The RNA helicase Ddx52 functions as a growth switch in juvenile zebrafish.

Vertebrate animals usually display robust growth trajectories during juvenile stages, and reversible suspension of this growth momentum by a single genetic determinant has not been reported. Here, we report a single genetic factor that is essential for juvenile growth in zebrafish. Using a forward genetic screen, we recovered a temperature-sensitive allele, pan (after Peter Pan), that suspends whole-organism growth at juvenile stages. Remarkably, even after growth is halted for a full 8-week period, pan mutants are able to resume a robust growth trajectory after release from the restrictive temperature, eventually growing into fertile adults without apparent adverse phenotypes. Positional cloning and complementation assays revealed that pan encodes a probable ATP-dependent RNA helicase (DEAD-Box Helicase 52; ddx52) that maintains the level of 47S precursor ribosomal RNA. Furthermore, genetic silencing of ddx52 and pharmacological inhibition of bulk RNA transcription similarly suspend the growth of flies, zebrafish and mice. Our findings reveal evidence that safe, reversible pauses of juvenile growth can be mediated by targeting the activity of a single gene, and that its pausing mechanism has high evolutionary conservation.

Evaluating Effectiveness and Safety in Chronic Kidney Disease with Atrial Flutter Using an Anticoagulation Strategy.

Background and Objectives: Recent randomized trials of oral antithrombotic drugs with atrial flutter (AFL) excluded patients with renal impairment because of their increased risk of bleeding. To date, no relevant studies have assessed the effectiveness and safety of different antithrombotic drugs in chronic kidney disease (CKD) patients with AFL. This cohort study evaluated the effectiveness and safety of different antithrombotic drugs in CKD patients with AFL. This study also investigated the risk of cardiovascular events from antithrombotic drugs through different risk profiles of stroke stratified by the CHA2DS2-VASc score. Materials and Methods: This cohort study was performed in patients with AFL and CKD who were extracted from the National Health Insurance (NHI) Database in Taiwan. Oral antithrombotic therapy (oral anticoagulants (OAC) or antiplatelets (APT)) was administered to patients who had been diagnosed with AFL after being diagnosed with CKD between 2011 and 2015. Primary outcomes, including ischemic stroke, systemic embolism, and composite of stroke, and secondary outcomes, including major adverse cardiac events (MACEs), major bleeding, all-cause mortality, and cardiovascular-related death, were examined. Results: A total of 2468 patients were included in this study. The results showed no statistically significant differences in the risk of primary outcomes. For the secondary outcomes, there were also no statistically significant differences in the risk of MACEs and major bleeding. However, the pooled results indicated that the hazard ratio (HR) for all-cause mortality with OAC was 0.24 (95% confidence interval (CI) = 0.10-0.55) compared with combination therapy, and the HR for APT compared with OAC was 2.86 (95% CI = 1.48-5.53). Conclusions: In the studied population, OAC or APT alone were proved equally effective for stroke prophylaxis. Furthermore, OAC might reduce the all-cause mortality rate compared with APT and should be considered as the first choice of oral antithrombotic drugs in patients with AFL and CKD.

Enterobius vermicularis infection: prevalence and risk factors among preschool children in kindergarten in the capital area, Republic of the Marshall Islands.

BACKGROUND: Enterobius vermicularis (pinworm) is one of the most common human parasitic helminths, and children are the most susceptible group. Some behavioral and environmental factors may facilitate pinworm infection. In the Republic of the Marshall Islands (RMI), the status of pinworm infections among children remains unknown. METHODS: In Majuro City, there are 14 kindergartens with a total of 635 preschool children (PSC) whose age range of 5~6 years. The present investigation attempted to determine the pinworm prevalence and associated risk factors as well as investigate whether eggs contaminated the clothes of PSC or the ground and tables in classrooms of 14 kindergartens. Informed consent form and a self-administered questionnaire were given to parents prior to pinworm screening. Perianal specimens were collected by an adhesive scotch tape method, and clothing of belly and hip sites and the ground and tables of the classrooms were inspected using a cellophane tape method to detect any eggs contamination. RESULTS: In total, 392 PSC (5.28 ± 0.56 yrs. old) participated in this project. The overall prevalence of pinworm infection was 22.4% (88/392). Boys (24.5%) had higher prevalence than girls (20.31%) (p = 0.32). PSC aged > 5 years (32.77%) showed a significantly higher prevalence than those aged ≤5 years (17.95%) (p = 0.01). A univariate analysis indicated that PSC who lived in urban areas (22.95%) had a higher prevalence than those who lived in rural areas (20.69%) (p = 0.69). The employment status of the parents showed no association with the pinworm infection rate (p > 0.05). A logistic regression analysis indicated that "having an older sister" produced a higher risk of acquiring pinworm infection for PSC compared to those who did not have an older sister (OR = 2.02; 95%CI = 1.05~3.88; p = 0.04). No significant association between various other risk factors and pinworm infection was found (p > 0.05). Also, no eggs contamination was found on the clothes of the belly and hip sites or on the ground and tables in the 14 kindergartens. CONCLUSIONS: Mass screening and treatment of infected PSC are important measures in pinworm control in the RMI.

