Single-cell analysis of intermediate horseshoe bat (Rhinolophus affinis) organs reveals viral infections and antiviral immune signatures

Viruses and hosts have coevolved for millions of years, leading to the development of complex host–pathogen interactions. Influenza A virus (IAV) causes severe pulmonary pathology and is a recurrent threat to human health. Innate immune sensing of IAV triggers a complex chain of host responses. IAV has adapted to evade host defense mechanisms, and the host has coevolved to counteract these evasion strategies. However, the molecular mechanisms governing the balance between host defense and viral immune evasion is poorly understood. Here, we show that the host protein DEAD-box helicase 3 X-linked (DDX3X) is critical to orchestrate a multifaceted antiviral innate response during IAV infection, coordinating the activation of the nucleotide-binding oligomerization domain-like receptor with a pyrin domain 3 (NLRP3) inflammasome, assembly of stress granules, and type I interferon (IFN) responses. DDX3X activated the NLRP3 inflammasome in response to WT IAV, which carries the immune evasive nonstructural protein 1 (NS1). However, in the absence of NS1, DDX3X promoted the formation of stress granules that facilitated efficient activation of type I IFN signaling. Moreover, induction of DDX3X-containing stress granules by external stimuli after IAV infection led to increased type I IFN signaling, suggesting that NS1 actively inhibits stress granule–mediated host responses and DDX3X-mediated NLRP3 activation counteracts this action. Furthermore, the loss of DDX3X expression in myeloid cells caused severe pulmonary pathogenesis and morbidity in IAV-infected mice. Together, our findings show that DDX3X orchestrates alternate modes of innate host defense which are critical to fight against NS1-mediated immune evasion strategies during IAV infection.

Since the end of 2019, the emergence of novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has accelerated the research on host immune responses toward the coronaviruses. When there is no approved drug or vaccine to use against these culprits, host immunity is the major strategy to fight such infections. Type I interferons are an integral part of the host innate immune system and define one of the first lines of innate immune defense against viral infections. The in vitro antiviral role of type I IFNs against Middle East respiratory syndrome coronavirus (MERS-CoV) and SARS-CoV (severe acute respiratory syndrome coronavirus) is well established. Moreover, the involvement of type I IFNs in disease pathology has also been reported. In this study, we have reviewed the protective and the immunopathogenic role of type I IFNs in the pathogenesis of MERS-CoV, SARS-CoV, and SARS-CoV-2. This review will also enlighten the potential implications of type I IFNs for the treatment of COVID-19 when used in combination with IFN-γ.

Gastrointestinal Disease in Simian Immunodeficiency Virus-Infected Rhesus Macaques Is Characterized by Proinflammatory Dysregulation of the Interleukin-6-Janus Kinase/Signal Transducer and Activator of Transcription3 Pathway

Host-targeting agents for prevention and treatment of chronic hepatitis C – Perspectives and challenges

Targeting Innate Immunity: A New Step in the Development of Combination Therapy for Chronic Hepatitis B

Hepatitis C. Development of new drugs and clinical trials: promises and pitfalls. Summary of an AASLD hepatitis single topic conference, Chicago, IL, February 27-March 1, 2003.

Infections, Immunity & their Effects on Asthma

Phages in the fight against COVID-19?

This article provides a comprehensive overview of research focusing on the role of antibodies, cytokines, complement proteins, major histocompatibility complex (MHC) molecules, and Toll-like receptors (TLRs) in the immune response and their potential as targets for immunotherapy. The review specifically examines the influence of various carriers on the immune activity of proteins, with a particular emphasis on the role of carriers in developing therapeutic approaches for diseases including cancer, autoimmune disorders, and infections. The findings highlight the importance of understanding the molecular mechanisms underlying the immune response and the role of different components of the immune system. Antibodies, as key components of adaptive immunity, play a crucial role in pathogen neutralization and can be utilized as targets for immunotherapy. Cytokines and complement proteins serve multiple functions, including immune cell activation, antiviral activity, and regulation of inflammatory processes. MHC molecules facilitate antigen presentation and activation of adaptive immunity. TLRs recognize pathogen-associated molecular patterns and initiate the immune response. Current research has also demonstrated the potential of lipid-based carriers, proteins, carbohydrates, and nucleic acids for enhancing the immune activity of proteins. The review discusses the use of carriers to improve the immune activity of proteins, which can be valuable for developing new vaccines and therapeutic agents. In recent years, there has been increasing interest in proteinbased therapeutic approaches, including monoclonal antibodies, cytokines, and others. The efficacy of these methods is influenced by the choice of carrier molecule. Conjugation of proteins with other molecules such as nanoparticles or liposomes can enhance stability, specificity, and efficacy. The presence of carriers on the surface of tumor cells can stimulate anti-tumor immune responses. However, challenges remain in the development of carrier-based therapies including potential carrier-induced immunogenicity, which may trigger undesired immune responses and limit therapeutic efficacy. Additionally, the complex selection of appropriate protein carriers for specific therapeutic applications requires further investigation into the underlying mechanisms of carrier function and immune activation. As based on the analysis of scientific literature, this review establishes that the use of carriers and ligands represents a promising approach for enhancing protein immune activity and developing new vaccination and immunotherapy strategies.

