Coronavirus disease 2019 (COVID-19) causes pulmonary edema, which disrupts the lung alveoli-capillary barrier and leads to pulmonary cell apoptosis, the main cause of death. However, the molecular mechanism behind SARS-CoV-2's apoptotic activity remains unknown. Here, we revealed that SARS-CoV-2-ORF-3a mediates the pulmonary pathology associated with SARS-CoV-2, which is demonstrated by the fact that it causes lung tissue damage. The in vitro results showed that SARS-CoV-2-ORF-3a triggers cell death via the disruption of mitochondrial homeostasis, which is modulated through the regulation of Mitochondrial ATP-sensitive Potassium Channel (MitoKATP). The addition of exogenous Potassium (K+) in the form of potassium chloride (KCl) attenuated mitochondrial apoptosis along with the inflammatory interferon response (IFN-β) triggered by SARS-ORF-3a. The addition of exogenous K+ strongly suggests that dysregulation of K+ ion channel function is the central mechanism underlying the mitochondrial dysfunction and stress response induced by SARS-CoV-2-ORF-3a. Our results designate that targeting the potassium channel or its interactions with ORF-3a may represent a promising therapeutic strategy to mitigate the damaging effects of infection with SARS-CoV-2.

By the end of 2019, the COVID-19 pandemic, resulting from the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), had diffused widely across the globe, with 770 million infected individuals and over 7 million deaths reported. In addition to its high infectivity and pathogenicity and its rapid mutation rate, the unique capacity of SARS-CoV-2 to circumvent the immune system has also contributed to the widespread nature of this pandemic. SARS-CoV-2 elicits the onset of innate immune system activation and initiates antiviral responses once it has infected the host. While battling the host’s immune responses, SARS-CoV-2 has established many countermeasures to evade attack and clearance. As the exploration of SARS-CoV-2 continues, substantial evidence has revealed that the 29 proteins synthesized by the SARS-CoV-2 genome are integral to the viral infection process. They not only facilitate viral replication and transmission, but also assist SARS-CoV-2 in escaping the host’s immune defenses, positioning them as promising therapeutic targets that have attracted considerable attention in recent studies. This review summarizes the manner in which SARS-CoV-2 interfaces with the innate immune system, with a particular focus on the continuous evolution of SARS-CoV-2 and the implications of mutations.

A new threat to global health re-emerged with monkeypox’s advent in early 2022. As of November 10, 2022, nearly 80,000 confirmed cases had been reported worldwide, with most of them coming from places where the disease is not common. There were 53 fatalities, with 40 occurring in areas that had never before recorded monkeypox and the remaining 13 appearing in the regions that had previously reported the disease. Preliminary genetic data suggest that the 2022 monkeypox virus is part of the West African clade; the virus can be transmitted from person to person through direct interaction with lesions during sexual activity. It is still unknown if monkeypox can be transmitted via sexual contact or, more particularly, through infected body fluids. This most recent epidemic’s reservoir host, or principal carrier, is still a mystery. Rodents found in Africa can be the possible intermediate host. Instead, the CDC has confirmed that there are currently no particular treatments for monkeypox virus infection in 2022; however, antivirals already in the market that are successful against smallpox may mitigate the spread of monkeypox. To protect against the disease, the JYNNEOS (Imvamune or Imvanex) smallpox vaccine can be given. The spread of monkeypox can be slowed through measures such as post-exposure immunization, contact tracing, and improved case diagnosis and isolation. Final Thoughts: The latest monkeypox epidemic is a new hazard during the COVID-19 epidemic. The prevailing condition of the monkeypox epidemic along with coinfection with COVID-19 could pose a serious condition for clinicians that could lead to the global epidemic community in the form of coinfection.

In the context of the global COVID-19 pandemic, the phenomenon that the elderly have higher morbidity and mortality is of great concern. Existing evidence suggests that senescence and viral infection interact with each other. Viral infection can lead to the aggravation of senescence through multiple pathways, while virus-induced senescence combined with existing senescence in the elderly aggravates the severity of viral infections and promotes excessive age-related inflammation and multiple organ damage or dysfunction, ultimately resulting in higher mortality. The underlying mechanisms may involve mitochondrial dysfunction, abnormal activation of the cGAS-STING pathway and NLRP3 inflammasome, the role of pre-activated macrophages and over-recruited immune cells, and accumulation of immune cells with trained immunity. Thus, senescence-targeted drugs were shown to have positive effects on the treatment of viral infectious diseases in the elderly, which has received great attention and extensive research. Therefore, this review focused on the relationship between senescence and viral infection, as well as the significance of senotherapeutics for the treatment of viral infectious diseases.