Children's exposure to secondhand smoke at home before and after smoke-free legislation in Taiwan.

INTRODUCTION: In January 2009, Taiwan broadened smoke-free legislation, requiring mass transportation systems, indoor public areas and indoor workplaces with 3 or more people, to become smoke-free. We investigated the secondhand smoke (SHS) exposure at home for children aged 3-11 years in Taiwan before and after the implantation of the legislation. METHODS: We studied 7911 children from the 2005, 2009 and 2013 National Health Interview Surveys (cross-sectional, nationally representative household surveys). Logistic regression modelling estimated adjusted ORs (AOR) and 95% CIs for children's SHS exposure at home in 2009 and 2013 (2005 as reference) for the overall sample and for each category of household socioeconomic status (SES) and household composition. RESULTS: Prevalence of children SHS exposure at home decreased from 51% (2005) to 32% (2009) and 28% (2013). Compared to 2005, children in 2009 and 2013 had lower likelihoods of SHS exposure at home with AOR of 0.45 (95% CI 0.41 to 0.51) and 0.41 (95% CI 0.36 to 0.46), respectively. All children had reduced SHS exposure at home after the legislation, irrespective of household SES and compositions. Low household income, low parental education level, living with grandparents or living with other adults was individually associated with increased SHS exposure. DISCUSSION: The proportion of children exposed to SHS at home in Taiwan declined substantially from 2005 to 2009 after smoke-free legislation, and fell further by 2013, irrespective of SES and household compositions. Still, inequality in SHS exposure at home by SES and household composition warrants future research.

[Self-Awareness of Disease Stigma: Reflections of Healthcare Professionals].

People who suffer from disease frequently experience disease-related stigmas. Stigma presents in daily life during normal human interactions. The stereotypes promoted by the media often impact public opinion significantly. Moreover, healthcare professionals may exacerbate stigmatization due to their misunderstanding of patients and their disease issues. Therefore, the reflection on stigma of healthcare professionals cannot be ignored. The present article illustrates the issue of stigmas held by healthcare professionals, their related stigmas, and their self-awareness. It is hoped that all healthcare professionals may cooperate to develop an anti-stigma strategy and to become true spokespersons for their patients.

Polymorphisms in the feline TNFA and CD209 genes are associated with the outcome of feline coronavirus infection.

Feline infectious peritonitis (FIP), caused by feline coronavirus (FCoV) infection, is a highly lethal disease without effective therapy and prevention. With an immune-mediated disease entity, host genetic variant was suggested to influence the occurrence of FIP. This study aimed at evaluating cytokine-associated single nucleotide polymorphisms (SNPs), i.e., tumor necrosis factor alpha (TNF-α), receptor-associated SNPs, i.e., C-type lectin DC-SIGN (CD209), and the five FIP-associated SNPs identified from Birman cats of USA and Denmark origins and their associations with the outcome of FCoV infection in 71 FIP cats and 93 FCoV infected non-FIP cats in a genetically more diverse cat populations. A promoter variant, fTNFA - 421 T, was found to be a disease-resistance allele. One SNP was identified in the extracellular domain (ECD) of fCD209 at position +1900, a G to A substitution, and the A allele was associated with FIP susceptibility. Three SNPs located in the introns of fCD209, at positions +2276, +2392, and +2713, were identified to be associated with the outcome of FCoV infection, with statistical relevance. In contrast, among the five Birman FIP cat-associated SNPs, no genotype or allele showed significant differences between our FIP and non-FIP groups. As disease resistance is multifactorial and several other host genes could involve in the development of FIP, the five genetic traits identified in this study should facilitate in the future breeding of the disease-resistant animal to reduce the occurrence of cats succumbing to FIP.

An eight-year epidemiologic study based on baculovirus-expressed type-specific spike proteins for the differentiation of type I and II feline coronavirus infections.