Scientists have been investigating the critical role type 1 interferons (IFN-I) play in controlling viral infections for more than 50 y. Common pathogen motifs present on viral particles trigger intracellular and membrane-associated pattern recognition receptors, leading to the production of IFN-I and rapid expression of interferon stimulated genes (ISIGs).1 ISIGs encode proteins with direct antiviral activity, as well modulating multiple parameters of the immune response. However, in situations of persistent viral infections, such as HIV, although produced, IFN-Is are not able to quench the initial infection, which eventually establishes life-long persistence. In this situation, the chronic IFN-I mediated immune activation/inflammation that accompanies persistent HIV infection is strongly associated with disease progression, even in patients with antiretroviral therapy-suppressed viral titers.2 In fact, in the SIV model of primate infection, immune activation, CD4 T cell depletion, and disease progression are integrally correlated with IFN-I signaling regardless of virus titers.3-5 Thus, while the precise mechanisms driving immune activation in HIV infection still remain to be determined, there is mounting evidence implicating IFN-I. Excitingly, independent work from our laboratory and from Michael Oldstone’s laboratory using a mouse model of persistent virus infection demonstrated that prolonged IFN-I signaling is highly detrimental to the antiviral immune response, and that, astonishingly, quenching IFN-I signals results in control of infection.6,7 These studies indicate the important and somewhat counterintuitive possibility that blocking IFN-I signaling in persistent infection may be an effective therapy for controlling virus replication and halting disease progression. Lymphocytic choriomeningitis virus (LCMV) in mice has been utilized for decades as an experimental model to explore immune responses to persistent infection. Using the LCMV system, the 2 groups established that a surprising amount of the immune dysfunctions associated with viral persistence are indeed due to prolonged IFN-I signaling. Chronic IFN-I signaling enhanced expression of activation markers on total T cell populations, caused functional suppression/depletion of virus-specific CD4+ T cells, and led to severe disruption of lymphoid tissue architecture. IFN-I also drove expression of multiple factors and cell types that inhibit antiviral immunity, such as the immunoregulatory cytokine IL-10, the inhibitory receptor PDL1, and immunoregulatory APC populations that co-express multiple suppressive factors.6-8 Blockade of IFN-I during persistent LCMV infection reversed the immune defects, diminished the expression of immunosuppressive molecules, and restored lymphoid tissue architecture. Consistent with the ongoing antiviral activity of IFN-I, blockade of IFN-I signaling initially increased virus titers, but then ultimately facilitated the control of the persistent infection. The exact mechanisms underlying the increased control of virus replication through IFN-I blockade are still under investigation and will likely be highly complex and multi-factorial, involving enhancements through the relief of chronic activation and a switch from an immunosuppressive to pro-immune environment, as well as other as-yet-undetermined mechanisms. As a first step in unraveling the mechanisms, initial experiments identified a need for CD4 T cells and IFNγ expression,6,7 but how they individually contribute to immune health and viral clearance in the absence of IFN-I is still unclear. Ultimately, these studies reveal a duality in IFN-I signaling, wherein strong initial interferon responses are necessary to directly inhibit virus replication and establish effective antiviral immune responses; however, prolonged IFN-I signals chronically activate the immune environment and induce tissue pathology and suppression of antiviral immunity. Thus, our studies have identified IFN-I signaling as the critical rheostat in an immunologic surveillance system that measures the duration and magnitude of virus replication (i.e., whether the host or pathogen is winning the battle) and then modulates the balance between pro- and anti-inflammatory immune programs accordingly. Cumulatively, this data stimulates interest in potentially blocking IFN-I signaling to therapeutically resolve other persistent infections characterized by high levels of chronic immune activation. However, given the critical antiviral affects of IFN-I, future studies should focus on dissecting out the multiple functions of IFN-I (as well as the specific functions of individual IFNα’s and β) to preserve the beneficial antiviral properties while ablating the destructive and immunosuppressive effects. Whether or not this can be achieved remains to be determined, but if successful, it would represent a significant advance in our understanding of antiviral immunity and our potential to develop effective antiviral immunotherapies. (Fig. 1) Figure 1. The yin-yang of type I interferon signaling. IFN-Is elicit seemingly opposite yet interrelated positive and negative influences on virus replication and dissemination. Throughout the course of viral infection IFN-I is constantly monitoring ...

When small red beans (azuki bean; Vigna angularis Ohwi et Ohashi) were soaked and warmed in water or saline, the beans began to absorb water to swell and exuded kinds of substances probably as a prerequisite step for seed germination. Such exudate fluids displayed strong antiviral activity against the rabies virus infections in culture. On the other hand, little anti-rabies activity was detected in the aqueous extracts from the red beans when tested soon after the extraction from powdered beans, while low titers of antiviral activity appeared gradually in the extracts during cold storage. In contrast, no antiviral activity was detected in the exudate fluids from non-colored azuki beans (white azuki), implicating that a certain anthocyanin-related substance is involved in the antiviral activity of red beans. Production of antiviral and cytotoxic activities were affected differently depending on the bean-soaking conditions. In addition, the antiviral activity resisted to 10 min-heating in boiling water, while the cytotoxicity was greatly weakened by the heating, suggesting that different substances are involved in the antiviral and cytotoxic activities. Further studies on the antiviral activity of the exudate fluids demonstrated that anti-rabies activity of the bean exudates affected not only the very early phase of infection cycle, but the viral infectivity was also affected similarly, implicating a possible application of azuki bean exudate fluids to post-exposure treatment of rabid dog-bite injuries in combination with vaccination.

83 : Antiviral and immunomodulatory activity of different human interferon-α subtypes during chronic viral infections

Editorial: In vitro mechanistic evaluation of nucleic acid polymers: A cautionary tale

How Viral Infections Cause Exacerbation of Airway Diseases

Interferon-stimulated genes and their role in controlling hepatitis C virus