One antibody for all and all antibodies for one: Antibodies against related flavi-viruses such as dengue (DENV) and West Nile (WNV) can cross-react with Zika virus (ZIKV) and could thereby increase disease severity. Bardina et al. tested whether DENV and WNV antibodies from humans, or even yellow fever vaccination, could enhance ZIKV infection. In a mouse model, low titers of DENV and WNV antibodies enhanced ZIKV viremia, especially in the spinal cord and testes, whereas high titers remained protective. Generally, WNV antibodies were less disease-enhancing than DENV antibodies, and, in macaques, yellow fever vaccination had very little effect. Science , this issue p. 175

Dengue fever is an Aedes mosquito-borne illness caused by any one of the four different dengue virus (DENV) serotypes (1–4) and manifests in the form of symptoms ranging from mild or asymptomatic to severe disease with vascular leakage, leading to shock, and viral hemorrhagic syndrome. Increased risk of severe disease occurs during secondary infection with a virus serotype distinct from that of prior dengue infection. This occurs by antibody dependent enhancement (ADE) of infection, wherein sub-neutralizing antibodies against the virus particles opsonize dengue virus entry via formation of immune complexes that interact with fragment crystallizable gamma receptors (FcγR) on monocytes, dendritic cells, and macrophages. The ADE phenomenon has two components: Extrinsic and Intrinsic ADE. While extrinsic ADE contributes to enhanced virus entry, intrinsic ADE results in heightened virus production by inhibition of type1 interferon and activation of interleukin-10 biosynthesis, thereby favoring a Th2 type immune response. Intrinsic ADE has greater contribution in enhancing Dengue replication as compared to extrinsic ADE. Detailed elucidation of intrinsic ADE during secondary dengue infection can increase our understanding of DENV-pathogenesis and aid in the development of host-targeting antivirals. Here we review literature focusing on intrinsic factors contributing to severe dengue pathology and suggest possible avenues for further research.

While our battle with the COVID-19 pandemic continues, a multitude of Omics data have been generated from patient samples in various studies. Translation of these data into clinical interventions against COVID-19 remains to be accomplished. Exploring host response to COVID-19 in the upper respiratory tract can unveil prognostic markers and therapeutic targets. We conducted a meta-analysis of published transcriptome and proteome profiles of respiratory samples of COVID-19 patients to shortlist high confidence upregulated host factors. Subsequently, mRNA overexpression of selected genes was validated in nasal swabs from a cohort of COVID-19 positive/negative, symptomatic/asymptomatic individuals. Guided by this analysis, we sought to check for potential drug targets. An FDA-approved drug, Auranofin, was tested against SARS-CoV-2 replication in cell culture and Syrian hamster challenge model. The meta-analysis and validation in the COVID-19 cohort revealed S100 family genes (S100A6, S100A8, S100A9, and S100P) as prognostic markers of severe COVID-19. Furthermore, Thioredoxin (TXN) was found to be consistently upregulated. Auranofin, which targets Thioredoxin reductase, was found to mitigate SARS-CoV-2 replication in vitro. Furthermore, oral administration of Auranofin in Syrian hamsters in therapeutic as well as prophylactic regimen reduced viral replication, IL-6 production, and inflammation in the lungs. Elevated mRNA level of S100s in the nasal swabs indicate severe COVID-19 disease, and FDA-approved drug Auranofin mitigated SARS-CoV-2 replication in preclinical hamster model. This study was supported by the DBT-IISc partnership program (DBT (IED/4/2020-MED/DBT)), the Infosys Young Investigator award (YI/2019/1106), DBT-BIRAC grant (BT/CS0007/CS/02/20) and the DBT-Wellcome Trust India Alliance Intermediate Fellowship (IA/I/18/1/503613) to ST lab.

Interferons (IFNs) are multifaceted proteins that play pivotal roles in orchestrating robust antiviral immune responses and modulating the intricate landscape of host immunity. The major signaling pathway activated by IFNs is the JAK/STAT (Janus kinase/signal transducer and activator of transcription) pathway, which leads to the transcription of a battery of genes, collectively known as IFN-stimulated genes (ISGs). While the well-established role of IFNs in coordinating the innate immune response against viral infections is widely acknowledged, recent years have provided a more distinct comprehension of the functional significance attributed to non-canonical, IFN-independent induction of ISGs. In this review, we summarize the non-conventional signaling pathways of ISG induction. These alternative pathways offer new avenues for developing antiviral strategies or immunomodulation in various diseases.

An ideal vaccine provides long lasting protection against a pathogen by eliciting a well-rounded immune response which engages both innate and adaptive immunity. However, we have a limited understanding of how components of innate immunity, antibody and cell-mediated adaptive immunity interact and function together at a systems level. With advances in high-throughput ‘Omics’ methodologies it has become possible to capture global changes in the host, at a cellular and molecular level, that are induced by vaccination and infection. Analysis of these datasets has shown the promise of discovering mechanisms behind vaccine mediated protection, immunological memory, adverse effects as well as development of more efficient antigens and adjuvants. In this review, we will discuss how systems vaccinology takes advantage of new technology platforms and big data analysis, to enable the rational development of better vaccines.