BACKGROUND: Feline infectious peritonitis (FIP) is a fatal disease caused by feline coronavirus (FCoV). FCoVs are divided into two serotypes with markedly different infection rates among cat populations around the world. A baculovirus-expressed type-specific domain of the spike proteins of FCoV was used to survey the infection of the two viruses over the past eight years in Taiwan. RESULTS: An immunofluorescence assay based on cells infected with the recombinant viruses that was capable of distinguishing between the two types of viral infection was established. A total of 833 cases from a teaching hospital was surveyed for prevalence of different FCoV infections. Infection of the type I FCoV was dominant, with a seropositive rate of 70.4%, whereas 3.5% of cats were infected with the type II FCoV. In most cases, results derived from serotyping and genotyping were highly agreeable. However, 16.7% (4/24) FIP cats and 9.8% (6/61) clinically healthy cats were found to possess antibodies against both viruses. Moreover, most of the cats (84.6%, 22/26) infected with a genotypic untypable virus bearing a type I FCoV antibody. CONCLUSION: A relatively simple serotyping method to distinguish between two types of FCoV infection was developed. Based on this method, two types of FCoV infection in Taiwan was first carried out. Type I FCoV was found to be predominant compared with type II virus. Results derived from serotyping and genotyping support our current understanding of evolution of disease-related FCoV and transmission of FIP.

Nanomechanics insights into the performance of healthy and osteoporotic bones.

In situ nanoscopic observations of healthy and osteoporotic bone nanopillars under compression were performed. The structural-mechanical property relationship at the atomic scale suggests that cortical bone performance is correlated to the feature, arrangement, movement, distortion, and fracture of hydroxyapatite nanocrystals. Healthy bone comprising tightly bound mineral nanocrystals shows high structural stability with nanoscopic lattice distortions and dislocation activities. On the other hand, osteoporotic bone exhibits brittleness owing to the movements of dispersed minerals in and intergranular fracture along a weak organic matrix.

An outbreak of feline infectious peritonitis in a Taiwanese shelter: epidemiologic and molecular evidence for horizontal transmission of a novel type II feline coronavirus.

Feline infectious peritonitis (FIP) is a fatal disease caused by feline coronavirus (FCoV) infection. FCoV can be divided into serotypes I and II. The virus that causes FIP (FIPV) is believed to occur sporadically and spread infrequently from cat to cat. Recently, an FIP outbreak from an animal shelter was confirmed in Taiwan. FCoV from all the cats in this shelter were analyzed to determine the epidemiology of this outbreak. Thirteen of 46 (28.2%) cats with typical signs of FIP were identified. Among them, seven cats were confirmed by necropsy and/or histopathological examinations. Despite the fact that more than one FCoV was identified in this multi-cat environment, the eight FIP cats were invariably found to be infected with a type II FCoV. Sequence analysis revealed that the type II FIPV detected from fecal samples, body effusions and granulomatous tissue homogenates from the cats that succumbed to FIP all harbored an identical recombination site in their S gene. Two of the cats that succumbed to FIP were found to harbor an identical nonsense mutation in the 3c gene. Fecal shedding of this type II virus in the effusive form of FIP can be detected up to six days before death. Taken together, our data demonstrate that horizontal transmission of FIPV is possible and that FIP cats can pose a potential risk to other cats living in the same environment.

Facile growth of thermochromic VO2 nanostructures with greatly varied phases and morphologies.

We have successfully and reproducibly synthesized a variety of novel vanadium dioxide (VO2) nanostructures, including metastable monoclinic VO2(B) nanoneedles and nanocorals, orthorhombic VO2(O) nanoparticles, and monoclinic VO2(M) nanofacets by manipulating the aging time of a facile sol-gel approach and the subsequent postannealing conditions. We envision that this previously unreported highly controlled synthesis and the resulting distinct morphologies of VO2 will not only provide a promising route for reliably selecting the phase, size, and morphology of these nanostructures, as well as achieving a fundamental understanding of their unusual temperature-dependent optical transmittance, but also facilitate the synthesis of functional VO2 nanostructures for a number of novel applications.

Comparative efficacies of various corticosteroids for preventing postextubation stridor and reintubation: a systematic review and network meta-analysis.