Viral infection in respiratory tract usually leads to cell death, impairing respiratory function to cause severe disease. However, the diversity of clinical manifestations of SARS-CoV-2 infection increases the complexity and difficulty of viral infection prevention, and especially the high-frequency asymptomatic infection increases the risk of virus transmission. Studying how SARS-CoV-2 affects apoptotic pathway may help to understand the pathological process of its infection. Here, we uncovered SARS-CoV-2 imployed a distinct anti-apoptotic mechanism via its N protein. We found SARS-CoV-2 virus-like particles (trVLP) suppressed cell apoptosis, but the trVLP lacking N protein didn't. Further study verified that N protein repressed cell apoptosis in cultured cells, human lung organoids and mice. Mechanistically, N protein specifically interacted with anti-apoptotic protein MCL-1, and recruited a deubiquitinating enzyme USP15 to remove the K63-linked ubiquitination of MCL-1, which stabilized this protein and promoted it to hijack Bak in mitochondria. Importantly, N protein promoted the replications of IAV, DENV and ZIKV, and exacerbated death of IAV-infected mice, all of which could be blocked by a MCL-1 specific inhibitor, S63845. Altogether, we identifed a distinct anti-apoptotic function of the N protein, through which it promoted viral replication. These may explain how SARS-CoV-2 effectively replicates in asymptomatic individuals without cuasing respiratory dysfunction, and indicate a risk of enhanced coinfection with other viruses. We anticipate that abrogating the N/MCL-1-dominated apoptosis repression is conducive to the treatments of SARS-CoV-2 infection as well as coinfections with other viruses.

Many studies have shown that β-glucan induces a trained immune phenotype in innate immune cells to defend against bacterial and fungal infections. The specific mechanism involves cellular metabolism and epigenetic reprogramming. However, it is unclear whether β-glucan plays a role in antiviral infection. Therefore, this study investigated the role of trained immunity induced by Candida albicans and β-glucan in antiviral innate immunity. It showed that C. albicans and β-glucan promoted the expression of interferon-β (IFN-β) and interleukin-6 (IL-6) in mouse macrophages triggered by viral infection. In addition, β-glucan pretreatment attenuated the pathological damage induced by the virus in mouse lungs and promoted the expression of IFN-β. Mechanistically, β-glucan could promote the phosphorylation and ubiquitination of TANK Binding Kinase 1 (TBK1), a key protein of the innate immune pathway. These results suggest that β-glucan can promote innate antiviral immunity, and this bioactive material may be a potential therapeutic target for antiviral treatment.

Endosomal sorting complex required for transport (ESCRT) is essential in the functional operation of endosomal transport in envelopment and budding of enveloped RNA viruses. However, in nonenveloped RNA viruses such as enteroviruses of the Picornaviridae family, the precise function of ESCRT pathway in viral replication remains elusive. Here, we initially evaluated that the ESCRT pathway is important for viral replication upon enterovirus 71 (EV71) infection. Furthermore, we discovered that YM201636, a specific inhibitor of phosphoinositide kinase, FYVE finger containing (PIKFYVE) kinase, significantly suppressed EV71 replication and virus-induced inflammation in vitro and in vivo. Mechanistically, YM201636 inhibits PIKFYVE kinase to block the ESCRT pathway and endosomal transport, leading to the disruption of viral entry and replication complex in subcellular components and ultimately repression of intracellular RNA virus replication and virus-induced inflammatory responses. Further studies found that YM201636 broadly represses the replication of other RNA viruses, including coxsackievirus B3 (CVB3), poliovirus 1 (PV1), echovirus 11 (E11), Zika virus (ZIKV), and vesicular stomatitis virus (VSV), rather than DNA viruses, including adenovirus 3 (ADV3) and hepatitis B virus (HBV). Our findings shed light on the mechanism underlying PIKFYVE-modulated ESCRT pathway involved in RNA virus replication, and also provide a prospective antiviral therapy during RNA viruses infections.

