Replication Kinetics Research Articles

Game Analysis on the Influence of Participants' Psychology on Value Co-Creation in Community E-Commerce Platform Supply Chain.

As e-commerce continues to develop, online shopping is becoming more and more popular, and community e-commerce platform emerges as the times require. To make the participants in the supply chain of community e-commerce platform play a greater role in value creation, the supply chain of community e-commerce platform can get more benefits. This paper studies the psychology of all participants in the supply chain of community e-commerce platform, so as to establish the value creation mechanism of community e-commerce platform. Through the research, it is found that by studying the psychology of the two main participants in the supply chain of community-based online store, community e-commerce platform and community leader, and considering whether they will do their best to participate in value co-creation, a two-party evolutionary game model is constructed. By calculating the dynamic replication equation, the influence of the psychology of the participants in the supply chain of the community-based online store on the supply chain revenue of the community-based online store is obtained, and the evolutionary trend of both parties in the game is simulated by Matlab. It is concluded that the key factors that affect the co-creation of the value of a community-based online store supply chain are the proportion of increased income, the cost of participating in co-creation of value, and the purchasing power of consumers brought by participating with both parties. Finally, some suggestions and countermeasures are put forward through the analysis of simulation results.

Self-Repairing Herpesvirus Saimiri Deletion Variants.

Herpesvirus saimiri (HVS) is discussed as a possible vector in gene therapy. In order to create a self-repairing HVS vector, the F plasmid vector moiety of the bacterial artificial chromosome (BAC) was transposed via Red recombination into the virus genes ORF22 or ORF29b, both important for virus replication. Repetitive sequences were additionally inserted, allowing the removal of the F-derived sequences from the viral DNA genome upon reconstitution in permissive epithelial cells. Moreover, these self-repair-enabled BACs were used to generate deletion variants of the transforming strain C488 in order to minimalize the virus genome. Using the en passant mutagenesis with two subsequent homologous recombination steps, the BAC was seamlessly manipulated. To ensure the replication capacity in permissive monkey cells, replication kinetics for all generated virus variants were documented. HVS variants with increased insert capacity reached the self-repair within two to three passages in permissive epithelial cells. The seamless deletion of ORFs 3/21, 12–14, 16 or 71 did not abolish replication competence. Apoptosis induction did not seem to be altered in human T cells transformed with deletion variants lacking ORF16 or ORF71. These virus variants form an important step towards creating a potential minimal virus vector for gene therapy, for example, in human T cells.

A Method for In Situ Reverse Genetic Analysis of Proteins Involved mtDNA Replication.

The unavailability of tractable reverse genetic analysis approaches represents an obstacle to a better understanding of mitochondrial DNA replication. Here, we used CRISPR-Cas9 mediated gene editing to establish the conditional viability of knockouts in the key proteins involved in mtDNA replication. This observation prompted us to develop a set of tools for reverse genetic analysis in situ, which we called the GeneSwap approach. The technique was validated by identifying 730 amino acid (aa) substitutions in the mature human TFAM that are conditionally permissive for mtDNA replication. We established that HMG domains of TFAM are functionally independent, which opens opportunities for engineering chimeric TFAMs with customized properties for studies on mtDNA replication, mitochondrial transcription, and respiratory chain function. Finally, we present evidence that the HMG2 domain plays the leading role in TFAM species-specificity, thus indicating a potential pathway for TFAM-mtDNA evolutionary co-adaptations.

Potential and action mechanism of favipiravir as an antiviral against Junin virus.

Favipiravir is a nucleoside analogue that inhibits the replication and transcription of a broad spectrum of RNA viruses, including pathogenic arenaviruses. In this study, we isolated a favipiravir-resistant mutant of Junin virus (JUNV), which is the causative agent of Argentine hemorrhagic fever, and analyzed the antiviral mechanism of favipiravir against JUNV. Two amino acid substitutions, N462D in the RNA-dependent RNA polymerase (RdRp) and A168T in the glycoprotein precursor GPC, were identified in the mutant. GPC-A168T substitution enhanced the efficiency of JUNV internalization, which explains the robust replication kinetics of the mutant in the virus growth analysis. Although RdRp-N462D substitution did not affect polymerase activity levels in a minigenome system, comparisons of RdRp error frequencies showed that the virus with RdRp-D462 possessed a significantly higher fidelity. Our next generation sequence (NGS) analysis showed a gradual accumulation of both mutations as we passaged the virus in presence of favipiravir. We also provided experimental evidence for the first time that favipiravir inhibited JUNV through the accumulation of transition mutations, confirming its role as a purine analogue against arenaviruses. Moreover, we showed that treatment with a combination of favipiravir and either ribavirin or remdesivir inhibited JUNV replication in a synergistic manner, blocking the generation of the drug-resistant mutant. Our findings provide new insights for the clinical management and treatment of Argentine hemorrhagic fever.