Objectives: We assessed the efficacies of various corticosteroid treatments for preventing postexubation stridor and reintubation in mechanically ventilated adults with planned extubation. Methods: We searched the Pubmed, Embase, the Cochrane databases and ClinicalTrial.gov registration for articles published through September 29, 2022. Only randomized controlled trials (RCTs) that compared the clinical efficacies of systemic corticosteroids and other therapeutics for preventing postextubation stridor and reintubation were included. The primary outcome was postextubation stridor and the secondary outcome was reintubation. Results: The 11 assessed RCTs reported 4 nodes: methylprednisolone, dexamethasone, hydrocortisone, and placebo, which yielded 3 possible pairs for comparing the risks of post extubation stridor and 3 possible pairs for comparing the risks of reintubation. The risk of postextubation stridor was significantly lower in dexamethasone- and methylprednisolone-treated patients than in placebo-treated patients (dexamethasone: OR = 0.39; 95% CI = 0.22-0.70; methylprednisolone: OR = 0.22; 95% CI = 0.11-0.41). The risk of postextubation stridor was significantly lower in methylprednisolone-treated patients than in hydrocortisone-treated: OR = 0.24; 95% CI = 0.08-0.67) and dexamethasone-treated patients: OR = 0.55; 95% CI = 0.24-1.26). The risk of reintubation was significantly lower in dexamethasone- and methylprednisolone-treated patients than in placebo-treated patients: (dexamethasone: OR = 0.34; 95% CI = 0.13-0.85; methylprednisolone: OR = 0.42; 95% CI = 0.25-0.70). Cluster analysis showed that dexamethasone- and methylprednisolone-treated patients had the lowest risks of stridor and reintubation. Subgroup analyses of patients with positive cuff-leak tests showed similar results. Conclusions: Methylprednisolone and dexamethasone were the most effective agents against postextubation stridor and reintubation.

SARS-CoV-2 Omicron (B.1.1.529) shows minimal neurotropism in a double-humanized mouse model.

Although severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) initially infects the respiratory tract, it also directly or indirectly affects other organs, including the brain. However, little is known about the relative neurotropism of SARS-CoV-2 variants of concern (VOCs), including Omicron (B.1.1.529), which emerged in November 2021 and has remained the dominant pathogenic lineage since then. To address this gap, we examined the relative ability of Omicron, Beta (B.1.351), and Delta (B.1.617.2) to infect the brain in the context of a functional human immune system by using human angiotensin-converting enzyme 2 (hACE2) knock-in triple-immunodeficient NGC mice with or without reconstitution with human CD34+ stem cells. Intranasal inoculation of huCD34+-hACE2-NCG mice with Beta and Delta resulted in productive infection of the nasal cavity, lungs, and brain on day 3 post-infection, but Omicron was surprisingly unique in its failure to infect either the nasal tissue or brain. Moreover, the same infection pattern was observed in hACE2-NCG mice, indicating that antiviral immunity was not responsible for the lack of Omicron neurotropism. In independent experiments, we demonstrate that nasal inoculation with Beta or with D614G, an ancestral SARS-CoV-2 with undetectable replication in huCD34+-hACE2-NCG mice, resulted in a robust response by human innate immune cells, T cells, and B cells, confirming that exposure to SARS-CoV-2, even without detectable infection, is sufficient to induce an antiviral immune response. Collectively, these results suggest that modeling of the neurologic and immunologic sequelae of SARS-CoV-2 infection requires careful selection of the appropriate SARS-CoV-2 strain in the context of a specific mouse model.

A Zika virus mutation enhances transmission potential and confers escape from protective dengue virus immunity.

Zika virus (ZIKV) and dengue virus (DENV) are arthropod-borne pathogenic flaviviruses that co-circulate in many countries. To understand some of the pressures that influence ZIKV evolution, we mimic the natural transmission cycle by repeating serial passaging of ZIKV through cultured mosquito cells and either DENV-naive or DENV-immune mice. Compared with wild-type ZIKV, the strains passaged under both conditions exhibit increased pathogenesis in DENV-immune mice. Application of reverse genetics identifies an isoleucine-to-valine mutation (I39V) in the NS2B proteins of both passaged strains that confers enhanced fitness and escape from pre-existing DENV immunity. Introduction of I39V or I39T, a naturally occurring homologous mutation detected in recent ZIKV isolates, increases the replication of wild-type ZIKV in human neuronal precursor cells and laboratory-raised mosquitoes. Our data indicate that ZIKV strains with enhanced transmissibility and pathogenicity can emerge in DENV-naive or -immune settings, and that NS2B-I39 mutants may represent ZIKV variants of interest.

SREBP2-dependent lipid gene transcription enhances the infection of human dendritic cells by Zika virus.

