Early autoimmunity and outcome in virus encephalitis: a retrospective study based on tissue-based assay.

To explore the autoimmune response and outcome in the central nervous system (CNS) at the onset of viral infection and correlation between autoantibodies and viruses. METHODS: A retrospective observational study was conducted in 121 patients (2016-2021) with a CNS viral infection confirmed via cerebrospinal fluid (CSF) next-generation sequencing (cohort A). Their clinical information was analysed and CSF samples were screened for autoantibodies against monkey cerebellum by tissue-based assay. In situ hybridisation was used to detect Epstein-Barr virus (EBV) in brain tissue of 8 patients with glial fibrillar acidic protein (GFAP)-IgG and nasopharyngeal carcinoma tissue of 2 patients with GFAP-IgG as control (cohort B). RESULTS: Among cohort A (male:female=79:42; median age: 42 (14-78) years old), 61 (50.4%) participants had detectable autoantibodies in CSF. Compared with other viruses, EBV increased the odds of having GFAP-IgG (OR 18.22, 95% CI 6.54 to 50.77, p<0.001). In cohort B, EBV was found in the brain tissue from two of eight (25.0%) patients with GFAP-IgG. Autoantibody-positive patients had a higher CSF protein level (median: 1126.00 (281.00-5352.00) vs 700.00 (76.70-2899.00), p<0.001), lower CSF chloride level (mean: 119.80±6.24 vs 122.84±5.26, p=0.005), lower ratios of CSF-glucose/serum-glucose (median: 0.50[0.13-0.94] vs 0.60[0.26-1.23], p=0.003), more meningitis (26/61 (42.6%) vs 12/60 (20.0%), p=0.007) and higher follow-up modified Rankin Scale scores (1 (0-6) vs 0 (0-3), p=0.037) compared with antibody-negative patients. A Kaplan-Meier analysis revealed that autoantibody-positive patients experienced significantly worse outcomes (p=0.031). CONCLUSIONS: Autoimmune responses are found at the onset of viral encephalitis. EBV in the CNS increases the risk for autoimmunity to GFAP.

[Clinical characteristics in patients with persistent positive pharyngeal swab of omicron variant and analysis on nucleic acid testing of anal swabs].

OBJECTIVE: To analyze the clinical characteristics in patients with persistent positive pharyngeal swab of 2019 novel coronavirus Omicron variant and results of nucleic acid testing of anal swabs to provide basis for prevention and control measures. METHODS: This study included 93 patients whose pharyngeal swab nucleic acid test were persistent positive and admitted to the ward of Daping Hospital in the National Exhibition and Convention Center (Shanghai) Makeshift Hospital from May 1 to May 24, 2022. The gender, age, underlying diseases, vaccination status, clinical symptoms, interval between infection onset and anal sampling, length of hospital stay, the nucleic acid test result of pharyngeal swabs and anal swabs and the time turning negative were collected and analyzed. RESULTS: The age of 93 patients ranged from 8 to 72 years old with a median of (46.0±16.0) years old. Among them, 30 cases (32.3%) were male and 63 cases (67.7%) were female. Sixty-five patients (69.9%) received 2-3 shots of vaccine, 2 patients (2.1%) received 1 shot, and 26 patients (28.0%) did not receive any vaccination. Twenty patients (21.5%) had underlying diseases, of which hypertension (13 cases, 14.0%) and type 2 diabetes mellitus (6 cases, 6.5%) were the most common. Twenty-four patients (25.8%) had asymptomatic infection and the rest (69 cases, 74.2%) had mild symptoms. Cough (50 cases, 53.8%) and sore throat (28 cases, 30.1%) were the most common clinical manifestations of the upper respiratory tract in these patients. Only 6 patients (6.5%) had gastrointestinal symptoms (including diarrhea in 5 patients and diarrhea with vomiting in 1 patient). Pharyngeal and anal swabs were collected simultaneously from all 93 patients at 8-16th days [(11.55±2.27) days] after 2019 novel coronavirus Omicron variant infection. The pharyngeal swabs were positive in 79 patients (85.0%) and the anal swabs were positive in 5 patients (5.4%). The time of pharyngeal swabs turning negative was (14.7±2.9) days, and that of anal swab turning positive was (14.2±1.9) days. The median length of hospital stay was (16.7±2.9) days. CONCLUSIONS: In patients with persistent positive nucleic acid of the 2019 novel coronavirus Omicron variant, there were more mild infection than asymptomatic. The upper respiratory tract symptoms such as cough and sore throat were the most. The likelihood of transmission of 2019 novel coronavirus Omicron variant through the digestive tract may be low. The correlation between gastrointestinal symptoms and 2019 novel coronavirus Omicron variant RNA in the digestive tract is uncertain.