Small world can alleviate the social dilemmas originating from self-regulation or community policing issues

Self-regulation and government regulation, community policing and external powerful forces, respectively, form vital part of today’s global economy and social management. The implementation of regulation from self-regulation or community policing requires considerable disciplined members to share the costs of execution, while government or external powerful forces are more likely to make an strong intervention as the industry or community is being widely eroded, which are thus two definitely different feedback regulation schemes. Together with those wrong-doers, the organizations of the two feedback regulation schemes consist of both first-order and novel second-order social dilemma. It still remains a significant challenge to identify an optimal structure to simultaneously alleviate the two dilemmas, and even to additionally favor the altruistic individuals. To address this issue, in this paper we adopt an evolutionary game model within the framework of the public good model, by considering defector-driven and cooperator-driven punishment to map the two feedback regulation schemes, respectively. Through a series of extensive Monte Carlo simulation experiments and mean-field analysis based on replicator dynamics, we finally uncover the combination of clustering and shortcuts, say the small-world structure, is required to largely alleviate both first-order and novel second-order dilemma, which can not only yield optimal public goods by successfully eliminating defectors through strong network reciprocity from dense local connections, but also provide sufficient shortcuts to promote the dominance of defector-driven punishers. Our findings can be beneficial for improving self-regulation or community policing systems by constructing novel monitoring networks.

Evolutionary Dynamics and Phi-Regret Minimization in Games

Regret has been established as a foundational concept in online learning, and likewise has important applications in the analysis of learning dynamics in games. Regret quantifies the difference between a learner’s performance against a baseline in hindsight. It is well known that regret-minimizing algorithms converge to certain classes of equilibria in games; however, traditional forms of regret used in game theory predominantly consider baselines that permit deviations to deterministic actions or strategies. In this paper, we revisit our understanding of regret from the perspective of deviations over partitions of the full mixed strategy space (i.e., probability distributions over pure strategies), under the lens of the previously-established Φ-regret framework, which provides a continuum of stronger regret measures. Importantly, Φ-regret enables learning agents to consider deviations from and to mixed strategies, generalizing several existing notions of regret such as external, internal, and swap regret, and thus broadening the insights gained from regret-based analysis of learning algorithms. We prove here that the well-studied evolutionary learning algorithm of replicator dynamics (RD) seamlessly minimizes the strongest possible form of Φ-regret in generic 2 × 2 games, without any modification of the underlying algorithm itself. We subsequently conduct experiments validating our theoretical results in a suite of 144 2 × 2 games wherein RD exhibits a diverse set of behaviors. We conclude by providing empirical evidence of Φ-regret minimization by RD in some larger games, hinting at further opportunity for Φ-regret based study of such algorithms from both a theoretical and empirical perspective.

In Vitro Growth, Receptor Usage and Pathogenesis of Feline Morbillivirus in the Natural Host.

Feline morbillivirus (FeMV) is a recently discovered virus belonging to the genus Morbillivirus of the virus family Paramyxoviridae. Often, the virus has been detected in urine of cats with a history of urinary disease and has a worldwide distribution. Currently, it is unclear which receptor the virus uses to enter the target cells. Furthermore, many aspects of FeMV biology in vivo, including tissue tropism, pathogenesis, and virus excretion in the natural host remain unclear. In this study we analyzed the replication of FeMV in various cell lines. Secondly, we tested if the presence of feline SLAMF1 (Signaling Lymphocytic Activation Molecule family 1/CD150, principal entry receptor for other members of the Morbillivirus genus) improved FeMV replication efficiency in vitro. Finally, to elucidate in vivo biology in cats, as a natural host for FeMV, we experimentally infected a group of cats and monitored clinical symptoms, viremia, and excretion of the virus during the course of 56 days. Our study showed that FeMV shares some features with other morbilliviruses like the use of the SLAMF1 receptor. For the first time, experimental infection of SPF cats showed that FeMV does not induce an acute clinical disease like other morbilliviruses but can induce lesions in the kidneys, including tubulointerstitial nephritis. Further investigations are needed to confirm the site and dynamics of replication of FeMV in the urinary tract and the longer-term impact of FeMV-induced lesions on the renal function. Whether FeMV infection can result in chronic kidney disease will require the monitoring of cats over a longer period.

