Results 1-25 of about 1,000
  1. Abstract Background The high frequency of Zika virus (ZIKV) infection prompted the World Health Organization (WHO) to declare it an emerging threat in 2016. Presently, countries in South America continue to report a significant number of Zika virus cases. Zika virus infection has been associated with neurological diseases. This article explores the impact of ZIKV infection on IgG + Zika-reactive conditions using a neurosphere model. Methods Neurospheres derived from Wistar rats were exposed to Zika virus and IgG + Zika-reactive conditions. The study assessed the area, irregularity rate, and relative gene expression of NOTCH-1, HES-1, and HEY-1, as well as the expression of GCSF and IL-10. Results The irregularity rate of ZIKV neurospheres decreased at its lowest concentration; however, our morphology analysis was insufficient to fully elucidate the impact of ZIKV on neurospheres. Interestingly, IgG + serum exhibited neuroprotective effects against subsequent Zika virus exposure, restoring NOTCH-1 and HES-1 expression levels to normal. HEY-1 expression remained unaffected by Zika virus exposure but decreased with IgG + serum. Surprisingly, levels of the anti-inflammatory markers GCSF and IL-10 showed no significant changes. Conclusions These findings highlight the complex interplay between ZIKV infection, immune response, and neurodevelopmental processes. Further research is necessary to elucidate the precise mechanisms underlying these observations and explore potential therapeutic interventions.
    Date: 2024-04-26
    Authors: Plentz I, Pazzin D, Previato T, Wagner F, Boff M, Fernandes L, Gonçalvez J, Marinowic D, Costa J.
    Ref: Research Square
  2. The Advisory Committee on Immunization Practices (ACIP) recommended that dengue pre-vaccination screening tests for Dengvaxia administration have at least 98% specificity and 75% sensitivity. This study evaluates the performance of commercial anti-DENV IgG tests to identify tests that could be used for pre-vaccination screening. First, for 7 tests, we evaluated sensitivity and specificity in early convalescent dengue virus (DENV) infection, using 44 samples collected 7-30 days after symptom onset and confirmed by RT-PCR. Next, for the 5 best performing tests and two additional tests (with and without an external test reader) that became available later, we evaluated performance to detect past dengue infection among a panel of 44 specimens collected in 2018-2019 from healthy 9-16-year-old children from Puerto Rico. Finally, a full-scale evaluation was done with the 4 best performing tests using 400 specimens from the same population. We used virus focus reduction neutralization test and an in-house DENV IgG ELISA as reference standards. Of seven tests, five showed ≥75% sensitivity detecting anti-DENV IgG in early convalescent specimens with low cross-reactivity to Zika virus. For the detection of previous DENV infections the tests with the highest performance were the Euroimmun NS1 IgG ELISA (sensitivity 84.5%, specificity 97.1%) and CTK Dengue IgG rapid test R0065C with the test reader (sensitivity 76.2% specificity 98.1%). There are IgG tests available that can be used to accurately classify individuals with previous DENV infection as eligible for dengue vaccination to support safe vaccine implementation.
    Date: 2024-04-21
    Authors: Medina FA, Vila F, Adams LE, Cardona J, Carrion J, Lamirande E, Acosta LN, De León-Rodríguez CM, Beltran M, Grau D, Rivera-Amill V, Balmaseda A, Harris E, Madewell ZJ, Waterman SH, Paz-Bailey G, Whitehead S, Muñoz-Jordán JL.
    Ref: medRxiv
  3. ABSTRACT Mosquito-borne Zika virus (ZIKV; orthoflavivirus, Flaviviridae ) has become a global health problem due to expansion of the geographic distribution of Asian Lineage virus. Contemporary ZIKV strains of African lineage have recently gained increased attention due to their epidemic potential and their capacity to be highly teratogenic in humans. The ZIKV non-structural NS1 protein from recent West African strains Africa was been studied where with view of its importance in the pathogenicity. NS1 protein from contemporary West African ZIKV (NS1 CWA ) and historical African ZIKV strain MR766 (NS1 MR766 ) differ by seven amino-acid substitutions. Expression of recombinant NS1 proteins showed differences in the subcellular distribution between NS1 CWA and NS1 MR766 in HEK-293T cells. There was an increased secretion efficiency of soluble NS1 CWA compared to NS1 MR766 . The replication of a chimeric MR766/NS1 CWA virus was studied in Vero and A549 cells. Insertion of NS1 CWA into MR766 enhances virus replication in both cell lines leading to more pronounced cell death. This correlated with lower up-regulation of IFN-β and interferon-stimulated gene mRNA in A549 cells infected by MR766/NS1 CWA virus. Our data raise the question on the importance of NS1 protein in the pathogenicity of contemporary ZIKV from West Africa, and point to differences within viral strains belonging to the same African lineage. AUTHOR SUMMARY Mosquito-borne Zika virus (ZIKV) of African lineage has the potential to cause epidemic along with a high risk of fetal pathogenicity. Too little is still known on the features of contemporary ZIKV from West Africa. We find there is a remarkable conservation of NS1 amino-acid residues between ZIKV strains recently isolated in Senegal and Guinea. Analysis of recombinant ZIKV NS1 protein revealed efficient secretion of contemporary African NS1 protein from human cells. Using infectious molecular clone of African ZIKV, we showed that contemporary West Africa NS1 protein influences virus replication and innate immune activation. The NS1 protein has been proposed as playing a major role in the pathogenicity of contemporary ZIKV from West Africa.
