The new coronavirus that emerged, called SARS-CoV-2, is the causative agent of the COVID-19 pandemic. The identification of potential drug candidates that can rapidly enter clinical trials for the prevention and treatment of COVID-19 is an urgent need, despite the recent introduction of several new vaccines for the prevention and protection of this infectious disease, which in many cases becomes severe. Drug repurposing (DR), a process for studying existing pharmaceutical products for new therapeutic indications, represents one of the most effective potential strategies employed to increase the success rate in the development of new drug therapies. We identified raloxifene, a known Selective Estrogen Receptor Modulator (SERM), as a potential pharmacological agent for the treatment of COVID-19 patients. Following a virtual screening campaign on the most relevant viral protein targets, in this work we report the results of the first pharmacological characterization of raloxifene in relevant cellular models of COVID-19 infection. The results obtained on all the most common viral variants originating in Europe, United Kingdom, Brazil, South Africa and India, currently in circulation, are also reported, confirming the efficacy of raloxifene and, consequently, the relevance of the proposed approach. Taken together, all the information gathered supports the clinical development of raloxifene and confirms that the drug can be proposed as a viable new option to fight the pandemic in at least some patient populations. The results obtained so far have paved the way for a first clinical study to test the safety and efficacy of raloxifene, just concluded in patients with mild to moderate COVID-19.

Epigenetic mechanisms are responsible for a wide range of biological phenomena in insects, controlling embryonic development, growth, aging and nutrition. Despite this, the role of epigenetics in shaping insect-pathogen interactions has received little attention. Gene expression in eukaryotes is regulated by histone acetylation/deacetylation, an epigenetic process mediated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). In this study, we explored the role of the Aedes aegypti histone acetyltransferase CBP (AaCBP) after infection with Zika virus (ZIKV), focusing on the two main immune tissues, the midgut and fat body. We showed that the expression and activity of AaCBP could be positively modulated by blood meal and ZIKV infection. Nevertheless, Zika-infected mosquitoes that were silenced for AaCBP revealed a significant reduction in the acetylation of H3K27 (CBP target marker), followed by downmodulation of the expression of immune genes, higher titers of ZIKV and lower survival rates. Importantly, in Zika-infected mosquitoes that were treated with sodium butyrate, a histone deacetylase inhibitor, their capacity to fight virus infection was rescued. Our data point to a direct correlation among histone hyperacetylation by AaCBP, upregulation of antimicrobial peptide genes and increased survival of Zika-infected- A. aegypti . Author summary Pathogens have coevolved with mosquitoes to optimize transmission to hosts. As natural vectors, mosquitoes are permissive to and allow systemic and persistent arbovirus infection, which intriguingly does not result in dramatic pathological sequelae that affect their lifespan. In this regard, mosquitoes have evolved mechanisms to tolerate persistent infection and develop efficient antiviral strategies to restrict viral replication to nonpathogenic levels. There is a great deal of evidence supporting the implication of epigenetics in the modulation of the biological interaction between hosts and pathogens. This study reveals that Zika virus infection positively modulates the expression and activity of A. aegypti histone acetyltransferase CBP (AaCBP). This study shows that AaCBP plays a role in the activation of immune-responsive genes to limit Zika virus replication. This first description that Zika virus infection has epigenomic consequences in the regulation of A. aegypti immunity opens a new avenue for research on mosquito factors that can drive vector competence.

This article tries to investigate the connectedness between Bitcoin and Crude Oil, S&P500 and Natural Gas with the health crisis. That is why one might apply fractional cointegration analysis on daily data over the period 01/09/2019-30/04/2020. Our results indicate the presence of fractional integration in residual series, implying the existence of a fractional cointegration relationship. A short-run joint dynamics between Bitcoin and some other assets (Crude Oil, S&P500 and Natural Gas) is nevertheless well-pronounced. Such analysis of the long and short-term dependencies between different assets could be interesting from a portfolio perspective.