Characterization of the induction kinetics and antiviral functions of IRF1, ISG15 and ISG20 in cells infected with gammacoronavirus avian infectious bronchitis virus.

Coronavirus infection induces a variety of cellular antiviral responses either dependent on or independent of type I interferons (IFNs). Our previous studies using Affymetrix microarray and transcriptomic analysis revealed the differential induction of three IFN-stimulated genes (ISGs), IRF1, ISG15 and ISG20, by gammacoronavirus infectious bronchitis virus (IBV) infection of IFN-deficient Vero cells and IFN-competent, p53-defcient H1299 cells, respectively. In this report, the induction kinetics and anti-IBV functions of these ISGs as well as mechanisms underlying their differential induction are characterized. The results confirmed that these three ISGs were indeed differentially induced in H1299 and Vero cells infected with IBV, significantly more upregulation of IRF1, ISG15 and ISG20 was elicited in IBV-infected Vero cells than that in H1299 cells. Induction of these ISGs was also detected in cells infected with human coronavirus-OC43 (HCoV-OC43) and porcine epidemic diarrhea virus (PEDV), respectively. Manipulation of their expression by overexpression, knockdown and/or knockout demonstrated that IRF1 played an active role in suppressing IBV replication, mainly through the activation of the IFN pathway. However, a minor, if any, role in inhibiting IBV replication was played by ISG15 and ISG20. Furthermore, p53, but not IRF1, was implicated in regulating the IBV infection-induced upregulation of ISG15 and ISG20. This study provides new information on the mechanisms underlying the induction of these ISGs and their contributions to the host cell antiviral response during IBV infection.

Virus diversity, wildlife-domestic animal circulation and potential zoonotic viruses of small mammals, pangolins and zoo animals.

Wildlife is reservoir of emerging viruses. Here we identified 27 families of mammalian viruses from 1981 wild animals and 194 zoo animals collected from south China between 2015 and 2022, isolated and characterized the pathogenicity of eight viruses. Bats harbor high diversity of coronaviruses, picornaviruses and astroviruses, and a potentially novel genus of Bornaviridae. In addition to the reported SARSr-CoV-2 and HKU4-CoV-like viruses, picornavirus and respiroviruses also likely circulate between bats and pangolins. Pikas harbor a new clade of Embecovirus and a new genus of arenaviruses. Further, the potential cross-species transmission of RNA viruses (paramyxovirus and astrovirus) and DNA viruses (pseudorabies virus, porcine circovirus 2, porcine circovirus 3 and parvovirus) between wildlife and domestic animals was identified, complicating wildlife protection and the prevention and control of these diseases in domestic animals. This study provides a nuanced view of the frequency of host-jumping events, as well as assessments of zoonotic risk.

Gammacoronavirus Avian Infectious Bronchitis Virus and Alphacoronavirus Porcine Epidemic Diarrhea Virus Exploit a Cell-Survival Strategy via Upregulation of cFOS to Promote Viral Replication.