    Date: 2024-04-11
    Authors: Dana M, Marie-Pierre C, Eva O, Alain K, Desprès P, Marjolaine R.
    Ref: bioRxiv
  4. Previous studies about vector-borne diseases have emphasized the feedback between human psychology and diseases but neglected the changes in psychological processes. Here I first studied whether and how the two types of psychological dynamics in people’s Terror-To-Death (TTD) — periodical terror reinforcement and memory decay of terror — can influence the host-vector-pathogen interactions. Through developing a generic Ross-MacDonald model with TTD dynamics tailored for Zika virus transmitted by Aedes aegypti mosquito, I found that in general, the increase in initial terror increases control effort, while memory decay of terror decreases disease control. Memory decay also exhibits a threshold effect: when initial terror is below certain level, TTD decay would not influence the system much; once initial terror reaches a threshold, memory decay of TTD can largely reduce the public’s control effort, increase mosquito population and disease level in the system under a larger mosquitoes’ carrying capacity. Adding periodical terror reinforcement could introduce dynamical oscillation to the system, dampen the peak of human infection, and shorten the time of disease outbreak. If the reinforcement frequency is large enough, system dynamics could approach the scenario with constant TTD in the absence of memory decay. This work significantly advances the theory in disease epidemiology and biopsychology and can provide guidance for disease control by considering the joint effects of initial terror, the public’s memory decay, and the frequency of terror reinforcement simultaneously.
    Date: 2024-04-05
    Authors: Jiao J.
    Ref: Research Square
  5. Mosquito-borne viruses cause more than 400 million annual infections and place over half of the world’s population at risk. Despite this importance, the mechanisms by which arboviruses infect the mosquito host and disseminate to tissues required for transmission are not well understood. Here, we provide evidence that mosquito immune cells, known as hemocytes, play an integral role in the dissemination of dengue virus (DENV) and Zika virus (ZIKV) in the mosquito Aedes aegypti . We establish that phagocytic hemocytes are a focal point for virus infection and demonstrate that these immune cell populations facilitate virus dissemination to the ovaries and salivary glands. Additional transfer experiments confirm that virus-infected hemocytes confer a virus infection to non-infected mosquitoes more efficiently than free virus in acellular hemolymph, revealing that hemocytes are an important tropism to enhance virus dissemination in the mosquito host. These data support a “trojan horse” model of virus dissemination where infected hemocytes transport virus through the hemolymph to deliver virus to mosquito tissues required for transmission and parallels vertebrate systems where immune cell populations promote virus dissemination to secondary sites of infection. In summary, this study significantly advances our understanding of virus infection dynamics in mosquitoes and highlights conserved roles of immune cells in virus dissemination across vertebrate and invertebrate systems.
    Date: 2024-04-04
    Authors: Hall DR, Johnson RM, Kwon H, Ferdous Z, Laredo-Tiscareño SV, Blitvich BJ, Brackney DE, Smith RC.
    Ref: bioRxiv
  6. Usutu (USUV), West Nile (WNV), and Zika virus (ZIKV) are neurotropic arthropod-borne viruses (arboviruses) that cause severe neurological disease in humans. However, USUV-associated neurological disease is rare, suggesting a block in entry to or infection of the brain. To investigate whether USUV is able to infect the brain similarly to WNV and ZIKV, we determined the replication, cell tropism and neurovirulence of these arboviruses in human brain tissue using a well-characterized human fetal organotypic brain slice culture model. Furthermore, we assessed the efficacy of interferon-β and 2’C-methyl-cytidine, a synthetic nucleoside analogue, in restricting viral replication. All three arboviruses replicated within the brain slices, with WNV reaching the highest titers. USUV and ZIKV reached comparable titers and all three viruses primarily infected neuronal cells. USUV- and WNV-infected cells exhibited a shrunken morphology, not associated with detectable cell death. Pre-treatment with interferon-β inhibited replication of the arboviruses, while 2’C-methyl-cytidine reduced titers of USUV and ZIKV, but not WNV. Collectively, USUV can infect human brain tissue, showing similarities in replication, tropism and neurovirulence as WNV and ZIKV. Further, this model system can be applied as a preclinical model to determine the efficacy and safety of drugs to treat viral infections of the brain.
    Date: 2024-04-04
    Authors: Marshall EM, Rashidi AS, Gent M, Rockx B, Verjans GMGM.
    Ref: Research Square
  7. Zika virus (ZIKV) is a notable arbovirus with maternal, sexual, and TORCH-related transmission capabilities. After 2015, Brazil had the highest number of ZIVK-infected pregnant women who lost their babies or delivered them with Congenital ZIKV Syndrome (CZS). ZIKV infection has been linked to variations in endogenous retroviruses (ERVs) and interleukins within the placenta. ERVs, remnants of ancient viral infections integrated into the genome, include syncytin receptors crucial for placental development. Interleukins, immune response regulators, aid immune tolerance and support syncytial structure development in the placenta, where syncytin receptors facilitate vital cell-to-cell fusion events. Since ZIKV can infect trophoblast cells, we investigated the relationship between ZIKV infections and ERV and interleukin modulations. Investigating the impact of ZIKV on trophoblast cells, we examined two cell types (BeWo and HTR8) infected with ZIKV-MR766 (African) and ZIKV-IEC-Paraíba (Asia-Brazilian) using Taqman and RT2 Profiler PCR Array assays. While early ZIKV infection (24-48 hours) did not induce differential ERV and interleukin expression, future studies involving additional trophoblastic cell lineages and extended infection timelines will illuminate the dynamic interplay between ZIKV, HERVs, interleukins, and cytokines essential for placental formation and function.