COVID-19 has become a part of everyone's day-to-day life, since the outbreak in 2019 the novel coronavirus disease (COVID-19) has caused more than 4.5 million deaths with over 200 million cases reported globally. Currently, the number of infections and deaths are gradually lowering in different countries however the underlying challenges still exist. COVID-19 threatens human life, social functioning and development. Although numerous studies have been carried out in the past to highlight the key challenges very limited studies have been conducted from an ordinary person's viewpoint. In the fight against COVID-19, humanity has been pushed to a level which cannot be accepted where establishing that balance is a priority. This study focuses on highlighting the common issues faced by the ordinary public in the current era. Five key areas were identified to be the most essential; education, technological adaptation, transportation, mental health and gender-based violence (GBV).

Ever since the start of the pandemic, SARS-CoV-2 has taken the lives of millions of people around the globe. Several COVID-19 vaccines have been developed with rapidity to prevent acquiring COVID-19 infection, hospitalizations and deaths. The routine side effects of these vaccines are commonly known and non-severe. Few serious side-effects such as thrombosis with thrombocytopenia syndrome (TTS) and Guillain Barré Syndrome (GBS) are increasingly reported particularly after inoculation with ChAdOx1 nCoV-19 (Oxford/AstraZeneca) and Ad26.COV 2.S (Johnson & Johnson’s Janssen). Rare cases of GBS after BNT162b2 (Pfizer-BioNTech), an mRNA vaccine are also reported. However, the true association of these cases to COVID-19 continues to be unclear and the safety of these vaccines continues to be great in preventing deaths from COVID-19 infection. We report a case of middle-aged female who had a gradual onset of lower extremity weakness with a nadir of symptoms reached 10 and 12 weeks after the onset. This protracted course (sub-acute) is atypical for a ‘classical’ GBS. The presence of an antecedent event, autonomic symptoms such as hypotension and the need for ventilator support favored the diagnosis of GBS than chronic inflammatory demyelinating polyneuropathy (CIDP). This is the first known case to be reported of sub-acute onset of Guillain Barré Syndrome after receiving the mRNA-1273 vaccine.

Aedes albopictus is a competent vector of several arboviruses that has spread throughout the United States over the last three decades after it was initially detected in Texas in 1985. With the emergence of Zika virus in the Americas in 2015-2016 and an increased need to better understand the current distributions of Ae. albopictus in the US, we initiated surveillance efforts to determine the abundance of invasive Aedes species in Iowa. Here, we describe the resulting surveillance efforts from 2016-2020 in which we detect stable and persistent populations of Aedes albopictus in three Iowa counties. Based on temporal patterns in abundance and genetic analysis of mitochondrial DNA haplotypes between years, our data support that populations of Ae. albopictus are overwintering and have likely become established in the state. In addition, the localization of Ae. albopictus predominantly in areas of urbanization and noticeable absence in rural areas suggests that these ecological factors may represent potential barriers to their further spread and contribute to overwintering success. Together, these data document the establishment of Ae. albopictus in Iowa and their expansion into the Upper Midwest, where freezing winter temperatures were previously believed to limit their spread. With increasing globalization, urbanization, and rising temperatures associated with global warming, the range of invasive arthropod vectors, such as Ae. albopictus , is expected to only further expand, creating increased risks for vector-borne disease.

Despite the urgent need for effective antivirals against SARS-CoV-2 to mitigate the catastrophic impact of the COVID-19 pandemic, there are still no proven effective and widely available antivirals for COVID-19 treatment. Favipiravir and Ivermectin are among common repurposed drugs, which have been provisionally used in some countries. There have been clinical trials with mixed results, and therefore, it is still inconclusive whether they are effective or should be dismissed. It is plausible that the lack of clear-cut clinical benefits was due to the finding of only marginal levels of in vivo antiviral activity. An obvious way to improve the activity of antivirals is to use them in synergistic combinations. Here we show that Favipiravir and Ivermectin had the synergistic effects against SARS-CoV-2 in Vero cells. The combination may provide better efficacy in COVID-19 treatment. In addition, we found that Favipiravir had an additive effect with Niclosamide, another repurposed anti-parasitic drug with anti-SARS-CoV-2 activity. However, the anti-SARS-CoV-2 activity of Favipiravir was drastically reduced when tested in Calu-3 cells. This suggested that this cell type might not be able to metabolize Favipiravir into its active form, and that this deficiency in some cell types may affect in vivo efficacy of this drug.