The emergence of Zika virus (ZIKV) as a global health threat has highlighted the unmet need for ZIKV-specific vaccines and antiviral treatments. ZIKV infects dendritic cells (DC), which have pivotal functions in activating innate and adaptive antiviral responses; however, the mechanisms by which DC function is subverted to establish ZIKV infection are unclear. Here we develop a genomics profiling method that enables discrete analysis of ZIKV-infected versus neighboring, uninfected primary human DCs to increase the sensitivity and specificity with which ZIKV-modulated pathways can be identified. The results show that ZIKV infection specifically increases the expression of genes enriched for lipid metabolism-related functions. ZIKV infection also increases the recruitment of sterol regulatory element-binding protein (SREBP) transcription factors to lipid gene promoters, while pharmacologic inhibition or genetic silencing of SREBP2 suppresses ZIKV infection of DCs. Our data thus identify SREBP2-activated transcription as a mechanism for promoting ZIKV infection amenable to therapeutic targeting.

Epidemiologic Study of Enterobius vermicularis Infection among Schoolchildren in the Republic of Marshall Islands.

The prevalence and risk factors of Enterobius vermicularis (pinworm) infection among primary schoolchildren (PSC) in the Marshall Islands remain unknown; thus, investigation on the status of pinworm infection rate is necessary to establish baseline data. After parents'/guardians' consent, a total of 346 children (179 boys and 167 girls) participated in this study. Individual's perianal area and thumbs were inspected by using the Scotch tape technique and cellophane tape method, respectively. For each child, demographic and risk factor data were collected by a structured questionnaire and statistically analyzed. The overall prevalence of pinworm infection was 12.14% (42/346). Univariate analysis indicated significant differences in PSC who live in an urban area compared to those who live in the rural area (p=0.01). Multivariate analysis still found that PSC who live in the rural area had higher chances to acquire pinworm infection. However, no risk factors were identified to be associated with personal hygiene, sibling number, and parent's educational level or occupation. Nevertheless, a pinworm-like egg was detected on the thumb of one male participant. Children living in the rural area and thumb-sucking behavior are two of the important risk factors of transmitting pinworm infection in the PSC in the Marshall Islands. We suggested an urgent and continuous provision of adequate hygienic sensitization in the school and the community.

SARS-CoV-2 monoclonal antibodies with therapeutic potential: Broad neutralizing activity and No evidence of antibody-dependent enhancement.

Monoclonal antibodies (mAbs) are emerging as safe and effective therapeutics against SARS-CoV-2. However, variant strains of SARS-CoV-2 have evolved, with early studies showing that some mAbs may not sustain their efficacy in the face of escape mutants. Also, from the onset of the COVID-19 pandemic, concern has been raised about the potential for Fcγ receptor-mediated antibody-dependent enhancement (ADE) of infection. In this study, plaque reduction neutralization assays demonstrated that mAb 1741-LALA neutralizes SARS-CoV-2 strains B.1.351, D614 and D614G. MAbs S1D2-hIgG1 and S1D2-LALA mutant (STI-1499-LALA) did not neutralize B.1.351, but did neutralize SARS-CoV-2 strains D614 and D614G. LALA mutations did not result in substantial differences in neutralizing abilities between clones S1D2-hIgG1 vs STI-1499-LALA. S1D2-hIgG1, STI-1499-LALA, and convalescent plasma showed minimal ability to induce ADE in human blood monocyte-derived macrophages. Further, no differences in pharmacokinetic clearance of S1D2-hIgG1 vs STI-1499-LALA were observed in mice expressing human FcRn. These findings confirm that SARS-CoV-2 has already escaped some mAbs, and identify a mAb candidate that may neutralize multiple SARS-CoV-2 variants. They also suggest that risk of ADE in macrophages may be low with SARS-CoV-2 D614, and LALA Fc change impacts neither viral neutralization nor Ab clearance.

Topical clotrimazole cream for the treatment of tinea cruris: A retrospective study.

This retrospective study assessed the efficacy and safety of 1% topical clotrimazole cream for the treatment of patients with tinea cruris (TC).We included 86 patients with confirmed TC for the presence of fungal hyphae. Of those, 43 patients received 1% topical clotrimazole cream for a total of 4 consecutive weeks, and were assigned to an experimental group. The other 43 patients underwent 1% topical butenafine cream for a total of 2 consecutive weeks, and were allocated to a control group. The efficacy and safety were measured and analyzed after 4 weeks treatment.After treatment, patients in both groups achieved better improvements in erythema (P < .01), scaling (P < .01), itching (P < .01), and KOH-negative results (P < .01), compared with those in patients before the treatment. However, there were not significant differences in erythema (P = .61), scaling (P = .57), itching (P = .47), and KOH-negative results (P = .67) between 2 groups. In addition, no treatment-related adverse events were recorded in both groups.Both 1% topical clotrimazole and butenafine cream are found to be effective and safe for patients with TC. However, there is not significant difference in efficacy and safety between two groups.