    Date: 2024-04-02
    Authors: Costa ALd, Prieto-Oliveira P, Duarte-Barbosa M, Andreata-Santos R, Peter CM, Prolo T, Antoneli F, Carvalho MIVGd, Durães-Carvalho R, Briones MRdS, Maricato JT, Zanotto PMA, Jacob Machado D, Janini LMR.
    Ref: Preprints.org
  8. Background Metagenomics is a powerful approach for the detection of unknown and novel pathogens. Workflows based on Illumina short-read sequencing are becoming established in diagnostic laboratories. However, barriers to broader take-up include the need for high sequencing depths, long turnaround times, and limited sensitivity. Newer metagenomics protocols based on Oxford Nanopore Technologies (ONT) sequencing allow acquisition and analysis of data in real time, potentially reducing the need for high-volume sequencing and enabling point-of-care testing. Furthermore, targeted approaches that selectively amplify known pathogens could improve sensitivity. Methods We evaluated detection of viruses with readily available untargeted metagenomic workflows using Illumina and ONT, and an Illumina-based enrichment approach using the Twist Biosciences Viral Research Panel (VRP), which targets 3153 viruses. We tested samples consisting of a dilution series of a six-virus mock community in a human DNA/RNA background, designed to resemble clinical specimens with low microbial abundance and high host content. Protocols were designed to retain the host transcriptome, since this could help confirm the absence of infectious agents. We further compared the performance of commonly used taxonomic classifiers. Results Capture with the Twist VRP increased sensitivity by at least 10-100-fold over untargeted sequencing, making it suitable for the detection of low viral loads (60 genome copies per ml (gc/ml)), but additional methods may be needed in a diagnostic setting to detect untargeted organisms. While untargeted ONT had good sensitivity at high viral loads (60,000 gc/ml), at lower viral loads (600-6,000 gc/ml), longer and more costly sequencing runs would be required to achieve sensitivities comparable to the untargeted Illumina protocol. Untargeted ONT provided better specificity than untargeted Illumina sequencing. However, the application of robust thresholds standardized results between taxonomic classifiers. Host gene expression analysis is optimal with untargeted Illumina sequencing but possible with both the VRP and ONT. Conclusions Metagenomics has the potential to become standard-of-care in diagnostics and is a powerful tool for the discovery of emerging pathogens. Untargeted Illumina and ONT metagenomics and capture with the Twist VRP have different advantages with respect to sensitivity, specificity, turnaround time and cost, and the optimal method will depend on the clinical context.
    Date: 2024-03-29
    Authors: Buddle S, Forrest L, Akinsuyi N, Martin Bernal LM, Brooks T, Venturini C, Miller C, Brown JR, Storey N, Atkinson L, Best T, Roy S, Goldsworthy S, Castellano S, Simmonds P, Harvala H, Golubchik T, Williams R, Breuer J, Morfopoulou S, Torres Montaguth OE.
    Ref: medRxiv
  9. The 2016 outbreak of Zika virus (ZIKV) infected millions and resulted in thousands of infants born with malformations. Though the clusters of severe birth defects resulting from this outbreak have subsided, ZIKV continues to be a concern throughout much of Latin America and the Caribbean. Travel and sexual intercourse remain the dominant transmission risk factors for women of reproductive age and their partners. This is particularly true for communities in Brooklyn, New York, that comprise large immigrant and foreign-born populations. Practitioners of public health understand little about how women at risk for ZIKV are most likely to receive information about the virus or who they trust most to provide that information. In the context of five focus group discussions, this study explored the knowledge and communication preferences of 20 women of reproductive age in Central Brooklyn. Results derived from a thematic analysis suggest that while most women are familiar with mosquitos as ZIKV vectors, knowledge of sexual transmission is considerably lower. Many respondents believe that only women who are pregnant or trying to become pregnant are at risk, and public health agencies, such as the U.S. Centers for Disease Control and Prevention, remain the most trusted sources of information. These findings can support more effective communication about the risks of ZIKV infection and other vector-borne diseases to women in New York City and similar urban communities.
    Date: 2024-03-29
    Authors: Dowling R, Kolokotronis S, Thompson AB.
    Ref: medRxiv
  10. SUMMARY Subgenomic flavivirus RNAs (sfRNAs) are structured RNA elements encoded in the 3’-UTR of flaviviruses that promote viral infection by inhibiting cellular RNA decay machinery. Herein, we analyze the production of sfRNAs using single-molecule RNA fluorescence in situ hybridization (smRNA-FISH) and super-resolution microscopy during West Nile virus, Zika virus, or Dengue virus serotype 2 infection. We show that sfRNAs are initially localized diffusely in the cytosol or in processing bodies (P-bodies). However, upon activation of the host antiviral endoribonuclease, Ribonuclease L (RNase L), nearly all sfRNAs re-localize to antiviral biological condensates known as RNase L-induced bodies (RLBs). RLB-mediated sequestration of sfRNAs reduces sfRNA association with RNA decay machinery in P-bodies, which coincides with increased viral RNA decay. These findings establish a role of RLBs in promoting viral RNA decay, demonstrating the complex host-pathogen interactions at the level of RNA decay and biological condensation. Highlights Single-molecule imaging of sfRNA production and localization sfRNAs localize to RNase L-induced bodies RNase L-induced bodies sequester sfRNAs away from P-bodies Sequestration of sfRNAs by RNase L-induced bodies enhances decay of viral genomes
    Date: 2024-03-27
    Authors: Watkins JM, Burke JM.