Coronaviruses have evolved a variety of strategies to optimize cellular microenvironment for efficient replication. In this study, we report the induction of AP-1 transcription factors by coronavirus infection based on genome-wide analyses of differentially expressed genes in cells infected with avian coronavirus infectious bronchitis virus (IBV). Most members of the AP-1 transcription factors were subsequently found to be upregulated during the course of IBV and porcine epidemic diarrhea virus (PEDV) infection of cultured cells as well as in IBV-infected chicken embryos. Further characterization of the induction kinetics and functional roles of cFOS in IBV replication demonstrated that upregulation of cFOS at early to intermediate phases of IBV replication cycles suppresses IBV-induced apoptosis and promotes viral replication. Blockage of nuclear translocation of cFOS by peptide inhibitor NLSP suppressed IBV replication and apoptosis, ruling out the involvement of the cytoplasmic functions of cFOS in the replication of IBV. Furthermore, knockdown of ERK1/2 and inhibition of JNK and p38 kinase activities reduced cFOS upregulation and IBV replication. This study reveals an important function of cFOS in the regulation of coronavirus-induced apoptosis, facilitating viral replication.IMPORTANCE The ongoing pandemic of coronavirus disease 2019 (COVID-19), caused by a newly emerged zoonotic coronavirus (SARS-CoV-2), highlights the importance of coronaviruses as human and animal pathogens and our knowledge gaps in understanding the cellular mechanisms, especially mechanisms shared among human and animal coronaviruses, exploited by coronaviruses for optimal replication and enhanced pathogenicity. This study reveals that upregulation of cFOS, along with other AP-1 transcription factors, as a cell-survival strategy is such a mechanism utilized by coronaviruses during their replication cycles. Through induction and regulation of apoptosis of the infected cells at early to intermediate phases of the replication cycles, subtle but appreciable differences in coronavirus replication efficiency were observed when the expression levels of cFOS were manipulated in the infected cells. As the AP-1 transcription factors are multi-functional, further studies of their regulatory roles in proinflammatory responses may provide new insights into the pathogenesis and virus-host interactions during coronavirus infection.

Experiences investigation for COVID-19 vaccination in patients with epilepsy.

OBJECTIVE: This study aimed to investigate the safety of COVID-19 vaccination in patients with epilepsy (PWE) and their willingness to undergo vaccination. METHODS: This was a survey study. A questionnaire was completed by patients of the outpatient clinic and hospital ward at The Third Xiangya Hospital in 2021. The survey included general, epilepsy-specific, and COVID-specific questions. RESULTS: In total, 120 valid questionnaires were returned. Eighty-nine of 120 patients (74.2%) were not vaccinated, and 31 (25.8%) received the COVID-19 vaccine. Of the 31 vaccinated PWE, one (3.2%) had worsening of seizures and four (12.9%) had adverse reactions that were characteristic of the COVID-19 vaccine. The other 26 patients (83.9%) reported no adverse reactions, Moreover, there was no significant difference between the 18 PWE with well-controlled seizureand the 13 PWE with poorly-controlled seizure. Of the 89 unvaccinated PWE, 69.7% (62/89) were willing to receive the COVID-19 vaccine, 28.1% (25/89) were unsure, and 2.2% (2/89) declined to be vaccinated. SIGNIFICANCE: Among PWE, few adverse reactions occurred following the COVID-19 vaccination. Most PWE were willing to receive the COVID-19 vaccine. COVID-19 vaccination is safe for PWE.

Coronavirus RNA-dependent RNA polymerase interacts with the p50 regulatory subunit of host DNA polymerase delta and plays a synergistic role with RNA helicase in the induction of DNA damage response and cell cycle arrest in the S phase.

Disruption of the cell cycle is a common strategy shared by many viruses to create a conducible cellular microenvironment for their efficient replication. We have previously shown that infection of cells with gammacoronavirus infectious bronchitis virus (IBV) activated the theataxia-telangiectasia mutated (ATM) Rad3-related (ATR)/checkpoint kinase 1 (Chk1) pathway and induced cell cycle arrest in S and G2/M phases, partially through the interaction of nonstructural protein 13 (nsp13) with the p125 catalytic subunit of DNA polymerase delta (pol δ). In this study, we show, by GST pulldown, co-immunoprecipitation and immunofluorescent staining, that IBV nsp12 directly interacts with the p50 regulatory subunit of pol δ in vitro and in cells overexpressing the two proteins as well as in cells infected with a recombinant IBV harbouring an HA-tagged nsp12. Furthermore, nsp12 from severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2 was also able to interact with p50. These interactions play a synergistic role with nsp13 in the induction of S phase arrest. The fact that subunits of an essential cellular DNA replication machinery physically associate with two core replication enzymes from three different coronaviruses highlights the importance of these associations in coronavirus replication and virus-host interaction, and reveals the potential of targeting these subunits for antiviral intervention.