Theoretical analyses of stochastic evolutionary game systems

Evolutionary game theory is a powerful tool for studying the frequency-dependent selection, where the success of one strategy depends on the frequency of all strategies. The classic theoretical approach is the replicator equation, where the strategy evolution is deterministic for infinitely large populations. However for the stochastic evolutionary systems of finite populations, one of the most difficult obstacles lies in making qualitative or quantitative analytical deductions about evolutionary outcomes. In this paper, we present a brief yet important report about quantitative analytical methods for finite-size evolutionary game systems, from the two perspectives of how to calculate fixation probabilities and stationary frequencies. Importantly, we not only review some crucial developments about theoretical approaches which were achieved in this field but also put forward two remarkable prospects for further research.

A structured model and likelihood approach to estimate yeast prion propagon replication rates and their asymmetric transmission.

Prion proteins cause a variety of fatal neurodegenerative diseases in mammals but are generally harmless to Baker’s yeast (Saccharomyces cerevisiae). This makes yeast an ideal model organism for investigating the protein dynamics associated with these diseases. The rate of disease onset is related to both the replication and transmission kinetics of propagons, the transmissible agents of prion diseases. Determining the kinetic parameters of propagon replication in yeast is complicated because the number of propagons in an individual cell depends on the intracellular replication dynamics and the asymmetric division of yeast cells within a growing yeast cell colony. We present a structured population model describing the distribution and replication of prion propagons in an actively dividing population of yeast cells. We then develop a likelihood approach for estimating the propagon replication rate and their transmission bias during cell division. We first demonstrate our ability to correctly recover known kinetic parameters from simulated data, then we apply our likelihood approach to estimate the kinetic parameters for six yeast prion variants using propagon recovery data. We find that, under our modeling framework, all variants are best described by a model with an asymmetric transmission bias. This demonstrates the strength of our framework over previous formulations assuming equal partitioning of intracellular constituents during cell division.

Replicator dynamics of public goods games with global exclusion

Studies to date on the role of social exclusion in public cooperation have mainly focused on the peer or pool sanctioning types of excluding free-riders from the share of common goods. However, the exclusive behaviors are not necessarily performed by individuals or local organizations but may rather be implemented by a centralized enforcement institution at a global scale. Besides, previous modeling methods of either peer or pool exclusion often presuppose some particular forms of feedback between the individual or collective efforts and the efficiency of social exclusion and, therefore, cannot comprehensively evaluate their effects on the evolution of cooperation in the social dilemma situations. Here, we construct a general model of global exclusion by considering the successful construction of the centralized exclusive institution as an arbitrary non-decreasing and smooth function of the collective efforts made by the global excluders and then theoretically analyze its potential impacts in the replicator dynamics of the public goods game. Interestingly, we have shown that, despite the presence of both the first- and second-order free-riding problems, global exclusion can indeed lead to the emergence or even stabilization of public cooperation without the support of any other evolutionary mechanism. In addition, we have also observed rich dynamical behaviors, such as the occurrence of a global or local family of neutrally stable closed orbits revolving around a nonlinear center or the existence of stable heteroclinic cycles between defectors, cooperators as well as global excluders, which give rise to a classification of up to 21 different phases.

Rad53 arrests leading and lagging strand DNA synthesis via distinct mechanisms in response to DNA replication stress.

DNA replication stress threatens ordinary DNA synthesis. The evolutionarily conserved DNA replication stress response pathway involves sensor kinase Mec1/ATR, adaptor protein Mrc1/Claspin, and effector kinase Rad53/Chk1, which spurs a host of changes to stabilize replication forks and maintain genome integrity. DNA replication forks consist of largely distinct sets of proteins at leading and lagging strands that function autonomously in DNA synthesis in vitro. In this article, we discuss eSPAN and BrdU-IP-ssSeq, strand-specific sequencing technologies that permit analysis of protein localization and DNA synthesis at individual strands in budding yeast. Using these approaches, we show that under replication stress Rad53 stalls DNA synthesis on both leading and lagging strands. On lagging strands, it stimulates PCNA unloading, and on leading strands, it attenuates the replication function of Mrc1-Tof1. We propose that in doing so, Rad53 couples leading and lagging strand DNA synthesis during replication stress, thereby preventing the emergence of harmful ssDNA.