    Ref: bioRxiv
  11. Unbiased long read sequencing holds enormous potential for the detection of pathogen sequences in clinical samples. However, the untargeted nature of these methods precludes conventional PCR approaches, and the metagenomic content of each sample increases the challenge of bioinformatic analysis. Here, we evaluate a previously described novel workflow for unbiased RNA virus sequence identification in a series of contrived and real-world samples. The novel multiplex library preparation workflow was developed for the Oxford Nanopore Technologies (ONT) MinION TM sequencer using reverse transcription, whole genome amplification, and ONT’s Ligation Sequencing Kit with Native Barcode Expansion. The workflow includes spiked MS2 Phage as an internal positive control and generates an 8-plex library with 6 samples, a negative control and a gfp transcript positive control. Targeted and untargeted data analysis was performed using the EPI2ME Labs framework and open access tools that are readily accessible to most clinical laboratories. Contrived samples composed of common respiratory pathogens (Influenza A, Respiratory Syncytial Virus and Human Coronavirus 229E) in viral transport media (VTM) and bloodborne pathogens (Zika Virus, Hepatitis A Virus, Yellow Fever Virus and Chikungunya Virus) in human plasma were used to establish the limits of detection for this assay. We also evaluated the diagnostic accuracy of the assay using remnant clinical samples and found that it showed 100% specificity and 62.9% clinical sensitivity. More studies are needed to further evaluate pathogen detection and better position thresholds for detection and non-detection in various clinical sample metagenomic mixtures.
    Date: 2024-03-27
    Authors: Kappell AD, Schulte KQ, Scheuermann EA, Scholz MB, Keplinger NC, Scholes AN, Wolt TA, June VM, Schulte CJ, Allen LW, Ternus KL, Hewitt FC.
    Ref: medRxiv
  12. ABSTRACT Zika virus (ZIKV) have become a global health problem over the past decade due to the extension of the geographic distribution of ZIKV of Asian genotype. Epidemics of Asian ZIKV have been associated with developmental disorders in humans. ZIKV of African lineage would have an epidemic potential associated to fetal pathogenicity requiring a greater attention towards the most recently isolated viral strains from West Africa. In the present study, an infectious molecular clone GUINEA-18 has been obtained from viral strain ZIKV-15555 that had been sequenced from an individual infected by ZIKV in Guinea in 2018. A molecular clone-based comparative study between GUINEA-18 and viral clone MR766 MC from historical African ZIKV strain MR766 revealed a lower replication rate for GUINEA-18 associated to a weaker cytotoxicity and reduced innate immune system activation in Vero E6, A549 and HCM3 cell lines. Analysis of chimeric viruses between MR766 MC and GUINEA-18 stressed the importance NS1/NS4B proteins with a particular focus for NS4B on GUINEA-18 replication properties. ZIKV has developed strategies to prevent cytoplasmic stress granule formation which occurs in response to virus infection. Study of G3BP protein showed that GUINEA-18 but not MR766 MC was efficient to inhibit stress granule assembly in A549 cells subjected to a physiological stressor. GUINEA-18 depends on NS1/NS4B proteins for suppressing stress granule response to environmental stress. The involvement of GUINEA-18 NS1/NS4B proteins on virus replication capability and host-cell responses to ZIKV infection raises the question of the importance of nonstructural proteins in the pathogenicity of contemporary viral strains from West Africa. AUTHOR SUMMARY Most of studies having for objectives to understand the biology of Zika virus (ZIKV) were carried out using epidemic viral strains of Asian lineage. It is now admitted that ZIKV of African genotype would have also a great epidemic potential associated a high risk of fetal pathogenicity. Today, it is urgent to improve our knowledge on recently isolated ZIKV strains in West Africa. In our study, we used the sequence of viral strain from an individual infected by ZIKV in Guinea in 2018 to generate an infectious molecular clone. Analysis of viral clone highlighted the preponderant role of NS1/NS4B proteins in virus replication strategy and cell interactions with a particular focus on ZIKV-specific stress granule formation blockade. We believe that our data will improve our knowledge on the biology of contemporary West Africa ZIKV opening perspectives towards a better understanding on the pathogenicity of African viral strains.
    Date: 2024-03-14
    Authors: Machmouchi D, Courageot M, El-Kalamouni C, Kohl A, Desprès P.