A survey of health status of healthcare providers in a square cabin hospital during the new corona omicron outbreak: A cross-sectional study

Background The coronavirus omicron variant outbroke in early 2022 in Shanghai. Although previous studies indicated that long working hours in a square cabin hospital might increase the risk of mental health among frontline healthcare providers, few studies have investigated whether the mental health risk could be reduced among well-trained professionals following the new guidelines. Objective This study aimed to investigate the health situation of frontline healthcare providers in Shanghai square cabin during the omicron variant circulation. Methods An online survey was used to evaluate those healthcare providers working in the square cabin hospitals from March 1, 2022, to May 31, 2022. The first online survey was conducted and emailed to the health providers on April 1. The second survey was conducted and sent to the nonrespondents on May 31. Overall, 142 frontline healthcare providers completed the online survey. Their mental health was assessed by the Insomnia Severity Index Scale, the Generalized Anxiety Disorder Scale, the Patient Health Questionnaire-9, and the Psychological Resilience Scale. We estimated multiple clinical systems and identified factors associated with those symptoms among participants. Multivariable logistic regression models were used to assess the risk factors of these symptoms. Results Overall, 66.20%, 45.07%, and 27.46% of frontline healthcare providers in Shanghai City reported symptoms of insomnia, depression, and anxiety, respectively. In addition, the most common symptoms included dry eyes (57.75%), lumbar muscle strain (47.18%), dry mouth (35.92%), itching (31.69%), headache (29.58%), and sore throat (28.87%) among the frontline healthcare providers. There was no statistical difference in symptoms by gender, age, personnel category, or job position (p > 0.05). Conclusion In the case of an unexpected pandemic, the mental health of healthcare providers is not optimistic. This situation still exists more than 2 years after the global outbreak of the COVID-19 pandemic. Therefore, the physical and mental health of long-term healthcare providers working in a square cabin hospital still needs monitoring.

Evaluation of the presence of SARS-CoV-2 in vaginal and anal swabs of women with omicron variants of SARS-CoV-2 infection.

Objectives: The study aimed to determine whether SARS-CoV-2 Omicron variant could be detected in the vaginal fluid and anal swabs of reproductive-aged and postmenopausal women infected with SARS-CoV-2 Omicron variant. Methods: Included in this study were 63 women who were laboratory confirmed as having SARS-CoV-2 Omicron variant infection and admitted to the responsible ward of Daping Hospital of at the National Exhibition and Convention Center(Shanghai) Makeshift Hospital from May 1-24, 2022.From them, vaginal and anal swabs were obtained with informed consent. The demographic and baseline clinical characteristics and the swab test results were analyzed. Results: The 63 included patients ranged in age from 18 to 72 years with a median of 47.71 ± 15.21 years. Of them, 38 women (60.3%) were in their reproductive years. Most of the participants (77.8%) were healthy without significant underlying diseases. Fourteen patients (22.2%) had asymptomatic infection and the remaining 49 (77.8%) had mild infection. The upper respiratory tract symptoms including cough (40/63.5%) and sore throat (18/28.6%)were the most common clinical manifestations of these mildly infected patients. Only 5 patients (7.8%) had gastrointestinal (GI) symptoms, including simple diarrhea in 4 patients, and diarrhea with vomiting in one patient. Pharyngeal,vaginal and anal swabs were collected simultaneously from all 63 patients 8-16 (mean 11.25 ± 2.23) days after SARS-Cov-2 Omicron variant infection. The vaginal swabs were negative for SARS-CoV-2 in all 63 patients, and the anal swabs were positive in 4 patients (6.5%). The overall median hospitalization duration was 16.73 ± 3.16 days. Conclusion: The results of the present study suggest that there is a low possibility of SARS-Cov-2 Omicron variant transmission via the digestive tract and vaginal fluid. The correlation between the GI symptoms and the presence of viral RNA in anal swabs is uncertain.