In patients with severe COVID-19, acute respiratory distress syndrome (ARDS), multiple organ dysfunction syndrome (MODS), and even mortality can result from cytokine storm, which is a hyperinflammatory medical condition caused by the excessive and uncontrolled release of pro-inflammatory cytokines. High levels of numerous crucial pro-inflammatory cytokines, such as interleukin-1 (IL-1), IL-2, IL-6, tumor necrosis factor-alpha, interferon (IFN)-gamma, IFN-induced protein 10 kDa, granulocyte-macrophage colony-stimulating factor, monocyte chemoattractant protein-1, and IL-10 and so on, have been found in severe COVID-19. They participate in cascade amplification pathways of pro-inflammatory responses through complex inflammatory networks. Here, we review the involvements of these critical inflammatory cytokines in SARS-CoV-2 infection and discuss their potential roles in triggering or regulating cytokine storm, which can help to understand the pathogenesis of severe COVID-19. So far, there is rarely effective therapeutic strategy for patients with cytokine storm besides using glucocorticoids, which is proved to result in fatal side effects. Clarifying the roles of key involved cytokines in the complex inflammatory network of cytokine storm will help to develop an ideal therapeutic intervention, such as neutralizing antibody of certain cytokine or inhibitor of some inflammatory signal pathways.

Abstract Molecular oxygen (O2) is essential for most biological reactions in mammalian cells. When the intracellular oxygen content decreases, it is called hypoxia. The process of hypoxia is linked to several biological processes, including pathogenic microbe infection, metabolic adaptation, cancer, acute and chronic diseases, and other stress responses. The mechanism underlying cells respond to oxygen changes to mediate subsequent signal response is the central question during hypoxia. Hypoxia-inducible factors (HIFs) sense hypoxia to regulate the expressions of a series of downstream genes expression, which participate in multiple processes including cell metabolism, cell growth/death, cell proliferation, glycolysis, immune response, microbe infection, tumorigenesis, and metastasis. Importantly, hypoxia signaling also interacts with other cellular pathways, such as phosphoinositide 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) signaling, nuclear factor kappa-B (NF-κB) pathway, extracellular signal-regulated kinases (ERK) signaling, and endoplasmic reticulum (ER) stress. This paper systematically reviews the mechanisms of hypoxia signaling activation, the control of HIF signaling, and the function of HIF signaling in human health and diseases. In addition, the therapeutic targets involved in HIF signaling to balance health and diseases are summarized and highlighted, which would provide novel strategies for the design and development of therapeutic drugs.

SARS-CoV-2 is highly pathogenic in humans and poses a great threat to public health worldwide. Clinical data shows a disturbed type I interferon (IFN) response during the virus infection. In this study, we discovered that the nucleocapsid (N) protein of SARS-CoV-2 plays an important role in the inhibition of interferon beta (IFN-β) production. N protein repressed IFN-β production induced by poly(I:C) or upon Sendai virus (SeV) infection. We noted that N protein also suppressed IFN-β production, induced by several signaling molecules downstream of the retinoic acid-inducible gene I (RIG-I) pathway, which is the crucial pattern recognition receptor (PRR) responsible for identifying RNA viruses. Moreover, our data demonstrated that N protein interacted with the RIG-I protein through the DExD/H domain, which has ATPase activity and plays an important role in the binding of immunostimulatory RNAs. These results suggested that SARS-CoV-2 N protein suppresses the IFN-β response through targeting the initial step, potentially the cellular PRR–RNA-recognition step in the innate immune pathway. Therefore, we propose that the SARS-CoV-2 N protein represses IFN-β production by interfering with RIG-I.

Excessive inflammatory responses induced upon SARS-CoV-2 infection are associated with severe symptoms of COVID-19. Inflammasomes activated in response to SARS-CoV-2 infection are also associated with COVID-19 severity. Here, we show a distinct mechanism by which SARS-CoV-2 N protein promotes NLRP3 inflammasome activation to induce hyperinflammation. N protein facilitates maturation of proinflammatory cytokines and induces proinflammatory responses in cultured cells and mice. Mechanistically, N protein interacts directly with NLRP3 protein, promotes the binding of NLRP3 with ASC, and facilitates NLRP3 inflammasome assembly. More importantly, N protein aggravates lung injury, accelerates death in sepsis and acute inflammation mouse models, and promotes IL-1β and IL-6 activation in mice. Notably, N-induced lung injury and cytokine production are blocked by MCC950 (a specific inhibitor of NLRP3) and Ac-YVAD-cmk (an inhibitor of caspase-1). Therefore, this study reveals a distinct mechanism by which SARS-CoV-2 N protein promotes NLRP3 inflammasome activation and induces excessive inflammatory responses.