Simultaneous dengue virus (DENV) and West Nile virus (WNV) outbreaks in Florida, USA, in 2020 resulted in 71 dengue virus serotype 1 and 86 WNV human cases. Our outbreak response leveraged a molecular diagnostic screen of mosquito populations for DENV and WNV in Miami-Dade County to quickly employ targeted mosquito abatement efforts. We detected DENV serotypes 2 and 4 in mosquito pools, highlighting the silent circulation of diverse dengue serotypes in mosquitoes. Additionally, we found WNV-positive mosquito pools in areas with no historical reports of WNV transmission. These findings demonstrate the importance of proactive, strategic arbovirus surveillance in mosquito populations to prevent and control outbreaks, particularly when other illnesses (e.g., COVID-19), which present with similar symptoms are circulating concurrently. Growing evidence for substantial infection prevalence of dengue in competent mosquito vectors in the absence of local index cases suggests a higher level of dengue endemicity in Florida than previously thought. Article Summary Line Evidence of increasing dengue endemicity in Florida: Vector surveillance during dengue and West Nile virus outbreaks revealed widespread presence of other dengue virus serotypes in the absence of local index cases.

The global pandemic of Coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus 2 has become a severe global health problem because of its rapid spread( 1 ). Both angiotensin-converting enzyme 2 and neuropilin 1 provide initial viral binding sites for SARS-CoV-2 ( 2, 3 ). Here, we show that three cysteine residues located in a1/a2 and b1 domains of neuropilin 1 are necessary for SARS-CoV-2 spike protein internalization in human cells. Mutating cysteines C82, C104 and C147 altered neuropilin 1 stability and binding ability as well as cellular internalization and lysosomal translocation of the spike protein. This resulted in up to 4 times reduction in spike protein load in cells for the original, alpha and delta SARS-CoV-2 variants even in the presence of the endogenous angiotensin-converting enzyme 2 receptor. Transcriptome analysis of cells transfected with mutated NRP1 revealed significantly reduced expression of genes involved in viral infection and replication, including eight members of the ribosomal protein L, ten members of ribosomal protein S and five members of the proteasome β subunit family proteins. We also observed higher expression of genes involved in suppression of inflammation and endoplasmic reticulum associated degradation. These observations suggest that these cysteines offer viable targets for therapies against COVID-19.

Background Poliovirus vaccination induces an adaptive humoral immune response; in vitro experiments show polio-immune sera contain antibodies against the poliovirus RNA transcriptase that cross-react with SARS-CoV-2. While structural similarities between poliovirus and SARS-CoV-2 could have major implications for the COVID-19 response worldwide, polio-induced immune responses against SARS-CoV-2 have not been confirmed in prospective clinical trials. Objective To evaluate whether immune sera from adults who recently received inactivated poliovirus vaccination (IPV) can block SARS-CoV-2’s ability to synthesize RNA. Intervention IPV intramuscular injection. Measurements Pre-inoculation and 4-weeks post-inoculation sera were tested for anti-3D pol (RNA-dependent RNA polymerase, RdRp) antibodies using enzyme-linked immunosorbent assays (ELISA). To assess IPV’s ability to induce antibodies that inhibit SARS-CoV-2 RNA synthesis, immune-based detection assays tested RdRp enzymatic activity in polio-immune sera. Results 298 of the 300 enrolled participants completed both on-site visits. Comparing pre-inoculation to 4-week samples, 85.2% of participants demonstrated an increase in anti-3D pol antibodies against RdRp proteins. Among tested post-inoculation samples, 94.4% demonstrated inhibition of SARS-CoV-2 RNA synthesis. Few inoculation-related side effects were reported (2.0%), all were minor. Limitations Participants were not systematically tested for COVID-19, though known exposures were reported and positive results (1.7%) were documented. Conclusion IPV can induce antibodies that inhibit SARS-CoV-2 RNA synthesis, minimizing the risk of viral replication in infected individuals. This finding has practical implications for resource-deficient areas that may have limited access to newly developed COVID-19 vaccines and/or areas with low COVID-19 vaccination rates due to hesitancy. Funding Source Private donors. Registration ClinicalTrials.gov NCT04639375 .