Early Prompt Response to COVID-19 in Taiwan: Comprehensive surveillance, decisive border control, and information technology support.

Since the COVID-19 outbreak was detected in Wuhan in December 2019 by the event-based surveillance of Taiwan Centers for Disease Control, Taiwan has been aligning risk management to policy planning with the assistance of comprehensive surveillance and regular rapid risk assessments. Taiwan Central Epidemic Command Center (CECC) promptly initiated stepwise border control for major cities and provinces in China, European and American countries, and eventually expanded it to the whole world in March 2020. With stringent quarantine measures, the early response not only successfully blocked the first wave of imported cases, but also slowed down subsequent large local outbreaks. Digital technologies including digital fencing and government database linkage were adopted to facilitate the application of public health interventions and data collection. The experience of Taiwan's prompt and comprehensive response at the early stage may contribute to the preparedness for the next disease X outbreak.

Establishment and Cross-Protection Efficacy of a Recombinant Avian Gammacoronavirus Infectious Bronchitis Virus Harboring a Chimeric S1 Subunit.

Infectious bronchitis virus (IBV) is a gammacoronavirus that causes a highly contagious disease in chickens and seriously endangers the poultry industry. A diversity of serotypes and genotypes of IBV have been identified worldwide, and the currently available vaccines do not cross-protect. In the present study, an efficient reverse genetics technology based on Beaudette-p65 has been used to construct a recombinant IBV, rIBV-Beaudette-KC(S1), by replacing the nucleotides 21,704-22,411 with the corresponding sequence from an isolate of QX-like genotype KC strain. Continuous passage of this recombinant virus in chicken embryos resulted in the accumulation of two point mutations (G21556C and C22077T) in the S1 region. Further studies showed that the T248S (G21556C) substitution may be essential for the adaptation of the recombinant virus to cell culture. Immunization of chicks with the recombinant IBV elicited strong antibody responses and showed high cross-protection against challenges with virulent M41 and a QX-like genotype IBV. This study reveals the potential of developing rIBV-Beau-KC(S1) as a cell-based vaccine with a broad protective immunity against two different genotypes of IBV.

Transcriptomic analysis reveals crucial regulatory roles of immediate-early response genes and related signaling pathways in coronavirus infectious bronchitis virus infection.

Coronavirus infection of cells differentially regulates the expression of host genes and their related pathways. In this study, we present the transcriptomic profile of cells infected with gammacoronavirus infectious bronchitis virus (IBV). In IBV-infected human non-small cell lung carcinoma cells (H1299 cells), a total of 1162 differentially expressed genes (DEGs), including 984 upregulated and 178 downregulated genes, was identified. These DEGs were mainly enriched in MAPK and Wnt signaling pathways, and 5 out of the 10 top upregulated genes in all transcripts were immediate-early response genes (IEGs). In addition, the induction of 11 transcripts was validated in IBV-infected H1299 and Vero cells by RT-qPCR. The accuracy, reliability and genericity of the transcriptomic data were demonstrated by functional characterization of these IEGs in cells infected with different coronaviruses in our previous publications. This study provides a reliable transcriptomic profile of host genes and pathways regulated by coronavirus infection.

