لتتمكن من متابعة معايير البحث التي قمت باختيارها
mircosoft-partner

هل ترغب بارسال اشعارات عن اخر التحديثات في شمرا-اكاديميا