Recapitulating infection, thermal sensitivity and antiviral treatment of seasonal coronaviruses in human airway organoids

SummaryBackgroundHuman seasonal coronaviruses usually cause mild upper-respiratory tract infection, but severe complications can occur in specific populations. Research into seasonal coronaviruses is limited and robust experimental models are largely lacking. This study aims to establish human airway organoids (hAOs)-based systems for seasonal coronavirus infection and to demonstrate their applications in studying virus-host interactions and therapeutic development.MethodsThe infections of seasonal coronaviruses 229E, OC43 and NL63 in 3D cultured hAOs with undifferentiated or differentiated phenotypes were tested. The kinetics of virus replication and production was profiled at 33 °C and 37 °C. Genome-wide transcriptome analysis by RNA sequencing was performed in hAOs under various conditions. The antiviral activity of molnupiravir and remdesivir, two approved medications for treating COVID19, was tested.FindingsHAOs efficiently support the replication and infectious virus production of seasonal coronaviruses 229E, OC43 and NL63. Interestingly, seasonal coronaviruses replicate much more efficiently at 33 °C compared to 37 °C, resulting in over 10-fold higher levels of viral replication. Genome-wide transcriptomic analyses revealed distinct patterns of infection-triggered host responses at 33 °C compared to 37 °C temperature. Treatment of molnupiravir and remdesivir dose-dependently inhibited the replication of 229E, OC43 and NL63 in hAOs.InterpretationHAOs are capable of modeling 229E, OC43 and NL63 infections. The intriguing finding that lower temperature resembling that in the upper respiratory tract favors viral replication may help to better understand the pathogenesis and transmissibility of seasonal coronaviruses. HAOs-based innovative models shall facilitate the research and therapeutic development against seasonal coronavirus infections.FundingThis research is supported by funding of a VIDI grant (No. 91719300) from the Netherlands Organization for Scientific Research and the Dutch Cancer Society Young Investigator Grant (10140) to Q.P., and the ZonMw COVID project (114025011) from the Netherlands Organization for Health Research and Development to R.R.

Sustainable Organic Farming, Food Safety and Pest Management: An Evolutionary Game Analysis

There is an increasing realization that industrial, large-scale agriculture can negatively impact both food quality and the environment, and that alternatives should be thoroughly considered. Consisting of various participants with distinct and often competing interests, organic food chains have a dynamic structure. We consider an evolutionary game theory model for the dynamics of an organic supply chain with farmers, their customers and the government as the main stakeholders. After describing stakeholder strategies and constructing appropriate payoff matrices for the interactions between farmers and customers and between farmers and the government, respectively, sufficient conditions for the stability of the equilibria for the associated replicator equations were found. Those conditions were then interpreted in practical terms, the corresponding possible outcomes being determined and numerically illustrated. It was seen that a sustainable shift from a conventional strategy to an organic one requires the efforts of all involved stakeholders. As far as the evolutionary interaction between farmers and customers is concerned, it was seen that the purchasing power and the organic awareness of customers are of the utmost importance for the establishment and diffusion of organic strategies in the supply chain. Furthermore, a situation in which the preferences of farmers and consumers for an organic (or conventional) strategy change periodically may occur. Regarding the evolutionary interaction between farmers and the government, strong support for organic farmers is needed at first, and then the consumption habits and environmental awareness of the consumers can be cultivated. This promotes the establishment, development and enrichment of an organic supply chain which, at a certain point, can persist even without governmental subsidies.

Immunovirotherapy Based on Recombinant Vesicular Stomatitis Virus: Where Are We?

Vesicular stomatitis virus (VSV), a negative-strand RNA virus of the Vesiculovirus genus, has demonstrated encouraging anti-neoplastic activity across multiple human cancer types. VSV is particularly attractive as an oncolytic agent because of its broad tropism, fast replication kinetics, and amenability to genetic manipulations. Furthermore, VSV-induced oncolysis can elicit a potent antitumor cytotoxic T-cell response to viral proteins and tumor-associated antigens, resulting in a long-lasting antitumor effect. Because of this multifaceted immunomodulatory property, VSV was investigated extensively as an immunovirotherapy alone or combined with other anticancer modalities, such as immune checkpoint blockade. Despite these recent opportunities to delineate synergistic and additive antitumor effects with existing anticancer therapies, FDA approval for the use of oncolytic VSV in humans has not yet been granted. This mini-review discusses factors that have prompted the use of VSV as an immunovirotherapy in human cancers and provides insights into future perspectives and research areas to improve VSV-based oncotherapy.