Incorporating Sulfur and CO2 Emission Reduction Options into the Container Fleet Capacity Renewal Alternatives for a Shipping Operator in the Post-COVID-19 Era

In this article, a cost-benefit decision framework is proposed to analyze the three alternative options of the container fleet capacity renewal for a ship operator. In this decision framework, the ship operator can trade off the following factors: MGO fuel or LNG option vessels, carbon neutrality, and other investment factors. The following variables are considered: the distance of the round trip, the prices of LNG and MGO, the freight rates of each option, and the initial investment ratios of new vessels. It was found that (1) the retrofitted vessels were more stable and suitable in an uncertain shipping market and have better investment potential. (2) The MGO option was the best option before the epidemic of COVID-19. In the postepidemic era, under the double carbon (carbon neutral and carbon peaking) policy, the advantage of low fuel consumption for the LNG ships disappeared due to the increase in LNG prices, and the NPV advantage of MGO ships becomes significant. [ FROM AUTHOR] Copyright of Mathematical Problems in Engineering is the property of Hindawi Limited and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

Modulation of viral replication, apoptosis and antiviral response by induction and mutual regulation of EGR and AP-1 family genes during coronavirus infection.

Coronaviruses have evolved a variety of strategies to exploit normal cellular processes and signalling pathways for their efficient reproduction in a generally hostile cellular environment. One immediate-early response gene (IEG) family, the AP-1 gene family, was previously shown to be activated by coronavirus infection. In this study, we report that another IEG family, the EGR family, is also activated in cells infected with four different coronaviruses in three genera, i.e. gammacoronavirus infectious bronchitis virus (IBV), alphacoronaviruses porcine epidemic diarrhoea virus (PEDV) and human coronavirus-229E (HCoV-229E), and betacoronavirus HCoV-OC43. Knockdown of EGR1 reduced the expression of cJUN and cFOS, and knockdown of cJUN and/or cFOS reduced the expression of EGR1, demonstrating that these two IEG families may be cross-activated and mutual regulated. Furthermore, ERK1/2 was identified as an upstream kinase, and JNK and p38 as inhibitors of EGR1 activation in coronavirus-infected cells. However, upregulation of EGR family genes, in particular EGR1, appears to play a differential role in regulating viral replication, apoptosis and antiviral response. EGR1 was shown to play a limited role in regulation of coronavirus replication, and an anti-apoptotic role in cells infected with IBV or PEDV, but not in cells infected with HCoV-229E. Upregulation of EGR1 may also play a differential role in the regulation of antiviral response against different coronaviruses. This study reveals a novel regulatory network shared by different coronaviruses in the immediate-early response of host cells to infection.

A comprehensive evaluation of COVID-19 policies and outcomes in 50 countries and territories.

The COVID-19 pandemic struck the world unguarded, some places outperformed others in COVID-19 containment. This longitudinal study considered a comparative evaluation of COVID-19 containment across 50 distinctly governed regions between March 2020 and November 2021. Our analysis distinguishes between a pre-vaccine phase (March-November 2020) and a vaccinating phase (December 2020-November 2021). In the first phase, we develop an indicator, termed lockdown efficiency (LE), to estimate the efficacy of measures against monthly case numbers. Nine other indicators were considered, including vaccine-related indicators in the second phase. Linear mixed models are used to explore the relationship between each government policy & hygiene education (GP&HE) indicator and each vital health & socioeconomic (VH&SE) measure. Our ranking shows that surveyed countries in Oceania and Asian outperformed countries in other regions for pandemic containment prior to vaccine development. Their success appears to be associated with non-pharmaceutical interventions, acting early, and adjusting policies as needed. After vaccines have been distributed, maintaining non-pharmacological intervention is the best way to achieve protection from variant viral strains, breakthrough infections, waning vaccine efficacy, and vaccine hesitancy limiting of herd immunity. The findings of the study provide insights into the effectiveness of emerging infectious disease containment policies worldwide.

Activation of the MKK3-p38-MK2-ZFP36 Axis by Coronavirus Infection Restricts the Upregulation of AU-Rich Element-Containing Transcripts in Proinflammatory Responses.