ABSTRACT COVID-19 is a multi-system disease affecting many organs outside of the lungs, and patients generally develop varying degrees of neurological symptoms. Whereas, the pathogenesis underlying these neurological manifestations remains elusive. Although in vitro models and animal models are widely used in studies of SARS-CoV-2 infection, human organ models that can reflect the pathological alterations in a multi-organ context are still lacking. In this study, we propose a new strategy to probe the effects of SARS-CoV-2 on human brains in a linked alveolus-BBB organ chip platform. The new multi-organ platform allows to recapitulate the essential features of human alveolar-capillary barrier and blood-brain barrier in a microfluidic condition by co-culturing the organ-specific cells. The results reveal direct SARS-CoV-2 exposure has no obvious effects on BBB chip alone. While, infusion of endothelial medium from infected alveolus chips can cause BBB dysfunction and neuroinflammation on the linked chip platform, including brain endothelium disruption, glial cell activation and inflammatory cytokines release. These new findings suggest that SARS-CoV-2 could induce neuropathological alterations, which might not result from direct viral infection through hematogenous route, but rather likely from systemic inflammation following lung infection. This work provides a new strategy to study the virus-host interaction and neuropathology at an organ-organ context, which is not easily obtained by other in vitro models. This will facilitate to understand the neurological pathogenesis in SARS-CoV-2 and accelerate the development of new therapeutics. SUMMARY A linked human alveolus-BBB chip platform is established to explore the influences of SARS-CoV-2 on human brains in an organ-organ context. SARS-CoV-2 infection could induce BBB injury and neuroinflammation. The neuropathological changes are caused by SARS-CoV-2 indirectly, which might be mediated by systemic inflammation following lung infection, but probably not by direct viral neuroinvasion.

Investigations on the concordance in monozygotic (MZ) as compared to dizygotic (DZ) twins may reveal if there is a genetic component increasing the susceptibility or resistance against an infectious disease. Here, we compared the concordance rates of SARS-CoV-2 infection in MZ versus DZ young twins who shared the same bedrooms and were equally exposed to the virus. The concordance rate was higher in the MZ group supporting a complex multifactorial inheritance responsible for SARS-Cov-2 infection.

The ability of viruses to evade the host antiviral immune system determines their level of replication fitness, species specificity, and pathogenic potential. Flaviviruses rely on the subversion of innate immune barriers including the type I and type III IFN antiviral systems. Zika virus infection induces the degradation of STAT2, an essential component of the IFN stimulated gene transcription factor, ISGF3. The mechanisms that lead to STAT2 degradation by Zika virus are poorly understood, but it is known to be mediated by the viral NS5 protein that binds to STAT2 and targets it for proteasome-mediated destruction. To better understand how NS5 engages and degrades STAT2, functional analysis of the protein interactions that lead to Zika virus and NS5-dependent STAT2 proteolysis were investigated. Data implicate the STAT2 coiled-coil domain as necessary and sufficient for NS5 interaction and proteasome degradation after Zika virus infection. Molecular dissection reveals that the first two α-helices of the STAT2 coiled-coil contain a specific targeting region for IFN antagonism. These functional interactions provide a more complete understanding of the essential protein-protein interactions needed for Zika virus evasion of the host antiviral response, and identifies new targets for antiviral therapeutic approaches. Importance Zika virus infection can cause mild fever, rash, and muscle pain, and in rare cases lead to brain or nervous system diseases including Guillain–Barré syndrome. Infections in pregnant women can increase the risk of miscarriage or serious birth defects including brain anomalies and microcephaly. There are no drugs or vaccines for Zika disease. Zika virus is known to break down the host antiviral immune response, and this research project reveals how the virus suppresses interferon signaling, and may reveal therapeutic vulnerabilities.