Using Species a Rotavirus Reverse Genetics to Engineer Chimeric Viruses Expressing SARS-CoV-2 Spike Epitopes.

ABSTRACTSpecies A rotavirus (RVA) vaccines based on live attenuated viruses are used worldwide in humans. The recent establishment of a reverse genetics system for rotoviruses (RVs) has opened the possibility of engineering chimeric viruses expressing heterologous peptides from other viral or microbial species in order to develop polyvalent vaccines. We tested the feasibility of this concept by two approaches. First, we inserted short SARS-CoV-2 spike peptides into the hypervariable region of the simian RV SA11 strain viral protein (VP) 4. Second, we fused the receptor binding domain (RBD) of the SARS-CoV-2 spike protein, or the shorter receptor binding motif (RBM) nested within the RBD, to the C terminus of nonstructural protein (NSP) 3 of the bovine RV RF strain, with or without an intervening Thosea asigna virus 2A (T2A) peptide. Mutating the hypervariable region of SA11 VP4 impeded viral replication, and for these mutants, no cross-reactivity with spike antibodies was detected. To rescue NSP3 mutants, we established a plasmid-based reverse genetics system for the bovine RV RF strain. Except for the RBD mutant that demonstrated a rescue defect, all NSP3 mutants delivered endpoint infectivity titers and exhibited replication kinetics comparable to that of the wild-type virus. In ELISAs, cell lysates of an NSP3 mutant expressing the RBD peptide showed cross-reactivity with a SARS-CoV-2 RBD antibody. 3D bovine gut enteroids were susceptible to infection by all NSP3 mutants, but cross-reactivity with SARS-CoV-2 RBD antibody was only detected for the RBM mutant. The tolerance of large SARS-CoV-2 peptide insertions at the C terminus of NSP3 in the presence of T2A element highlights the potential of this approach for the development of vaccine vectors targeting multiple enteric pathogens simultaneously.IMPORTANCE We explored the use of rotaviruses (RVs) to express heterologous peptides, using SARS-CoV-2 as an example. Small SARS-CoV-2 peptide insertions (<34 amino acids) into the hypervariable region of the viral protein 4 (VP4) of RV SA11 strain resulted in reduced viral titer and replication, demonstrating a limited tolerance for peptide insertions at this site. To test the RV RF strain for its tolerance for peptide insertions, we constructed a reverse genetics system. NSP3 was C-terminally tagged with SARS-CoV-2 spike peptides of up to 193 amino acids in length. With a T2A-separated 193 amino acid tag on NSP3, there was no significant effect on the viral rescue efficiency, endpoint titer, and replication kinetics. Tagged NSP3 elicited cross-reactivity with SARS-CoV-2 spike antibodies in ELISA. We highlight the potential for development of RV vaccine vectors targeting multiple enteric pathogens simultaneously.

Competition of SARS-CoV-2 Variants in Cell Culture and Tissue: Wins the Fastest Viral Autowave.

Replication of viruses in living tissues and cell cultures is a “number game” involving complex biological processes (cell infection, virus replication inside infected cell, cell death, viral degradation) as well as transport processes limiting virus spatial propagation. In epithelial tissues and immovable cell cultures, viral particles are basically transported via Brownian diffusion. Highly non-linear kinetics of viral replication combined with diffusion limitation lead to spatial propagation of infection as a moving front switching from zero to high local viral concentration, the behavior typical of spatially distributed excitable media. We propose a mathematical model of viral infection propagation in cell cultures and tissues under the diffusion limitation. The model is based on the reaction–diffusion equations describing the concentration of uninfected cells, exposed cells (infected but still not shedding the virus), virus-shedding cells, and free virus. We obtain the expressions for the viral replication number, which determines the condition for spatial infection progression, and for the final concentration of uninfected cells. We determine analytically the speed of spatial infection propagation and validate it numerically. We calibrate the model to recent experimental data on SARS-CoV-2 Delta and Omicron variant replication in human nasal epithelial cells. In the case of competition of two virus variants in the same cell culture, the variant with larger individual spreading speed wins the competition and eliminates another one. These results give new insights concerning the emergence of new variants and their spread in the population.

Complete genome analysis of bacteriophage EFC1 infecting Enterococcus faecalis from chicken.