Coronavirus infections induce the expression of multiple proinflammatory cytokines and chemokines. We have previously shown that in cells infected with gammacoronavirus infectious bronchitis virus (IBV), interleukin 6 (IL-6), and IL-8 were drastically upregulated, and the MAP kinase p38 and the integrated stress response pathways were implicated in this process. In this study, we report that coronavirus infection activates a negative regulatory loop that restricts the upregulation of a number of proinflammatory genes. As revealed by the initial transcriptomic and subsequent validation analyses, the anti-inflammatory adenine-uridine (AU)-rich element (ARE)-binding protein, zinc finger protein 36 (ZFP36), and its related family members were upregulated in cells infected with IBV and three other coronaviruses, alphacoronaviruses porcine epidemic diarrhea virus (PEDV), human coronavirus 229E (HCoV-229E), and betacoronavirus HCoV-OC43, respectively. Characterization of the functional roles of ZFP36 during IBV infection demonstrated that ZFP36 promoted the degradation of transcripts coding for IL-6, IL-8, dual-specificity phosphatase 1 (DUSP1), prostaglandin-endoperoxide synthase 2 (PTGS2) and TNF-α-induced protein 3 (TNFAIP3), through binding to AREs in these transcripts. Consistently, knockdown and inhibition of JNK and p38 kinase activities reduced the expression of ZFP36, as well as the expression of IL-6 and IL-8. On the contrary, overexpression of mitogen-activated protein kinase kinase 3 (MKK3) and MAPKAP kinase-2 (MK2), the upstream and downstream kinases of p38, respectively, increased the expression of ZFP36 and decreased the expression of IL-8. Taken together, this study reveals an important regulatory role of the MKK3-p38-MK2-ZFP36 axis in coronavirus infection-induced proinflammatory response. IMPORTANCE Excessive and uncontrolled induction and release of proinflammatory cytokines and chemokines, the so-called cytokine release syndrome (CRS), would cause life-threatening complications and multiple organ failure in severe coronavirus infections, including severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS) and COVID-19. This study reveals that coronavirus infection also induces the expression of ZFP36, an anti-inflammatory ARE-binding protein, promoting the degradation of ARE-containing transcripts coding for IL-6 and IL-8 as well as a number of other proteins related to inflammatory response. Furthermore, the p38 MAP kinase, its upstream kinase MKK3 and downstream kinase MK2 were shown to play a regulatory role in upregulation of ZFP36 during coronavirus infection cycles. This MKK3-p38-MK2-ZFP36 axis would constitute a potential therapeutic target for severe coronavirus infections.

Taiwan's COVID-19 response: Timely case detection and quarantine, January to June 2020.

The coronavirus disease 2019 (COVID-19) pandemic has become severe threats to economic, societal, and healthcare systems. To analyze the epidemiological characteristics of the COVID-19 outbreak in Taiwan and evaluate the key interventions, we conducted a retrospective cohort study during January 17-June 30, 2020. As of June 30, the COVID-19 outbreak, including 447 laboratory-confirmed cases, was eliminated by mixed approaches: border control, enhanced surveillance, case detection with contact tracing, quarantine, and population-based interventions like face mask use. The improvement of median time from disease onset to notification (5 days [range -3 to 27] before March 1 to 1 day [range -8 to 22] after March 1) suggested the timeliness and comprehensiveness of surveillance and contact tracing. Travel restrictions with quarantine, resulting in fewer clusters, were also complementary to minimize disease spread. Under combined interventions, Taiwan successfully contained the COVID-19 spread within the country and minimized its impact on the society.

Induction of the Proinflammatory Chemokine Interleukin-8 Is Regulated by Integrated Stress Response and AP-1 Family Proteins Activated during Coronavirus Infection.