    Ref: bioRxiv
  13. RNA viruses play diverse functional roles in engineered ecosystems, influencing biotechnological process and serving as indicators of human health. Comprehending the ecological and health significance of RNA viruses in wastewater treatment plants (WWTPs) can derive their valuable implications on microbial community control and wastewater-based epidemiology. This study delved into an extensive analysis of RNA sequencing data, totally over 3.8 Tb, sourced from 557 metatranscriptomes across global WWTPs, to scrutinize the diversity, host associations, and auxiliary metabolic functions of RNA viruses. We identified 11414 RNA virus operational taxonomic units from the WWTPs, doubling the current known diversity of the RNA viruses in global engineered systems. Phylogenetic analysis of RNA-dependent RNA polymerases supported the establishment of the five established RNA virus phyla while also advocating for taxonomy revisions due to our discovery of novel clades. Notably, the RNA viral community within the WWTPs was predominated by prokaryotic viruses, encompassing both previously identified RNA phage lineages ( Leviviricetes and Cystoviridae ) and potential prokaryotic viruses from newly-identified clades. Detections of prevalent human RNA viruses such as Astrovirus , Respirovirus , Rotavirus , and Norovirus , alongside high-risk human RNA viruses like SARS-Cov-2 and Zika virus, highlighted the potential of leveraging wastewater-based surveillance for human health protection. Moreover, the presence of auxiliary metabolic genes encoded by RNA viruses suggested their involvement in diverse host metabolic processes, including enhancing translation efficiency, cellular respiration, nitrogen metabolism, and even antibiotic resistance. Collectively, our findings unveil the previously hidden diversity, health implications, and biochemical impacts of RNA viruses within WWTPs, underscoring their multifaceted roles in engineered environmental systems.
    Date: 2024-03-12
    Authors: Yuan L, Ju F.
    Ref: bioRxiv
  14. The influenza virus has been the primary cause of the pandemic, posing a constant threat to human society. Due to its genetic evolution and continuous outbreak, antiviral research currently focuses on exploring a novel lead agent. A comprehensive antiviral screening discovered a marine bacterium whose extract exerted excellent efficacy against influenza viruses. Parerythrobacter sp. M20A3S10, a novel strain under the family Erythrobacteraceae, could produce carotenoids exhibiting antiviral and anticancer activity by enhancing the cellular immune system. Post-treatment of M20A3S10 extract showed outstanding therapeutic indexes: against influenza virus A/PR8 (H1N1) [selectivity index (SI) = 24.0], A/Wisconsin/15/2009 (H3N2) (SI = 30.1) and B/Florida/78/2015 (SI = 38.2). Comparably, the effectiveness was demonstrated against Zika virus (ZIKV) and dengue virus type 2 (DENV2) with an SI of 22.5 and 24.1, respectively, namely broad-spectrum activity. Of note, the antiviral responses resulted from the common replication mechanism between IAV, ZIKV, and DENV2. The stimulation of apoptosis-mediated cellular immunity prevented the viral release and protected the host, suggesting that switching from necroptosis to apoptosis is a novel antiviral target. Although the specific compound affecting the antiviral activity was not identified, its promising efficacy with broad activity will contribute to developing a strategy for preventing future pandemics.
    Date: 2024-03-11
    Authors: Moon K, Choi G, Jung S, Kim H, Park J, Kwon YM, Cho E, Shin MY, Yu J, Choi JA, Baek Y, Park S.
    Ref: Preprints.org
  15. Host factors that regulate cellular vesicular trafficking also contribute to progeny virions’ destination, thus representing as potential antiviral drug targets. Here we demonstrate that genetic deletion of ARF4, a regulator in vesicle transport, repressed multiple pathogenic RNA viral infections including Zika virus (ZIKV), influenza A virus (IAV), SARS-CoV-2 and Vesicular Stomatitis virus (VSV). ARF4 activation was stimulated upon viral infection, and viral production was rescued when reconstituted with the activated ARF4, but not the inactivated mutants. Mechanically, ARF4 deletion obstructed viral normal translocation into Golgi complex, but led to mis-sorting for lysosomal degradation, consequently caused the blockage of final release. More importantly, ARF4 targeting peptides achieved significant therapeutic efficacy against ZIKV and IAV challenge in mice by blocking ARF4 activation. Hence, we clarify the critical role of ARF4 during viral infection, providing a broad-spectrum antiviral target and the basis for further pharmaceutical development.
    Date: 2024-03-11
    Authors: Qin C, Li M, Deng K, Cheng X, Siu LY, Naik TS, Stancheva VG, Cheung P, Gao Z, Teo QW, Leur SWv, Wong H, Lan Y, Zhang N, Zhang Y, Cao T, Yang F, Deng Y, Sanyal S.
    Ref: Research Square
  16. Although rare neurodevelopmental conditions have a large Mendelian component, common genetic variants also contribute to risk. However, little is known about how this polygenic risk is distributed among patients with these conditions and their parents, its interplay with rare variants, and whether parents’ polygenic background contributes to their children’s risk beyond the direct effect of variants transmitted to the child (i.e. via indirect genetic effects potentially mediated through the prenatal environment or ‘genetic nurture’). Here, we addressed these questions using genetic data from 11,573 patients with rare neurodevelopmental conditions, 9,128 of their parents and 26,869 controls. Common variants explained ∼10% of variance in overall risk. Patients with a monogenic diagnosis had significantly less polygenic risk than those without, supporting a liability threshold model, while both genetically undiagnosed patients and diagnosed patients with affected parents had significantly more risk than controls. In a trio-based model, using a polygenic score for neurodevelopmental conditions, the transmitted but not the non-transmitted parental alleles were associated with risk, indicating a direct genetic effect. In contrast, we observed no direct genetic effect of polygenic scores for educational attainment and cognitive performance, but saw a significant correlation between the child’s risk and non-transmitted alleles in the parents, potentially due to indirect genetic effects and/or parental assortment for these traits. Indeed, as expected under parental assortment, we show that common variant predisposition for neurodevelopmental conditions is correlated with the rare variant component of risk. Our findings thus suggest that future studies should investigate the possible role and nature of indirect genetic effects on rare neurodevelopmental conditions, and consider the contribution of common and rare variants simultaneously when studying cognition-related phenotypes.