Neonatal microcephaly and adult Guillain-Barré syndrome are severe complications of Zika virus (ZIKV) infection. The robustly induced inflammatory cytokine expressions in ZIKV-infected patients may constitute a hallmark for severe disease. In the present study, the potential role of high mobility group box 1 protein (HMGB1) in ZIKV infection was investigated. HMGB1 protein expression was determined by the enzyme-linked immunosorbent assay (ELISA) and immunoblot assay. HMGB1’s role in ZIKV infection was also explored using treatment with dexamethasone, an immunomodulatory drug. Antiviral effects of dexamethasone treatment on both wild-typed (WT) and HMGB1-knockdown (shHMGB1) Huh7 cells were determined by the focus-forming assay. Results showed that the Huh7 cells were highly susceptible to ZIKV infection. The infection was found to induce HMGB1 nuclear-to-cytoplasmic translocation, resulting in a >99% increase in the cytosolic HMGB1 expression at 72h.p.i. The extracellular HMGB1 level was elevated in a time- and multiplicity of infection (MOI)- dependent manner. Dexamethasone 150 µM treatment of the ZIKV-infected cells reduced HMGB1 extracellular release in a dose-dependent manner, with a maximum reduction of 71 ± 5.84% (p < 0.01). The treatment also reduced virus titers by over 83 ± 0.50% (p < 0.01). The antiviral effects, however, was not observed in the dexamethasone-treated HMGB1-knockdown cells, suggesting the importance of the intracellular HMGB1 in ZIKV infection. Overall, these results suggest that translocation of HMGB1 occurred during ZIKV infection and inhibition of the translocation reduced ZIKV replication. These findings highlight the potential of developing therapeutics against ZIKV infection by affecting the translocation of HMGB1 from the nucleus to the cytoplasm.

Using longitudinal survey data collected from 407 married women at peak childbearing ages, we compared self-reported changes to fertility plans in response to the 2016-2017 Zika and 2020 COVID-19 epidemics in Singapore. The Zika outbreak led to intentions to delay but not reduce childbearing, whereas the COVID-19 pandemic led to both. At the same time, some women reported accelerating and increasing childbearing due to COVID-19, with more intending to bring forward births as the pandemic dragged on. Educational background was more predictive of changes in fertility plans during the pandemic than during the Zika epidemic, and women who had already delayed childbearing due to Zika were more likely to further adjust timing of childbearing due to COVID-19. We considered three possible explanations for changes to fertility plans: fear of infection, change in subjective wellbeing, and income loss, and find stronger effects of perceptions of the virus on downward revisions of fertility plans during the Zika epidemic but a larger role for stress and income loss during the pandemic, reflecting the latter’s wider economic and social impacts.

Chikungunya virus (CHIKV) is an alphavirus transmitted by Aedes mosquitoes, causing fever, rash and arthralgia in mammals. The function of the CHIKV non-structural protein 3 (nsP3) remains enigmatic. Building on previous studies (Gao et al, 2019), we generated a panel of mutants in a conserved and surface-exposed cluster in the nsP3 alphavirus unique domain (AUD) and tested their replication using a sub-genomic replicon (SGR). Three of these SGR mutants replicated well in mosquito cells but poorly in mammalian cells. We observed that this difference was due to culture temperature (mosquito cells: 28 degrees C; mammalian cells: 37 degrees C), as the mutants exhibited no replication defect in mammalian cells grown at a sub-physiological temperature (28 degrees C). Similar phenotypes were observed for infectious CHIKV and the closely related O'Nyong Nyong virus. Intriguingly, the wildtype SGR replicated more efficiently in mammalian cells at 28 degrees C compared to 37 degrees C. To explore the mechanism behind this difference, we focused on two known antiviral pathways: interferon-stimulated genes (ISGs) and stress granules (SGs). SGR replication was concomitant with increased expression of ISGs at 37 degrees C, but this response was impaired at 28 degrees C. We also observed enhanced recruitment of the SG component G3BP1 into cytoplasmic sites of viral genome replication at 28 degrees C. These findings may have real-world implications as when a mosquito bites a mammal, the virus first infects cells in peripheral tissues which are often at sub-physiological temperatures. We propose that alphaviruses such as CHIKV have evolved mechanisms to both promote viral genome replication and concomitantly limit antiviral responses in these cells.