Infection induces the production of proinflammatory cytokines and chemokines such as interleukin-8 (IL-8) and IL-6. Although they facilitate local antiviral immunity, their excessive release leads to life-threatening cytokine release syndrome, exemplified by the severe cases of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In this study, we investigated the roles of the integrated stress response (ISR) and activator protein-1 (AP-1) family proteins in regulating coronavirus-induced IL-8 and IL-6 upregulation. The mRNA expression of IL-8 and IL-6 was significantly induced in cells infected with infectious bronchitis virus (IBV), a gammacoronavirus, and porcine epidemic diarrhea virus, an alphacoronavirus. Overexpression of a constitutively active phosphomimetic mutant of eukaryotic translation initiation factor 2α (eIF2α), chemical inhibition of its dephosphorylation, or overexpression of its upstream double-stranded RNA-dependent protein kinase (PKR) significantly enhanced IL-8 mRNA expression in IBV-infected cells. Overexpression of the AP-1 protein cJUN or its upstream kinase also increased the IBV-induced IL-8 mRNA expression, which was synergistically enhanced by overexpression of cFOS. Taken together, this study demonstrated the important regulatory roles of ISR and AP-1 proteins in IL-8 production during coronavirus infection, highlighting the complex interactions between cellular stress pathways and the innate immune response.

Comparison of Estimated Effectiveness of Case-Based and Population-Based Interventions on COVID-19 Containment in Taiwan.

Importance: Taiwan is one of the few countries with initial success in COVID-19 control without strict lockdown or school closure. The reasons remain to be fully elucidated. Objective: To compare and evaluate the effectiveness of case-based (including contact tracing and quarantine) and population-based (including social distancing and facial masking) interventions for COVID-19 in Taiwan. Design, Setting, and Participants: This comparative effectiveness study used a stochastic branching process model using COVID-19 epidemic data from Taiwan, an island nation of 23.6 million people, with no locally acquired cases of COVID-19 reported for 253 days between April and December 2020. Main Outcomes and Measures: Effective reproduction number of COVID-19 cases (the number of secondary cases generated by 1 primary case) and the probability of outbreak extinction (0 new cases within 20 generations). For model development and calibration, an estimation of the incubation period (interval from exposure to symptom onset), serial interval (time between symptom onset in an infector-infectee pair), and the statistical distribution of the number of any subsequent infections generated by 1 primary case was calculated. Results: This study analyzed data from 158 confirmed COVID-19 cases (median age, 45 years; interquartile range, 25-55 years; 84 men [53%]). An estimated 55% (95% credible interval [CrI], 41%-68%) of transmission events occurred during the presymptomatic stage. In our estimated analysis, case detection, contact tracing, and 14-day quarantine of close contacts (regardless of symptoms) was estimated to decrease the reproduction number from the counterfactual value of 2.50 to 1.53 (95% CrI, 1.50-1.57), which would not be sufficient for epidemic control, which requires a value of less than 1. In our estimated analysis, voluntary population-based interventions, if used alone, were estimated to have reduced the reproduction number to 1.30 (95% CrI, 1.03-1.58). Combined case-based and population-based interventions were estimated to reduce the reproduction number to below unity (0.85; 95% CrI, 0.78-0.89). Results were similar for additional analyses with influenza data and sensitivity analyses. Conclusions and Relevance: In this comparative effectiveness research study, the combination of case-based and population-based interventions (with wide adherence) may explain the success of COVID-19 control in Taiwan in 2020. Either category of interventions alone would have been insufficient, even in a country with an effective public health system and comprehensive contact tracing program. Mitigating the COVID-19 pandemic requires the collaborative effort of public health professionals and the general public.

Similarities and Dissimilarities of COVID-19 and Other Coronavirus Diseases.

In less than two decades, three deadly zoonotic coronaviruses, severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and SARS-CoV-2, have emerged in humans, causing SARS, MERS, and coronavirus disease 2019 (COVID-19), respectively. The current COVID-19 pandemic poses an unprecedented crisis in health care and social and economic development. It reinforces the cruel fact that CoVs are constantly evolving, possessing the genetic malleability to become highly pathogenic in humans. In this review, we start with an overview of CoV diseases and the molecular virology of CoVs, focusing on similarities and differences between SARS-CoV-2 and its highly pathogenic as well as low-pathogenic counterparts. We then discuss mechanisms underlying pathogenesis and virus-host interactions of SARS-CoV-2 and other CoVs, emphasizing the host immune response. Finally, we summarize strategies adopted for the prevention and treatment of CoV diseases and discuss approaches to develop effective antivirals and vaccines.