Innate immune recognition against SARS-CoV-2.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the causative virus of pandemic acute respiratory disease called coronavirus disease 2019 (COVID-19). Most of the infected individuals have asymptomatic or mild symptoms, but some patients show severe and critical systemic inflammation including tissue damage and multi-organ failures. Immune responses to the pathogen determine clinical course. In general, the activation of innate immune responses is mediated by host pattern-recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs) as well as host damage-associated molecular patterns (DAMPs), which results in the activation of the downstream gene induction programs of types I and III interferons (IFNs) and proinflammatory cytokines for inducing antiviral activity. However, the excessive activation of these responses may lead to deleterious inflammation. Here, we review the recent advances in our understanding of innate immune responses to SARS-CoV-2 infection, particularly in terms of innate recognition and the subsequent inflammation underlying COVID-19 immunopathology.

Targeting Selective Autophagy as a Therapeutic Strategy for Viral Infectious Diseases.

Autophagy is an evolutionarily conserved lysosomal degradation system which can recycle multiple cytoplasmic components under both physiological and stressful conditions. Autophagy could be highly selective to deliver different cargoes or substrates, including protein aggregates, pathogenic proteins or superfluous organelles to lysosome using a series of cargo receptor proteins. During viral invasion, cargo receptors selectively target pathogenic components to autolysosome to defense against infection. However, viruses not only evolve different strategies to counteract and escape selective autophagy, but also utilize selective autophagy to restrict antiviral responses to expedite viral replication. Furthermore, several viruses could activate certain forms of selective autophagy, including mitophagy, lipophagy, aggrephagy, and ferritinophagy, for more effective infection and replication. The complicated relationship between selective autophagy and viral infection indicates that selective autophagy may provide potential therapeutic targets for human infectious diseases. In this review, we will summarize the recent progress on the interplay between selective autophagy and host antiviral defense, aiming to arouse the importance of modulating selective autophagy as future therapies toward viral infectious diseases.

Plasmacytoid dendritic cells during COVID-19: Ally or adversary?

Plasmacytoid dendritic cells (pDCs) are specialized cells of the immune system that are thought to be the main cellular source of type I interferon alpha (IFNα) in response to viral infections. IFNs are powerful antivirals, whereas defects in their function or induction lead to impaired resistance to virus infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19. IFN production needs to be controlled, because sustained IFN production can also have detrimental effects on disease outcome. As such, pDCs are likely important for acute antiviral protection against SARS-CoV-2 infection but could potentially also contribute to chronic IFN levels. Here, we provide a historical overview of pDC biology and summarize existing literature addressing their involvement and importance during viral infections of the airways. Furthermore, we outline recent reports focused on the potential role of pDCs during SARS-CoV-2 infection, as well as the potential for this cellular subset to impact COVID-19 disease outcome.

Discovery and Use of Long dsRNA Mediated RNA Interference to Stimulate Antiviral Protection in Interferon Competent Mammalian Cells.

In invertebrate cells, RNA interference (RNAi) acts as a powerful immune defense that stimulates viral gene knockdown thereby preventing infection. With this pathway, virally produced long dsRNA (dsRNA) is cleaved into short interfering RNA (siRNA) by Dicer and loaded into the RNA-induced silencing complex (RISC) which can then destroy/disrupt complementary viral mRNA sequences. Comparatively, in mammalian cells it is believed that the type I interferon (IFN) pathway is the cornerstone of the innate antiviral response. In these cells, dsRNA acts as a potent inducer of the IFN system, which is dependent on dsRNA length, but not sequence, to stimulate an antiviral state. Although the cellular machinery for RNAi is intact and functioning in mammalian cells, its role to trigger an antiviral response using long dsRNA (dsRNAi) remains controversial. Here we show that dsRNAi is not only functional but has a significant antiviral effect in IFN competent mammalian cells. We found that pre-soaking mammalian cells with concentrations of sequence specific dsRNA too low to induce IFN production could significantly inhibit vesicular stomatitis virus expressing green fluorescent protein (VSV-GFP), and the human coronaviruses (CoV) HCoV-229E and SARS-CoV-2 replication. This phenomenon was shown to be dependent on dsRNA length, was comparable in effect to transfected siRNAs, and could knockdown multiple sequences at once. Additionally, knockout cell lines revealed that functional Dicer was required for viral inhibition, revealing that the RNAi pathway was indeed responsible. These results provide the first evidence that soaking with gene-specific long dsRNA can generate viral knockdown in mammalian cells. We believe that this novel discovery provides an explanation as to why the mammalian lineage retained its RNAi machinery and why vertebrate viruses have evolved methods to suppress RNAi. Furthermore, demonstrating RNAi below the threshold of IFN induction has uses as a novel therapeutic platform, both antiviral and gene targeting in nature.

Humanized mice reveal a macrophage-enriched gene signature defining human lung tissue protection during SARS-CoV-2 infection.