This study aims at providing some evidence-based insight into Sub-Saharan Africa’s first eighteen months of COVID-19 research by evaluating its research contributions, patterns of collaboration, and funding sources. Eighteen months (2020 January 1-2021 June 30) COVID-19 publication data of 46 Sub-Saharan African countries was collected from Scopus for analysis. Country of affiliation of the authors and funding agencies data was analyzed to understand country contributions, collaboration pattern and funding sources. USA (23.08%) and the UK (19.63%), the top two external contributors, collaborated with Sub-Saharan African countries about three times more than other countries. Collaborative papers between Sub-Saharan African countries - without contributions from outside the region-made up less than five percent of the sample, whereas over 50% of the papers were written in collaboration with researchers from outside the region. Organizations that are in USA and the UK funded 45% of all the COVID-19 research from Sub-Saharan Africa. 53.44% of all the funding from Sub-Saharan African countries came from South African organizations. This study provides evidence that pan-African COVID-19 research collaboration is low, perhaps due to poor funding and lack of institutional support within Sub-Saharan Africa. This mirrors the collaborative features of science in Sub-Saharan Africa before the COVID-19 pandemic. The high volume of international collaboration during the pandemic is a good development. There is also a strong need to forge more robust pan-African research collaboration networks, through funding from Africa’s national and regional government organizations, with the specific objective of meeting local COVID-19 and other healthcare needs.

Zika virus (ZIKV) emergence highlighted the need for a deeper understanding on virus-host interaction to pave the development of antiviral therapies. The present work aimed to address the response of neutrophils during ZIKV infection. Neutrophils are an important effector cell in innate immunity involved in the host response to neurotropic arboviruses. Our results indicate that human neutrophils were not permissive to Asian or African ZIKV strains replication. Indeed, after stimulation with ZIKV, neutrophils were not primed against the virus as evaluated by the absence of CD11b modulation, secretion of inflammatory cytokines and granule content, production of reactive oxygen species and neutrophil extracellular traps formation. Overall, neutrophils did not affect ZIKV infectivity. Moreover, ZIKV infection of primary innate immune cells in vitro did not trigger neutrophil migration. However, neutrophil co-cultured with ZIKV susceptible cells (A549) resulted in lower frequencies of infection on A549 cells by cell-to-cell contact. In vivo , neutrophil depletion from immunocompetent mice did not affect ZIKV spreading to the draining lymph nodes. The data suggest human neutrophils do not play a per se antiviral role against ZIKV, but these cells might participate in an infected environment shaping the ZIKV infection in other target cells.

Was the 2014 FIFA World Cup a blessing or a curse for Brazil? And could the hosting states benefit from the tournament in an economic recession? This study investigates whether the World Cup was a catalyst for Brazil’s economic downturn, after a prosperous decade of poverty reduction, political recognition and event planning. Therefore, Brazil’s economic situation between 2002 – 2019 is investigated on different alternative aspects before turning an eye on the hosting of the World Cup and later on Summer Olympics. The results show a negative economic impact for the hosting states of the World Cup on the GDP per capita growth, especially in preparing (-6.9 percent) and processing the aftermath (-11.25 percent). But also, that the World Cup itself seems to have a positive component, while the Olympics constantly harm the regional economy (-16.91 percent). This further indicates that emerging markets should not host mega-sport events to achieve economic goals.