Psychological effect of comprehensive nursing intervention in elderly patients with perforated peptic ulcer: A protocol of systematic review.

BACKGROUND: This study aims to assess the psychological effect of comprehensive nursing intervention (CNI) in elderly patients with perforated peptic ulcer (PPU). METHODS: This protocol will search all potential studies from inception to the present in electronic database sources (Cochrane Library, PUBMED, EMBASE, PsycINFO, WANGFANG, CBM, and CNKI), and other sources (such as clinical trial registry, and conference proceedings). We will not apply limitations to language and publication status. Two independent authors will scan literature, extract data, and appraise study quality. A third author will be invited to solve any disagreements between 2 authors. We will utilize RevMan 5.3 software for statistical analysis. If necessary, we will also carry out subgroup group, sensitivity analysis, and reporting bias. RESULTS: This protocol will summarize high quality evidence to evaluate the psychological effect of CNI in elderly patients with PPU. CONCLUSION: The results of this study may provide evidence to determine whether CNI is effective or not on psychological effect in elderly patients with PPU. STUDY REGISTRATION: INPLASY202080069.

Lipid Microbubble-Conjugated Anti-CD3 and Anti-CD28 Antibodies (Microbubble-Based Human T Cell Activator) Offer Superior Long-Term Expansion of Human Naive T Cells In Vitro.

Stimulation of human primary T cells with immobilized anti-CD3 and anti-CD28 Abs in vitro provide a system to study T cell activation and proliferation and an avenue for expanding T cells for immunotherapy. Magnetic beads conjugated with anti-CD3 and anti-CD28 Abs (Dynabeads Human T-Activator [D-TCA]) have been a golden standard for stimulating human primary T cells in vitro. In this study, we report that an application using anti-CD3 and anti-CD28 Abs conjugated on lipid microbubbles (microbubble-based human T cell activator [MB-TCA]) to stimulate primary human naive T cells resulted in expansion superior to D-TCA. In 56-d cultures with three repeated stimulation cycles (14 d per stimulation), we found that 1) MB-TCA induced significantly better expansion (20- and 10-fold increase) of naive CD4+ and CD8+ T cells than did D-TCA; 2) MB-TCA- and D-TCA-stimulated T cells had a similar number of initial cell divisions, but MB-TCA had significantly lower activation-induced cell death than D-TCA; 3) MB-TCA-stimulated T cells produced less TNF-α than did D-TCA; and 4) blocking TNF-α action via adding an Ab against TNF-αR (TNFRSF1A) significantly improved expansion of T cells activated by D-TCA in vitro. Together, we demonstrated that the MB-TCA induces a better expansion of human naive T cells in vitro and offers advantages in both basic and clinical applications in which the outcome depends on the number of T cells.

CD4+ T Cells Cross-Reactive with Dengue and Zika Viruses Protect against Zika Virus Infection.

The underlying mechanisms by which prior immunity to dengue virus (DENV) affords cross-protection against the related flavivirus Zika virus (ZIKV) are poorly understood. Here, we examine the ability of DENV/ZIKV-cross-reactive CD4+ T cells to protect against versus exacerbate ZIKV infection by using a histocompatibility leukocyte antigen (HLA)-DRB1∗0101 transgenic, interferon α/ß receptor-deficient mouse model that supports robust DENV and ZIKV replication. By mapping the HLA-DRB1∗0101-restricted T cell response, we identify DENV/ZIKV-cross-reactive CD4+ T cell epitopes that stimulate interferon gamma (IFNγ) and/or tumor necrosis factor (TNF) production. Vaccination of naive HLA-DRB1∗0101 transgenic mice with these peptides induces a CD4+ T cell response sufficient to reduce tissue viral burden following ZIKV infection. Notably, this protective response requires IFNγ and/or TNF secretion but not anti-ZIKV immunoglobulin G (IgG) production. Thus, DENV/ZIKV-cross-reactive CD4+ T cells producing canonical Th1 cytokines can suppress ZIKV replication in an antibody-independent manner. These results may have important implications for increasing the efficacy and safety of DENV/ZIKV vaccines and for developing pan-flavivirus vaccines.