Cytokine storm induced by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a major pathological feature of Coronavirus Disease 2019 (COVID-19) and a crucial determinant in COVID-19 prognosis. Understanding the mechanism underlying the SARS-CoV-2-induced cytokine storm is critical for COVID-19 control. Here, we identify that SARS-CoV-2 ORF3a and host hypoxia-inducible factor-1α (HIF-1α) play key roles in the virus infection and pro-inflammatory responses. RNA sequencing shows that HIF-1α signaling, immune response, and metabolism pathways are dysregulated in COVID-19 patients. Clinical analyses indicate that HIF-1α production, inflammatory responses, and high mortalities occurr in elderly patients. HIF-1α and pro-inflammatory cytokines are elicited in patients and infected cells. Interestingly, SARS-CoV-2 ORF3a induces mitochondrial damage and Mito-ROS production to promote HIF-1α expression, which subsequently facilitates SARS-CoV-2 infection and cytokines production. Notably, HIF-1α also broadly promotes the infection of other viruses. Collectively, during SARS-CoV-2 infection, ORF3a induces HIF-1α, which in turn aggravates viral infection and inflammatory responses. Therefore, HIF-1α plays an important role in promoting SARS-CoV-2 infection and inducing pro-inflammatory responses to COVID-19.

BACKGROUND:Extracellular adenosine triphosphate (ATP), a key danger-associated molecular pattern (DAMP) molecule, is released to the extracellular medium during inflammation by injured parenchymal cells, dying leukocytes, and activated platelets. ATP directly activates the plasma membrane channel P2X7 receptor (P2X7R), leading to an intracellular influx of K+, a key trigger inducing NLRP3 inflammasome activation. However, the mechanism underlying P2X7R-mediated activation of NLRP3 inflammasome is poorly understood, and additional molecular mediators have not been identified. Here, we demonstrate that Paxillin is the molecule connecting the P2X7 receptor and NLRP3 inflammasome through protein interactions.RESULTS:We show a distinct mechanism by which Paxillin promotes ATP-induced activation of the P2X7 receptor and NLRP3 inflammasome. Extracellular ATP induces Paxillin phosphorylation and then facilitates Paxillin-NLRP3 interaction. Interestingly, Paxillin enhances NLRP3 deubiquitination and activates NLRP3 inflammasome upon ATP treatment and K+ efflux. Moreover, we demonstrated that USP13 is a key enzyme for Paxillin-mediated NLRP3 deubiquitination upon ATP treatment. Notably, extracellular ATP promotes Paxillin and NLRP3 migration from the cytosol to the plasma membrane and facilitates P2X7R-Paxillin interaction and PaxillinNLRP3 association, resulting in the formation of the P2X7R-Paxillin-NLRP3 complex. Functionally, Paxillin is essential for ATP-induced NLRP3 inflammasome activation in mouse BMDMs and BMDCs as well as in human PBMCs and THP-1-differentiated macrophages.CONCLUSIONS:We have identified paxillin as a mediator of NLRP3 inflammasome activation. Paxillin plays key roles in ATP-induced activation of the P2X7 receptor and NLRP3 inflammasome by facilitating the formation of the P2X7R-Paxillin-NLRP3 complex.

The immune system is not only required for preventing threats exerted by pathogens but also essential for developing immune tolerance to avoid tissue damage. This study identifies a distinct mechanism by which MYSM1 suppresses innate immunity and autoimmunity. The expression of MYSM1 is induced upon DNA virus infection and by intracellular DNA stimulation. MYSM1 subsequently interacts with STING and cleaves STING K63-linked ubiquitination to suppress cGAS-STING signaling. Notably, Mysm1-deficient mice exhibit a hyper-inflammatory response, acute tissue damage, and high mortality upon virus infection. Moreover, in the PBMCs of patients with systemic lupus erythematosus (SLE), MYSM1 production decreases, while type I interferons and pro-inflammatory cytokine expressions increase. Importantly, MYSM1 treatment represses the production of IFNs and pro-inflammatory cytokines in the PBMCs of SLE patients. Thus, MYSM1 is a critical repressor of innate immunity and autoimmunity and is thus a potential therapeutic agent for infectious, inflammatory, and autoimmune diseases.