Significance The primary method of COVID-19 detection is reverse transcription polymerase chain reaction (RT-PCR) testing. PCR test sensitivity may decrease as more variants of concern arise. Aim We aimed to develop a reagent-free way to detect COVID-19 in a real-world setting with minimal constraints on sample acquisition. Approach We present a workflow for collecting, preparing and imaging dried saliva supernatant droplets using a non-invasive, label-free technique – Raman spectroscopy – to detect changes in the molecular profile of saliva associated with COVID-19 infection. Results Using machine learning and droplet segmentation, amongst all confounding factors, we discriminated between COVID-positive and negative individuals yielding receiver operating coefficient (ROC) curves with an area under curve (AUC) of 0.8 in both males (79% sensitivity, 75% specificity) and females (84% sensitivity, 64% specificity). Taking the sex of the saliva donor into account increased the AUC by 5%. Conclusion These findings may pave the way for new rapid Raman spectroscopic screening tools for COVID-19 and other infectious diseases.

Interferons establish an antiviral state in responding cells through the induction of hundreds of interferon-stimulated genes (ISGs). ISGs antagonize viral pathogens directly through diverse mechanisms acting at different stages of viral life cycles, and indirectly by modulating cell cycle and promoting programmed cell death. The mechanisms of action and viral specificities for most ISGs remain incompletely understood. To enable the high throughput interrogation of ISG antiviral functions in pooled genetic screens while mitigating the potentially confounding effects of endogenous IFN and potential antiproliferative/proapoptotic ISG activities, we adapted a CRISPR-activation (CRISPRa) system for inducible ISG induction in isogenic cell lines with and without the capacity to respond to IFN. Engineered CRISPRa cell lines demonstrated inducible, robust, and specific gRNA-directed expression of ISGs, which are functional in restricting viral infection. Using this platform, we screened for ISGs that restrict SARS-CoV-2, the causative agent of the COVID-19 pandemic. Results included ISGs previously described to restrict SARS-CoV-2 as well as multiple novel candidate antiviral factors. We validated a subset of candidate hits by complementary targeted CRISPRa and ectopic cDNA expression infection experiments, which, among other hits, confirmed OAS1 as a SARS-CoV-2 restriction factor. OAS1 exhibited strong antiviral effects against SARS-CoV-2, and these effects required OAS1 catalytic activity. These studies demonstrate a robust, high-throughput approach to assess antiviral functions within the ISG repertoire, exemplified by the identification of multiple novel SARS-CoV-2 restriction factors.

Zika virus (ZIKV) can be transmitted from mother to fetus during pregnancy, causing adverse fetal outcomes. Several studies have indicated that ZIKV can damage the fetal brain directly; however, whether the ZIKV-induced maternal placental injury contribute to adverse fetal outcomes are sparsely defined. Here, we discovered that ZIKV causes the pyroptosis of placental cells by activating the executor Gasdermin E (GSDME) in vitro and in vivo . Mechanistically, caspase-8 undergoes activation upon the recognition of 5’ untranslated region of viral RNA by RIG-I, followed by the stimulation of caspase-3 to ultimately escalate the GSDME cleavage. Further analyses revealed that the ablation of GSDME in ZIKV-infected pregnant mice attenuates placental pyroptosis, which consequently confers protection against adverse fetal outcomes. In conclusion, our study unveils a novel mechanism of ZIKV-induced adverse fetal outcomes via causing placental cell pyroptosis, which could be employed for developing new therapies for ZIKV-associated diseases. Significance statement Several studies have elucidated the link between ZIKV infection and congenital ZIKV syndroms (CZS), but the pathogenesis yet needs further study. Here, we reported a novel pathogenic mechanism of ZIKV which leads to pyroptosis of placental cells through activating the pyroptotic executor GSDME, rather than GSDMD. Upon ZIKV infection, GSDME-mediated pyroptosis damages the structure and function of the placenta, thereby affecting the development of the fetus and contributing to the adverse fetal outcomes. Our study highlights the importance of pyroptotic executor GSDME in regulate ZIKV pathogenicity and further confirms that placental injury caused by ZIKV infection is a key factor for CZS.