    Date: 2024-03-06
    Authors: Huang QQ, Wigdor EM, Campbell P, Malawsky DS, Samocha KE, Chundru VK, Danecek P, Lindsay S, Marchant T, Musa MK, Amanat S, Bonifanti D, Sheridan E, Radford EJ, Barrett JC, Wright CF, Firth HV, Warrier V, Young AS, Hurles ME, Martin HC.
    Ref: medRxiv
  17. At the start of the Zika virus (ZIKV) epidemic in 2015, ZIKV spread across South and Central America, and reached parts of the southern United States placing pregnant women at risk for fetal microcephaly, fetal loss, and other adverse pregnancy outcomes associated with congenital ZIKA syndrome (CZS). For this reason, testing of a safe and efficacious ZIKV vaccine remains a global health priority. Here we report that a single immunization with Ad26.M.Env ZIKV vaccine, when administered prior to conception, fully protects pregnant rhesus macaques from ZIKV viremia in blood and tissues with no adverse effects in dams and fetuses. Furthermore, vaccination prevents ZIKV distribution in fetal tissues including brain. ZIKV associated neuropathology was absent in offspring of Ad26.M.Env vaccinated dams, although pathology was limited in sham vaccinated controls. Vaccine efficacy is associated with induction of ZIKV neutralizing antibodies in pregnant rhesus macaques. A Phase I trial showed that Ad26.M.Env (Ad26.ZIKV.001) was safe and immunogenic in people. These data suggest the feasibility of vaccine prevention of ZCS in humans.
    Date: 2024-03-05
    Authors: Martinot A, Cox F, Abbink P, Hecht J, Bronson R, Borducchi E, Rinaldi W, Ferguson M, Barrera RDL, Fits Lvd, Barouch D.
    Ref: Research Square
  18. Neurons are post-mitotic, non-regenerative cells that have evolved fine-tuned immunological responses to maintain life-long cellular integrity; this includes resistance to common programmed cell death (PCD) pathways, including apoptosis and necroptosis. We have previously demonstrated a necroptosis-independent role for the key necroptotic kinase RIPK3 in host defense against neurotropic flavivirus infection. While this work showed that neuronal RIPK3 expression is essential for chemokine production and recruitment of peripheral immune cells to the infected CNS, the full RIPK3-dependent transcriptional signature, and the molecular mechanism underlying RIPK3-dependent transcription in neurons are incompletely understood. It also remains unclear what factors govern differential RIPK3 effector functions in different cell types. Here, we show that RIPK3 activation has distinct outcomes in primary cortical neurons when compared to mouse embryonic fibroblasts (MEFs) during Zika virus (ZIKV) infection or following sterile activation. We found that RIPK3 activation does not induce death in neurons; in these cells, RIPK3 is the dominant driver of antiviral gene transcription following ZIKV infection. While RIPK3 activation in MEF cells induces cell death, ablation of downstream cell death effectors unveils a RIPK3-dependent transcriptional program which largely overlaps with that observed in ZIKV-infected neurons. Using death resistant MEFs as a model to study RIPK3 signaling revealed that RIPK3 transcription relied on interactions with the RHIM domain-containing proteins RIPK1 and TRIF, effects mirrored in the RIPK3-dependent antiviral transcriptional signature observed in ZIKV-infected neurons. These findings suggest the pleotropic functions of RIPK3 are largely context dependent and that in cells that are resistant to cell death, RIPK3 acts as a mediator of inflammatory transcription. One Sentence Summary RHIM-domain containing proteins form a conserved signaling network capable of mediating inflammatory transcription and cell death.
    Date: 2024-03-02
    Authors: Kofman SB, Chu LH, Ames JM, Chavarria SD, Lichauco K, Daniels BP, Oberst A.
    Ref: bioRxiv
  19. Abstract Background This study delves into the complex interplay between Aedes aegypti salivary gland extract and immunological cells during Zika virus (ZIKV) infection. Focusing on key immune cells, including macrophages, dendritic cells, and mononuclear cells from human peripheral blood (PBMCs), it aims to unravel the intricate mechanisms through which mosquito saliva possibly modulates the immunological landscape, influencing ZIKV transmission, host susceptibility, and disease progression. The research sheds light on the role of mosquito saliva in enhancing viral replication and impairing cells involved in host defenses, offering new insights into arbovirus pathogenesis and potential intervention strategies. Methods Using the FIOCRUZ-PE243|2015 ZIKV strain, the research evaluates the Aedes aegypt salivary extracts (SGE's) impact on cytokine production in dendritic and macrophage cell lines, as well as its influence on the redox state and cytokine responses in human PBMCs. Flow cytometry assesses immune cell profiling, aiming to understand SGE's role in ZIKV infectivity and immune modulation. Results SGE enhances pro-inflammatory cytokine production in both dendritic cells and macrophages, while also inducing a Th2 cytokine profile, evidenced by decreased IFN-γ and increased IL-4 levels in PBMCs. Furthermore, SGE exposure leads to increased dendritic cell frequencies, altered T lymphocyte dynamics, and elevated oxidative stress markers. Conclusions It highlights how SGE not only facilitates ZIKV infection by modulating cytokine production and oxidative stress but also alters immune cell dynamics.
    Date: 2024-03-01
    Authors: Hilario G, Haubert A, Dorneles G, Freitas DN, Silva OS, Prophiro JS, Fazolo T, Fonseca SG, Romão PRT, Junior LR.
