Necroptosis in Pneumonia: Therapeutic Strategies and Future Perspectives.
Viruses
Pneumonia remains a major global health challenge, necessitating the development of effective therapeutic approaches. Recently, necroptosis, a regulated form of cell death, has garnered attention in the fields of pharmacology and immunology for its role in the pathogenesis of pneumonia. Characterized by cell death and inflammatory responses, necroptosis is a key mechanism contributing to tissue damage and immune dysregulation in various diseases, including pneumonia. This review comprehensively analyzes the role of necroptosis in pneumonia and explores potential pharmacological interventions targeting this cell death pathway. Moreover, we highlight the intricate interplay between necroptosis and immune responses in pneumonia, revealing a bidirectional relationship between necrotic cell death and inflammatory signaling. Importantly, we assess current therapeutic strategies modulating necroptosis, encompassing synthetic inhibitors, natural products, and other drugs targeting key components of the programmed necrosis pathway. The article also discusses challenges and future directions in targeting programmed necrosis for pneumonia treatment, proposing novel therapeutic strategies that combine antibiotics with necroptosis inhibitors. This review underscores the importance of understanding necroptosis in pneumonia and highlights the potential of pharmacological interventions to mitigate tissue damage and restore immune homeostasis in this devastating respiratory infection.
10.3390/v16010094
Influenza Virus Z-RNAs Induce ZBP1-Mediated Necroptosis.
Zhang Ting,Yin Chaoran,Boyd David F,Quarato Giovanni,Ingram Justin P,Shubina Maria,Ragan Katherine B,Ishizuka Takumi,Crawford Jeremy Chase,Tummers Bart,Rodriguez Diego A,Xue Jia,Peri Suraj,Kaiser William J,López Carolina B,Xu Yan,Upton Jason W,Thomas Paul G,Green Douglas R,Balachandran Siddharth
Cell
Influenza A virus (IAV) is a lytic RNA virus that triggers receptor-interacting serine/threonine-protein kinase 3 (RIPK3)-mediated pathways of apoptosis and mixed lineage kinase domain-like pseudokinase (MLKL)-dependent necroptosis in infected cells. ZBP1 initiates RIPK3-driven cell death by sensing IAV RNA and activating RIPK3. Here, we show that replicating IAV generates Z-RNAs, which activate ZBP1 in the nucleus of infected cells. ZBP1 then initiates RIPK3-mediated MLKL activation in the nucleus, resulting in nuclear envelope disruption, leakage of DNA into the cytosol, and eventual necroptosis. Cell death induced by nuclear MLKL was a potent activator of neutrophils, a cell type known to drive inflammatory pathology in virulent IAV disease. Consequently, MLKL-deficient mice manifest reduced nuclear disruption of lung epithelia, decreased neutrophil recruitment into infected lungs, and increased survival following a lethal dose of IAV. These results implicate Z-RNA as a new pathogen-associated molecular pattern and describe a ZBP1-initiated nucleus-to-plasma membrane "inside-out" death pathway with potentially pathogenic consequences in severe cases of influenza.
10.1016/j.cell.2020.02.050
Non-SARS Non-MERS Human Coronaviruses: Clinical Characteristics and Outcome.
Pathogens (Basel, Switzerland)
Human coronaviruses (HCoVs) have become evident sources of human respiratory infections with new emerging HCoVs as a significant cause of morbidity and mortality. The common four coronaviruses (229E, HKU1, NL63, and OC43) are known to cause respiratory illness in humans, but their clinical impact is poorly described in the literature. We analyzed the data of all patients who tested positive for at least one of the four HCoVs from October 2015 to January 2020 in a tertiary care center. HCoVs were detected in 1062 specimens, with an incidence rate of 1.01%, out of all documented respiratory illnesses. Detection of these viruses was reported sporadically throughout the years, with a peak of occurrence during winter seasons. OC43 had the highest incidence (53.7%), followed by NL63 (21.9%), HKU1 (12.6%), and 229E (11.8%). Most of these infections were community-acquired, with symptoms of both upper and lower respiratory tract. Co-detection with other viruses were observed, mostly with rhinovirus. 229E was the most frequent (26.4%) HCoV in patients requiring intensive care, while NL63 and 229E were the most common in patients requiring invasive ventilation. The highest 30-day mortality rate was observed in patients infected with 229E (6.4%). HCoVs are common circulating pathogens that have been present for decades, with 229E being the most virulent in this study cohort.
10.3390/pathogens10121549
Exacerbation of Influenza A Virus Disease Severity by Respiratory Syncytial Virus Co-Infection in a Mouse Model.