Aging is a universal feature of life that is a major focus of scientific research and a risk factor in many diseases. A comprehensive understanding of the cellular and molecular mechanisms of aging are critical to the prevention of diseases associated with the aging process. Here, it is shown that MYSM1 is a key suppressor of aging and aging-related pathologies. MYSM1 functionally represses cellular senescence and the aging process in human and mice primary cells and in mice organs. MYSM1 mechanistically attenuates the aging process by promoting DNA repair processes. Remarkably, MYSM1 deficiency facilitates the aging process and reduces lifespan, whereas MYSM1 over-expression attenuates the aging process and increases lifespan in mice. The functional role of MYSM1 is demonstrated in suppressing the aging process and prolonging lifespan. MYSM1 is a key suppressor of aging and may act as a potential agent for the prevention of aging and aging-associated diseases.

One of the fundamental reactions of the innate immune responses to pathogen infection is the release of pro-inflammatory cytokines, including IL-1β, processed by the NLRP3 inflammasome. The stimulator of interferon genes (STING) has the essential roles in innate immune response against pathogen infections. Here we reveal a distinct mechanism by which STING regulates the NLRP3 inflammasome activation, IL-1β secretion, and inflammatory responses in human cell lines, mice primary cells, and mice. Interestingly, upon HSV-1 infection and cytosolic DNA stimulation, STING binds to NLRP3 and promotes the inflammasome activation through two approaches. First, STING recruits NLRP3 and facilitates NLRP3 localization in the endoplasmic reticulum, thereby facilitating the inflammasome formation. Second, STING interacts with NLRP3 and attenuates K48- and K63-linked polyubiquitination of NLRP3, thereby promoting the inflammasome activation. Collectively, we demonstrate that the cGAS-STING-NLRP3 signaling is essential for host defense against HSV-1 infection.

One of the fundamental reactions of the innate immune responses to pathogen infection is the release of pro-inflammatory cytokines, including IL-1β, processed by the NLRP3 inflammasome. STING is essential for innate immune responses and inflammasome activation. Here we reveal a distinct mechanism by which STING regulates the NLRP3 inflammasome activation, IL-1β secretion, and inflammatory responses in human cell lines, mice primary cells, and mice. Interestingly, upon HSV-1 infection and cytosolic DNA stimulation, STING binds to NLRP3 and promotes the inflammasome activation through two approaches. First, STING recruits NLRP3 and promotes NLRP3 translocation to the endoplasmic reticulum, thereby facilitating the inflammasome formation. Second, STING interacts with NLRP3 and removes K48- and K63-linked polyubiquitination of NLRP3, thereby promoting the inflammasome activation. Collectively, we demonstrate that the cGAS-STING-NLRP3 signaling is essential for host defense against DNA virus infection.

Zika virus (ZIKV) has emerged as a global health threat due to its unexpected causal link to devastating neurological disorders such as fetal microcephaly; however, to date, no approved vaccine or specific treatment is available for ZIKV infection. Here we develop a biomimetic nanodecoy (ND) that can trap ZIKV, divert ZIKV away from its intended targets, and inhibit ZIKV infection. The ND, which is composed of a gelatin nanoparticle core camouflaged by mosquito medium host cell membranes, effectively adsorbs ZIKV and inhibits ZIKV replication in ZIKV-susceptible cells. Using a mouse model, we demonstrate that NDs significantly attenuate the ZIKV-induced inflammatory responses and degenerative changes and thus improve the survival rate of ZIKV-challenged mice. Moreover, by trapping ZIKV, NDs successfully prevent ZIKV from passing through physiologic barriers into the fetal brain and thereby mitigate ZIKV-induced fetal microcephaly in pregnant mice. We anticipate that this study will provide new insights into the development of safe and effective protection against ZIKV and various other viruses that threaten public health.

Zika virus (ZIKV) infection is a public health emergency and host innate immunity is essential for the control of virus infection. The NLRP3 inflammasome plays a key role in host innate immune responses by activating caspase-1 to facilitate interleukin-1β (IL-1β) secretion. Here we report that ZIKV stimulates IL-1β secretion in infected patients, human PBMCs and macrophages, mice, and mice BMDCs. The knockdown of NLRP3 in cells and knockout of NLRP3 in mice inhibit ZIKV-mediated IL-1β secretion, indicating an essential role for NLRP3 in ZIKV-induced IL-1β activation. Moreover, ZIKV NS5 protein is required for NLRP3 activation and IL-1β secretion by binding with NLRP3 to facilitate the inflammasome complex assembly. Finally, ZIKV infection in mice activates IL-1β secretion, leading to inflammatory responses in the mice brain, spleen, liver, and kidney. Thus we reveal a mechanism by which ZIKV induces inflammatory responses by facilitating NLRP3 inflammasome complex assembly and IL-1β activation.