    Ref: Research Square
  20. Zika virus (ZIKV) infection and pathogenesis are linked to the disruption of neurogenesis, congenital Zika syndrome and microcephaly by affecting neural progenitor cells. Nonstructural protein 5 (NS5) is the largest product encoded by ZIKV-RNA and is important for replication and immune evasion. Here, we studied the potential effects of NS5 on microtubules (MTs) and autophagy flux, together with the interplay of NS5 with histone deacetylase 6 (HDAC6). Fluorescence microscopy, biochemical cell-fractionation combined with the use of HDAC6 mutants, chemical inhibitors and RNA interference indicated that NS5 accumulates in nuclear structures and strongly promotes the acetylation of MTs that aberrantly reorganize in nested-like structures. Similarly, NS5 accumulates the p62 protein, an autophagic-flux marker. Therefore, NS5 alters events that are under the control of the autophagic tubulin-deacetylase HDAC6. HDAC6 appears to degrade NS5 by autophagy in a deacetylase- and BUZ domain-dependent manner and to control the cytoplasmic expression of NS5. Moreover, NS5 inhibits RNA-mediated RIG-I interferon (IFN) production, resulting in greater activity when autophagy is inhibited (i.e., effect correlated with NS5 stability). Therefore, it is conceivable that NS5 contributes to cell toxicity and pathogenesis, evading the IFN-immune response by overcoming HDAC6 functions. HDAC6 has emerged as an anti-ZIKV factor by targeting NS5.
    Date: 2024-02-29
    Authors: Pérez-Yanes S, Lorenzo-Sánchez I, Cabrera-Rodríguez R, García-Luis J, Trujillo-González R, Estévez-Herrera J, Valenzuela-Fernández A.
    Ref: Preprints.org
  21. Dengue (DENV) virus and Zika virus (ZIKV) are two flaviviruses of major public health concern. One drawback designing effective vaccines is our limited understanding of the mechanisms ruling protection or harm among DENV serotypes, or between DENV and ZIKV. Here, we depleted rhesus macaques of CD4 + T cells in vivo before primary DENV infection and/or secondary ZIKV challenge to recreate a sub-optimal priming of the humoral immune response. Our results support that CD4 + T cells are needed to induce a quantitative and type-specific effective humoral immune response against primary DENV, but also against secondary ZIKV in DENV-experimented subjects. Our results also indicate a limited contribution of the DENV-Memory B cells to anti-ZIKV response. Furthermore, our results suggest that a suboptimal B cell priming during a primary DENV infection does differentially impact different antibody (Abs) properties. While binding or neutralization of ZIKV or DENV during a subsequent exposure to ZIKV is not affected by the lack of CD4 + T - B cells interaction during a primary DENV infection, that interaction is critical to guarantee the Abs specificity. Also, we found that depleting CD4 + T cells before DENV primary infection but not before ZIKV challenge significantly increases Abs cross-reactivity against DENV-EDIII domain and DENV-NS1 protein but not against ZIKV-EDIII domain or NS1 protein. Furthermore, there was more cross-reactivity among the DENV-NS1 proteins than against DENV-EDIII domains, suggesting that during a primary DENV infection CD4 + T cells have a different weight in the responses against EDIII domain and NS1 protein. The proper Abs binding and neutralization with increased cross-reactivity profile was associated with limited frequency of circulating peripheral T helper cells (pTfh) with T helper 1 phenotype (CD4+/CXCR5+/CXCR3+) and expressing markers related to B cell activation (CXCR5+/CXCR3+/PD-1+/ICOS+) in the group depleted of CD4 + T cells only before primary DENV infection. However, memory B cells – but not Antibody Secreting Cells (ASC) activation 7 days after the infection – positively correlate with those two populations of pTfh. Finally, when Abs cross-reactivity values were incorporated in a Principal Component Analysis (PCA), the DENV-CD4 + T depleted group separates from the other two groups with similar Abs binding and neutralization profiles. Our result strongly suggests that during a heterologous sequential DENV/ZIKV infections Abs binding, and neutralization, may be regulated by different factors than their specificity. Before, the induction of cross-neutralizing Abs has been described in the context of secondary DENV infection. Here, for the first time, we are reproducing the experimental conditions leading to the generation of such Abs population in vivo . In summary, we show that suboptimal immune priming during a primary flavivirus infection has functional consequences during a secondary heterologous infection. These results have huge implications understanding the immune response to DENV vaccines (and maybe ZIKV), including why an optimal vaccine or natural-induced neutralizing response not necessarily protects or enhances pathogenesis during a subsequent natural heterologous exposure.
    Date: 2024-02-22
    Authors: Serrano-Collazo C, Miranda A, Cruz LA, Henein S, Sanchez-Rosado M, Alvarez L, Arana T, Martinez MI, Roman C, Burgos AG, de Silva A, Sariol CA.