George Junu A,AlShamsi Shaikha H,Alhammadi Maryam H,Alsuwaidi Ahmed R
Viruses
Influenza A virus (IAV) and respiratory syncytial virus (RSV) are leading causes of childhood infections. RSV and influenza are competitive in vitro. In this study, the in vivo effects of RSV and IAV co-infection were investigated. Mice were intranasally inoculated with RSV, with IAV, or with both viruses (RSV+IAV and IAV+RSV) administered sequentially, 24 h apart. On days 3 and 7 post-infection, lung tissues were processed for viral loads and immune cell populations. Lung functions were also evaluated. Mortality was observed only in the IAV+RSV group (50% of mice did not survive beyond 7 days). On day 3, the viral loads in single-infected and co-infected mice were not significantly different. However, on day 7, the IAV titer was much higher in the IAV+RSV group, and the RSV viral load was reduced. CD4 T cells were reduced in all groups on day 7 except in single-infected mice. CD8 T cells were higher in all experimental groups except the RSV-alone group. Increased airway resistance and reduced thoracic compliance were demonstrated in both co-infected groups. This model indicates that, among all the infection types we studied, infection with IAV followed by RSV is associated with the highest IAV viral loads and the most morbidity and mortality.
10.3390/v13081630
Coinfection with influenza A virus enhances SARS-CoV-2 infectivity.
Cell research
The upcoming flu season in the Northern Hemisphere merging with the current COVID-19 pandemic raises a potentially severe threat to public health. Through experimental coinfection with influenza A virus (IAV) and either pseudotyped or live SARS-CoV-2 virus, we found that IAV preinfection significantly promoted the infectivity of SARS-CoV-2 in a broad range of cell types. Remarkably, in vivo, increased SARS-CoV-2 viral load and more severe lung damage were observed in mice coinfected with IAV. Moreover, such enhancement of SARS-CoV-2 infectivity was not observed with several other respiratory viruses, likely due to a unique feature of IAV to elevate ACE2 expression. This study illustrates that IAV has a unique ability to aggravate SARS-CoV-2 infection, and thus, prevention of IAV infection is of great significance during the COVID-19 pandemic.
10.1038/s41422-021-00473-1
Mortality, morbidity, and hospitalisations due to influenza lower respiratory tract infections, 2017: an analysis for the Global Burden of Disease Study 2017.
The Lancet. Respiratory medicine
BACKGROUND:Although the burden of influenza is often discussed in the context of historical pandemics and the threat of future pandemics, every year a substantial burden of lower respiratory tract infections (LRTIs) and other respiratory conditions (like chronic obstructive pulmonary disease) are attributable to seasonal influenza. The Global Burden of Disease Study (GBD) 2017 is a systematic scientific effort to quantify the health loss associated with a comprehensive set of diseases and disabilities. In this Article, we focus on LRTIs that can be attributed to influenza. METHODS:We modelled the LRTI incidence, hospitalisations, and mortality attributable to influenza for every country and selected subnational locations by age and year from 1990 to 2017 as part of GBD 2017. We used a counterfactual approach that first estimated the LRTI incidence, hospitalisations, and mortality and then attributed a fraction of those outcomes to influenza. FINDINGS:Influenza LRTI was responsible for an estimated 145 000 (95% uncertainty interval [UI] 99 000-200 000) deaths among all ages in 2017. The influenza LRTI mortality rate was highest among adults older than 70 years (16·4 deaths per 100 000 [95% UI 11·6-21·9]), and the highest rate among all ages was in eastern Europe (5·2 per 100 000 population [95% UI 3·5-7·2]). We estimated that influenza LRTIs accounted for 9 459 000 (95% UI 3 709 000-22 935 000) hospitalisations due to LRTIs and 81 536 000 hospital days (24 330 000-259 851 000). We estimated that 11·5% (95% UI 10·0-12·9) of LRTI episodes were attributable to influenza, corresponding to 54 481 000 (38 465 000-73 864 000) episodes and 8 172 000 severe episodes (5 000 000-13 296 000). INTERPRETATION:This comprehensive assessment of the burden of influenza LRTIs shows the substantial annual effect of influenza on global health. Although preparedness planning will be important for potential pandemics, health loss due to seasonal influenza LRTIs should not be overlooked, and vaccine use should be considered. Efforts to improve influenza prevention measures are needed. FUNDING:Bill & Melinda Gates Foundation.
10.1016/S2213-2600(18)30496-X
Influenza A virus-induced apoptosis and virus propagation.
Ampomah Patrick B,Lim Lina H K
Apoptosis : an international journal on programmed cell death
Influenza A viruses (IAVs) are respiratory pathogens that cause severe morbidity and mortality worldwide. They affect cellular processes such as proliferation, protein synthesis, autophagy, and apoptosis. Although apoptosis is considered an innate cellular response to invading infectious pathogens, IAVs have evolved to encode viral proteins that modulate host cellular apoptosis in ways that support efficient viral replication and propagation. An understanding of the modulation of host responses is essential to the development of novel therapeutics for the treatment of IAV infections. In this review, we discuss the IAV lifecycle, biology, and strategies employed by the virus to modulate apoptosis to enhance viral survival and establish an infection.