A novel lytic Enterococcus faecalis phage, EFC1, was isolated from the sewage of a farm in Handan, China, and its genome was analyzed and described. The phage could infect 87.5% of the chicken-derived Enterococcus faecalis preserved in our laboratory. The genome of phage EFC1 consists of a circular double-stranded DNA with a length of 56,099bp and a G + C content of 39.96%, containing 89 predicted protein-coding genes as well as 2 tRNAs, which are involved in phage intron, structure, transcription, packaging, DNA replication, modification, cell lysis, and other functions, indicating the genetic and functional characteristics of this phage. Genome comparison analysis revealed that phage EFC1 can be regarded as new genus Saphexavirus phage in the Siphoviridae family.

Serotype I and II Feline Coronavirus Replication and Gene Expression Patterns of Feline Cells-Building a Better Understanding of Serotype I FIPV Biology.

Feline infectious peritonitis (FIP) is a disease of domestic cats caused by the genetic variant of the feline coronavirus (FCoV) and feline infectious peritonitis virus (FIPV), currently grouped into two serotypes, I and II. Although serotype I FIPV is more prevalent in cats with FIP, serotype II has been more extensively studied in vitro due to the relative ease in propagating this viral serotype in culture systems. As a result, more is known about serotype II FIPV than the more biologically prevalent serotype I. The primary cell receptor for serotype II has been determined, while it remains unknown for serotype I. The recent development of a culture-adapted feline cell line that more effectively propagates serotype I FIPV, FCWF-4 CU, derived from FCWF-4 cells available through the ATCC, offers the potential for an improved understanding of serotype I FIPV biology. To learn more about FIPV receptor biology, we determined targeted gene expression patterns in feline cells variably permissive to replication of serotype I or II FIPV. We utilized normal feline tissues to determine the immunohistochemical expression patterns of two known coronavirus receptors, ACE2 and DC-SIGN. Lastly, we compared the global transcriptomes of the two closely related FCWF-4 cell lines and identified viral transcripts with potential importance for the differential replication kinetics of serotype I FIPV.

DNA replication dynamics during erythrocytic schizogony in the malaria parasites Plasmodium falciparum and Plasmodium knowlesi.

Malaria parasites are unusual, early-diverging protozoans with non-canonical cell cycles. They do not undergo binary fission, but divide primarily by schizogony. This involves the asynchronous production of multiple nuclei within the same cytoplasm, culminating in a single mass cytokinesis event. The rate and efficiency of parasite reproduction is fundamentally important to malarial disease, which tends to be severe in hosts with high parasite loads. Here, we have studied for the first time the dynamics of schizogony in two human malaria parasite species, Plasmodium falciparum and Plasmodium knowlesi. These differ in their cell-cycle length, the number of progeny produced and the genome composition, among other factors. Comparing them could therefore yield new information about the parameters and limitations of schizogony. We report that the dynamics of schizogony differ significantly between these two species, most strikingly in the gap phases between successive nuclear multiplications, which are longer in P. falciparum and shorter, but more heterogenous, in P. knowlesi. In both species, gaps become longer as schizogony progresses, whereas each period of active DNA replication grows shorter. In both species there is also extreme variability between individual cells, with some schizonts producing many more nuclei than others, and some individual nuclei arresting their DNA replication for many hours while adjacent nuclei continue to replicate. The efficiency of schizogony is probably influenced by a complex set of factors in both the parasite and its host cell.

Variability in Susceptibility to Type I Interferon Response and Subgenomic RNA Accumulation Between Clinical Isolates of Dengue and Zika Virus From Oaxaca Mexico Correlate With Replication Efficiency in Human Cells and Disease Severity.

Dengue and Zika viruses cocirculate annually in endemic areas of Mexico, causing outbreaks of different magnitude and severity every year, suggesting a continuous selection of Flavivirus variants with variable phenotypes of transmissibility and virulence. To evaluate if Flavivirus variants with different phenotypes cocirculate during outbreaks, we isolated dengue and Zika viruses from blood samples of febrile patients from Oaxaca City during the 2016 and 2019 epidemic years. We compared their replication kinetics in human cells, susceptibility to type I interferon antiviral response, and the accumulation of subgenomic RNA on infected cells. We observed correlations between type I interferon susceptibility and subgenomic RNA accumulation, with high hematocrit percentage and thrombocytopenia. Our results suggest that Flaviviruses that cocirculate in Oaxaca, Mexico, have variable sensitivity to the antiviral activity of type I interferons, and this phenotypic trait correlates with the severity of the disease.