The human immunological mechanisms defining the clinical outcome of SARS-CoV-2 infection remain elusive. This knowledge gap is mostly driven by the lack of appropriate experimental platforms recapitulating human immune responses in a controlled human lung environment. Here, we report a mouse model (i.e., HNFL mice) co-engrafted with human fetal lung xenografts (fLX) and a myeloid-enhanced human immune system to identify cellular and molecular correlates of lung protection during SARS-CoV-2 infection. Unlike mice solely engrafted with human fLX, HNFL mice are protected against infection, severe inflammation, and histopathological phenotypes. Lung tissue protection from infection and severe histopathology associates with macrophage infiltration and differentiation and the upregulation of a macrophage-enriched signature composed of 11 specific genes mainly associated with the type I interferon signaling pathway. Our work highlights the HNFL model as a transformative platform to investigate, in controlled experimental settings, human myeloid immune mechanisms governing lung tissue protection during SARS-CoV-2 infection.

Vaccinal antibodies: Fc antibody engineering to improve the antiviral antibody response and induce vaccine-like effects.

The coronavirus disease 2019 (COVID-19) pandemic highlights the urgent clinical need for efficient virus therapies and vaccines. Although the functional importance of antibodies is indisputable in viral infections, there are still significant unmet needs that require vast improvements in antibody-based therapeutics. The IgG Fc domain can be engineered to produce antibodies with tailored and potent responses that will meet these clinical demands. Engaging Fc receptors (FcRs) to perform effector functions as cytotoxicity, phagocytosis, complement activation, intracellular neutralization and controlling antibody persistence. Furthermore, it produces vaccine-like effects by activating signals to stimulate T-cell responses, have proven to be required for protection, as neutralization alone does not off the full protection capacity of antibodies. This review highlights antiviral Fc functions and FcRs' contributions in linking innate and adaptive immunity against viral threats. Moreover, it provides the latest Fc engineering strategies to improve the safety and efficacy of human antiviral antibodies and vaccines.

SARS-CoV-2 infection activates a subset of intrinsic pathways to inhibit type I interferons in vitro and in vivo.

SARS-CoV-2 infection poses a global challenge to human health. Upon viral infection, host cells initiate the innate antiviral response, which primarily involves type I interferons (I-IFNs), to enable rapid elimination of the invading virus. Previous studies revealed that SARS-CoV-2 infection limits the expression of I-IFNs in vitro and in vivo, but the underlying mechanism remains incompletely elucidated. In the present study, we performed data mining and longitudinal data analysis using SARS-CoV-2-infected normal human bronchial epithelial (NHBE) cells and ferrets, and the results confirmed the strong inhibitory effect of SARS-CoV-2 on the induction of I-IFNs. Moreover, we identified genes that are negatively correlated with IFNB1 expression in vitro and in vivo based on Pearson correlation analysis. We found that SARS-CoV-2 activates numerous intrinsic pathways, such as the circadian rhythm, phosphatidylinositol signaling system, peroxisome, and TNF signaling pathways, to inhibit I-IFNs. These intrinsic inhibitory pathways jointly facilitate the successful immune evasion of SARS-CoV-2. Our study elucidates the underlying mechanism by which SARS-CoV-2 evades the host innate antiviral response in vitro and in vivo, providing theoretical evidence for targeting these immune evasion-associated pathways to combat SARS-CoV-2 infection.

Antiviral responses against chicken respiratory infections: Focus on avian influenza virus and infectious bronchitis virus.

Some of the respiratory viral infections in chickens pose a significant threat to the poultry industry and public health. In response to viral infections, host innate responses provide the first line of defense against viruses, which often act even before the establishment of the infection. Host cells sense the presence of viral components through germinal encoded pattern recognition receptors (PRRs). The engagement of PRRs with pathogen-associated molecular patterns leads to the induction of pro-inflammatory and interferon productions. Induced antiviral responses play a critical role in the outcome of the infections. In order to improve current strategies for control of viral infections or to advance new strategies aimed against viral infections, a deep understanding of host-virus interaction and induction of antiviral responses is required. In this review, we summarized recent progress in understanding innate antiviral responses in chickens with a focus on the avian influenza virus and infectious bronchitis virus.

Innate immune-mediated antiviral response to SARS-CoV-2 and convalescent sera a potential prophylactic and therapeutic agent to tackle COVID-19.

The whole world is confronting the pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Unfortunately, there is no vaccine to prevent novel coronavirus infection. Besides several experimental drugs, the strong immune responses and convalescent sera are the current two potential options to tackle coronavirus disease 2019 (COVID-19) infection. Innate immune-mediated antiviral responses are initiated by the recognition of viral invasion through pathogen-associated molecular patterns (PAMPs). In coronavirus, the PAMPs are recognized by Toll-like receptors 3 and 7, endosomal ribonucleic acid receptors, RNA in cytosol, and by pattern recognition receptor (RIG-1) in the alveolar cells and site of invasion. Nuclear factor-κB and interferon regulatory transcription factor (IRF3) are activated in response to the above recognition episode and translocate to nucleus. These transcription factors in the nucleus initiate the expression of interferon type 1 and pro-inflammatory cytokine storm, which leads to first line of defense at the site of viral entrance. The effectiveness of innate immune system is greatly relies on type 1 interferons and its cascade, because of their role in the inhibition of viral replication and initiation of adaptive immune responses. The successful interferon type 1 response put down the viral replication and transmission at prompt point. Passive immunization is the administering of antibodies into infected patients, which is taken from recovered individuals. The convalescent sera of the recovered COVID-19 patients are containing antiviral neutralizing antibodies and are used therapeutically for infected individuals by SARS-CoV-2 and for the purpose of prophylaxis in exposed individuals. The convalescent sera is found effective when administered early at the onset of symptoms.