10.1007/s10495-019-01575-3
Dynamic gene expression analysis in a H1N1 influenza virus mouse pneumonia model.
Bao Yanyan,Gao Yingjie,Shi Yujing,Cui Xiaolan
Virus genes
H1N1, a major pathogenic subtype of influenza A virus, causes a respiratory infection in humans and livestock that can range from a mild infection to more severe pneumonia associated with acute respiratory distress syndrome. Understanding the dynamic changes in the genome and the related functional changes induced by H1N1 influenza virus infection is essential to elucidating the pathogenesis of this virus and thereby determining strategies to prevent future outbreaks. In this study, we filtered the significantly expressed genes in mouse pneumonia using mRNA microarray analysis. Using STC analysis, seven significant gene clusters were revealed, and using STC-GO analysis, we explored the significant functions of these seven gene clusters. The results revealed GOs related to H1N1 virus-induced inflammatory and immune functions, including innate immune response, inflammatory response, specific immune response, and cellular response to interferon-beta. Furthermore, the dynamic regulation relationships of the key genes in mouse pneumonia were revealed by dynamic gene network analysis, and the most important genes were filtered, including Dhx58, Cxcl10, Cxcl11, Zbp1, Ifit1, Ifih1, Trim25, Mx2, Oas2, Cd274, Irgm1, and Irf7. These results suggested that during mouse pneumonia, changes in the expression of gene clusters and the complex interactions among genes lead to significant changes in function. Dynamic gene expression analysis revealed key genes that performed important functions. These results are a prelude to advancements in mouse H1N1 influenza virus infection biology, as well as the use of mice as a model organism for human H1N1 influenza virus infection studies.
10.1007/s11262-017-1438-y
Immunomodulatory and antiviral effects of Lycium barbarum glycopeptide on influenza a virus infection.
Microbial pathogenesis
Influenza is caused by a respiratory virus and has a major global impact on human health. Influenza A viruses in particular are highly pathogenic to humans and have caused multiple pandemics. An important consequence of infection is viral pneumonia, and with serious complications of excessive inflammation and tissue damage. Therefore, simultaneously reducing direct damage caused by virus infection and relieving indirect damage caused by excessive inflammation would be an effective treatment strategy. Lycium barbarum glycopeptide (LbGp) is a mixture of five highly branched polysaccharide-protein conjuncts (LbGp1-5) isolated from Lycium barbarum fruit. LbGp has pro-immune activity that is 1-2 orders of magnitude stronger than that of other plant polysaccharides. However, there are few reports on the immunomodulatory and antiviral activities of LbGp. In this study, we evaluated the antiviral and immunomodulatory effects of LbGp in vivo and in vitro and investigated its therapeutic effect on H1N1-induced viral pneumonia and mechanisms of action. In vitro, cytokine secretion, NF-κB p65 nuclear translocation, and CD86 mRNA expression in LPS-stimulated RAW264.7 cells were constrained by LbGp treatment. In A549 cells, LbGp can inhibit H1N1 infection by blocking virus attachment and entry action. In vivo experiments confirmed that administration of LbGp can effectively increase the survival rate, body weight and decrease the lung index of mice infected with H1N1. Compared to the model group, pulmonary histopathologic symptoms in lung sections of mice treated with LbGp were obviously alleviated. Further investigation revealed that the mechanism of LbGp in the treatment of H1N1-induced viral pneumonia includes reducing the viral load in lung, regulating the phenotype of pulmonary macrophages, and inhibiting excessive inflammation. In conclusion, LbGp exhibits potential curative effects against H1N1-induced viral pneumonia in mice, and these effects are associated with its good immuno-regulatory and antiviral activities.
10.1016/j.micpath.2023.106030
Emerging antiviral therapies and drugs for the treatment of influenza.
Expert opinion on emerging drugs
INTRODUCTION:Both vaccines and antiviral drugs represent the mainstay for preventing and treating influenza. However, approved M2 ion channel inhibitors, neuraminidase inhibitors, polymerase inhibitors, and various vaccines cannot meet therapeutic needs because of viral resistance. Thus, the discovery of new targets for the virus or host and the development of more effective inhibitors are essential to protect humans from the influenza virus. AREAS COVERED:This review summarizes the latest progress in vaccines and antiviral drug research to prevent and treat influenza, providing the foothold for developing novel antiviral inhibitors. EXPERT OPINION:Vaccines embody the most effective approach to preventing influenza virus infection, and recombinant protein vaccines show promising prospects in developing next-generation vaccines. Compounds targeting the viral components of RNA polymerase, hemagglutinin and nucleoprotein, and the modification of trusted neuraminidase inhibitors are future research directions for anti-influenza virus drugs. In addition, some host factors affect the replication of virus in vivo, which can be used to develop antiviral drugs.
10.1080/14728214.2022.2149734