ABSTRACT The flavivirids (family Flaviviridae ) are a group of positive-strand RNA viruses that pose serious risks to human and animal health on a global scale. Here we use flavivirid-derived DNA sequences, identified in animal genomes, to reconstruct the long-term evolutionary history of family Flaviviridae . We demonstrate that flavivirids are >100 million years old and show that this timing can be combined with dates inferred from co-phyletic analysis to produce a cohesive overview of their evolution, distribution and diversity wherein the main flavivirid subgroups originate in early animals and broadly co-diverge with major animal phyla. In addition, we reveal evidence that the ‘classical flaviviruses’ of vertebrates, most of which are transmitted via blood-feeding arthropod vectors, originally evolved in hematophagous arachnids and later acquired the capacity to be transmitted by insects. Our findings imply that the biological properties of flavivirids have been acquired gradually over the course of animal evolution. Thus, broad-scale comparative analysis will likely reveal fundamental insights into their biology. We therefore published our results via an open, extensible, database (Flavivirid-GLUE), which we constructed to facilitate the wider utilisation of genomic data and evolution-related domain knowledge in flavivirid research.

The novel coronavirus SARS-CoV-2 is responsible for the ongoing COVID-19 pandemic and has caused a major health and economic burden worldwide. Understanding how SARS-CoV-2 viral proteins behave in host cells can reveal underlying mechanisms of pathogenesis and assist in development of antiviral therapies. Here we use BioID to map the SARS-CoV-2 virus-host interactome using human lung cancer derived A549 cells expressing individual SARS-CoV-2 viral proteins. Functional enrichment analyses revealed previously reported and unreported cellular pathways that are in association with SARS-CoV-2 proteins. We have also established a website to host the proteomic data to allow for public access and continued analysis of host-viral protein associations and whole-cell proteomes of cells expressing the viral-BioID fusion proteins. Collectively, these studies provide a valuable resource to potentially uncover novel SARS-CoV-2 biology and inform development of antivirals.

Background: The incidence and burden of endemic or potentially endemic infectious diseases (IDs) is highest in Sub-Saharan Africa (SSA) with a new disease to emerge every 8 months on average. The epidemic of preventable IDs becoming endemic to SSA serves as a stack reminder of the region’s systematic failings to health security. It is more important now than ever to evaluate SSA’s vulnerability to COVID-19, a global pandemic becoming endemic to the region after it perhaps gets eliminated from the other world regions. Method: The International Health Regulations (IHR [2005]) and Global Health Security Index (GHSI) scores for SSA before COVID-19 reached the region were obtained and evaluated to assess its health security preparedness. The number of cases, deaths and stringency measures of the first year of the virus in the region were used to ascertain the possibility of the virus becoming endemic to SSA. By this, COVID-19 confirmed cases and deaths of the region were obtained from the COVID-19 Data Repository by the Centre for Systems Science and Engineering (CSSE) at Johns Hopkins University. The stringency measures put in place by each country were obtained from the Oxford COVID-19 Government Response Tracker (OxCGRT). Data from the Global Infectious Diseases and Epidemiology Online Network (GIDEON) was then used to evaluate the intensity and distribution of endemic or potentially endemic IDs after COVID-19 reached SSA. Findings: Before the virus reached the region, 31% and 37% of the SSA countries moderately adhered to the IHR and GHSI score respectively. The overall performance of the region in its first year of responding and containing the virus was 56% compared to a global average of 60%. For the first year period of the virus, South Africa with the highest GHSI of 54·8% before the virus reached the region accounted for 55% of the total cases within the first year. Majority of the cases (48%) and deaths (55%) of the first year were recorded in the last three months when values of the stringency measures fell below 50%. For the region, the number of mortalities to cases ratio for the first wave (July 2020) was 1·47:98·53 compared to the second wave (February 2021) of 3·54:96·46. It was also observed that, an average of 222 IDs were endemic or potentially endemic to SSA after COVID-19 reached the region. Interpretation: It was revealed that there is a high possibility of devastating subsequent waves of COVID-19 and it becoming endemic to the region after assessing the stringency measures that were put in place, relative to the number of cases and deaths over the first year period. Funding: None to declare. Declaration of Interest: None to declare.