    Ref: bioRxiv
  22. Temperature profoundly affects various aspects of ectotherm biology. Notably, in mosquito species that spread viral diseases, temperature influences not only vector biology, but also the dynamics of pathogen-vector interactions. However, research attempting to address the role of the thermal environment in disease transmission often employs constant temperatures, which do not reflect the natural diurnal fluctuations these organisms experience. Additionally, most studies focus on adult mosquitoes in the period following virus infection. Much less attention has been paid to evidence indicating that temperatures experienced during earlier developmental stages may also affect the ability of disease vectors to be infected with and transmit viruses. Here, we show that Aedes aegypti exposed to temperatures below 25 deg C, specifically during the pupal stage of development, exhibit heightened susceptibility to Zika virus (ZIKV), which increases transmission efficiency. Modeling suggests that exposing mosquitoes to cooler fluctuating diurnal temperature ranges only during the relatively short pupal stage increases the R0 or reproductive number of ZIKV. Data loggers placed near Harris County Mosquito Control trap sites consistently recorded temperatures below 25 deg C, indicating natural exposure to such conditions. These results highlight the significance of thermal heterogeneity in the microhabitats where container-breeding mosquitoes undergo development. Such heterogeneity may play a more important role in the transmission of mosquito-borne diseases than previously recognized.
    Date: 2024-02-16
    Authors: Pohlenz TD, Vela J, Reyna M, Fredregill C, Hur B, Erraguntla M, Lawley M, Debboun M, Adelman ZN, Ndeffo-Mbah ML, Myles KM.
    Ref: bioRxiv
  23. ABSTRACT Nucleic acid tests (NATs) are essential for biomedical diagnostics. Traditional NATs, often complex and expensive, have prompted the exploration of Toehold-Mediated Strand Displacement (TMSD) circuits as an economical alternative. However, the wide application of TMSD-based reactions is limited by ‘leakage’—the spurious activation of the reaction leading to high background signals and false positives. Here we introduce a new TMSD cascade that recognizes a custom nucleic acid input and generates an amplified output. The system is based on a pair of thermodynamically spring-loaded DNA modules. The binding of a predefined nucleic acid target triggers an intermolecular reaction that activates a T7 promoter, leading to the perpetual transcription of a fluorescent aptamer that can be detected by a smartphone camera. The system is designed to permit the selective depletion of leakage byproducts to achieve high sensitivity and zero-background signal in the absence of the correct trigger. Using Zika virus (ZIKV)- and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-derived nucleic acid sequences, we show that the assay generates a reliable target-specific readout. Native RNA can be directly detected under isothermal conditions, without requiring reverse transcription, with a sensitivity as low as 200 attomole. The modularity of the assay allows easy re-programming for the detection of other targets by exchanging a single sequence domain. This work provides a low-complexity and high-fidelity synthetic biology tool for point-of-care diagnostics and for the construction of more complex biomolecular computations.
    Date: 2024-02-14
    Authors: Gupta K, Krieg E.
    Ref: bioRxiv
  24. ABSTRACT Background The international flight network creates multiple routes by which pathogens can quickly spread across the globe. In the early stages of infectious disease outbreaks, analyses using flight passenger data to identify countries at risk of importing the pathogen are common and can help inform disease control efforts. A challenge faced in this modelling is that the latest aviation statistics (referred to as contemporary data) are typically not immediately available. Therefore, flight patterns from a previous year are often used (referred to as historical data). We explored the suitability of historical data for predicting the spatial spread of emerging epidemics. Methods We analysed monthly flight passenger data from the International Air Transport Association to assess how baseline air travel patterns were affected in outbreaks of MERS, Zika, and SARS-CoV-2 over the past decade. We then used a stochastic discrete time SEIR metapopulation model to simulate global spread of different pathogens, comparing how epidemic dynamics differed in simulations based on historical and contemporary data. Results We observed local, short-term disruptions to air travel from South Korea and Brazil for the MERS and Zika outbreaks we studied, whereas global and longer-term flight disruption occurred during the SARS-CoV-2 pandemic. For outbreak events that were accompanied by local, small, and short-term changes in air travel, epidemic models using historical flight data gave similar projections of timing and locations of disease spread as when using contemporary flight data. However, historical data were less reliable to model the spread of an atypical outbreak such as SARS-CoV-2 in which there were durable and extensive levels of global travel disruption. Conclusions The use of historical flight data as a proxy in epidemic models is an acceptable practice except in rare, large epidemics that lead to substantial disruptions to international travel.
    Date: 2024-02-13
    Authors: Wardle J, Bhatia S, Cori A, Nouvellet P.
    Ref: medRxiv
  25. Alzheimer’s Disease (AD), a progressive and debilitating condition, is reported to be the most common type of dementia, with at least 55 million people believed to be currently affected. Many causation hypotheses of AD exist, yet the intriguing link between viral infection and its possible contribution to the known etiology of AD has become an attractive focal point of research for the field and a challenging study task. In this review, we will explore the historical perspective and milestones that led the field to investigate the viral connection to AD. Specifically, several viruses such as Herpes Simplex Virus 1 (HSV-1), Zika virus (ZIKV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), along with several others mentioned, include the various viruses presently considered within the field. We delve into the strong evidence implicating these viruses in the development of AD. We will also extend beyond these mere associations by carefully analyzing the potential mechanisms by which viruses may contribute to AD pathology. This includes but is not limited to direct neuronal infections, dysregulation of immune responses, and the impact on protein processing. Controversies and challenges of the viral-AD relationship emerge as we tease out these potential mechanisms considered. Looking forward, we emphasize the future directions the field should take to tackle the remaining unanswered questions and the glaring research gaps that persist. Overall, this review aims to provide a comprehensive survey of the past, present, and future of the potential link between viral infections and their association with AD development.
    Date: 2024-02-08
    Authors: Rippee-Brooks MD, Wu W, Dong J, Pappolla M, Fang X, Bao X.
    Ref: Preprints.org
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