Abstract:RIPK3 was reported to play an important role in the protection against influenza A virus (IAV) in vivo. Here we show that the requirement of RIPK3 for protection against IAV infection in vivo is only apparent within a limited dose range of IAV challenge. We found that this protective outcome is independent from RIPK3 kinase activity and from MLKL. This shows that platform function of RIPK3 rather than its kinase activity is required for protection, suggesting that a RIPK3 function independent of necroptosis is… Show more
“…The Ripk3 −/− mice and their Ripk3 +/+ littermates were primed and immunized with the M2e-VLP vaccines or with phosphate-buffered saline (PBS), as a negative control. As expected at this high IAV challenge dose, there is no difference between unvaccinated Ripk3 −/− versus Ripk3 +/+ mice [ 14 ]. Almost all Ripk3 −/− mice, though vaccinated died soon after infection (Fig.…”
Section: Resultssupporting
confidence: 60%
“…2A ), while most Ripk3 +/+ littermates survived. This indicates that RIPK3 not only is involved in the protection against IAV infection [ 14 , 15 ], but is also crucial for the efficacy of vaccination against IAV. Fig.…”
Section: Resultsmentioning
confidence: 99%
“…3B ). Therefore we conclude that very likely the reduced recruitment of immune cells combined with the enhanced sensitivity of RIPK3-deficient mice for IAV infection [ 10 – 14 ] may explain the observed reduced survival of Ripk3 −/− mice following vaccination. Fig.…”
Section: Resultsmentioning
confidence: 99%
“…One key player in some of these pathways is Receptor-Interacting serine/threonine-Protein Kinase 3 (RIPK3) [ 9 ]. Indeed, RIPK3 is involved in the protection against IAV infection by several mechanisms [ 10 – 14 ]. RIPK3 kinase activity, for example, is implicated in TNF-and ZBP1-mediated necroptosis, while as a scaffold it is implicated in apoptosis upon IAV infection [ 14 ].…”
Section: Introductionmentioning
confidence: 99%
“…Indeed, RIPK3 is involved in the protection against IAV infection by several mechanisms [ 10 – 14 ]. RIPK3 kinase activity, for example, is implicated in TNF-and ZBP1-mediated necroptosis, while as a scaffold it is implicated in apoptosis upon IAV infection [ 14 ]. Beyond its involvement in the protection against IAV infection, the contribution of RIPK3 to vaccine-induced immune protection conferred by active vaccination strategies has not been addressed.…”
RIPK3 partially protects against disease caused by influenza A virus (IAV) infection in the mouse model. Here, we compared the immune protection of active vaccination with a universal influenza A vaccine candidate based on the matrix protein 2 ectodomain (M2e) and of passive immunization with anti-M2e IgG antibodies in wild type and Ripk3−/− mice. We observed that the protection against IAV after active vaccination with M2e viral antigen is lost in Ripk3−/− mice. Interestingly, M2e-specific serum IgG levels induced by M2e vaccination were not significantly different between wild type and Ripk3−/− vaccinated mice demonstrating that the at least the humoral immune response was not affected by the absence of RIPK3 during active vaccination. Moreover, following IAV challenge, lungs of M2e vaccinated Ripk3−/− mice revealed a decreased number of immune cell infiltrates and an increased accumulation of dead cells, suggesting that phagocytosis could be reduced in Ripk3−/− mice. However, neither efferocytosis nor antibody-dependent phagocytosis were affected in macrophages isolated from Ripk3−/− mice. Likewise following IAV infection of Ripk3−/− mice, active vaccination and infection resulted in decreased presence of CD8+ T-cells in the lung. However, it is unclear whether this reflects a deficiency in vaccination or an inability following infection. Finally, passively transferred anti-M2e monoclonal antibodies at higher dose than littermate wild type mice completely protected Ripk3−/− mice against an otherwise lethal IAV infection, demonstrating that the increased sensitivity of Ripk3−/− mice could be overcome by increased antibodies. Therefore we conclude that passive immunization strategies with monoclonal antibody could be useful for individuals with reduced IAV vaccine efficacy or increased IAV sensitivity, such as may be expected in patients treated with future anti-inflammatory therapeutics for chronic inflammatory diseases such as RIPK inhibitors.
“…The Ripk3 −/− mice and their Ripk3 +/+ littermates were primed and immunized with the M2e-VLP vaccines or with phosphate-buffered saline (PBS), as a negative control. As expected at this high IAV challenge dose, there is no difference between unvaccinated Ripk3 −/− versus Ripk3 +/+ mice [ 14 ]. Almost all Ripk3 −/− mice, though vaccinated died soon after infection (Fig.…”
Section: Resultssupporting
confidence: 60%
“…2A ), while most Ripk3 +/+ littermates survived. This indicates that RIPK3 not only is involved in the protection against IAV infection [ 14 , 15 ], but is also crucial for the efficacy of vaccination against IAV. Fig.…”
Section: Resultsmentioning
confidence: 99%
“…3B ). Therefore we conclude that very likely the reduced recruitment of immune cells combined with the enhanced sensitivity of RIPK3-deficient mice for IAV infection [ 10 – 14 ] may explain the observed reduced survival of Ripk3 −/− mice following vaccination. Fig.…”
Section: Resultsmentioning
confidence: 99%
“…One key player in some of these pathways is Receptor-Interacting serine/threonine-Protein Kinase 3 (RIPK3) [ 9 ]. Indeed, RIPK3 is involved in the protection against IAV infection by several mechanisms [ 10 – 14 ]. RIPK3 kinase activity, for example, is implicated in TNF-and ZBP1-mediated necroptosis, while as a scaffold it is implicated in apoptosis upon IAV infection [ 14 ].…”
Section: Introductionmentioning
confidence: 99%
“…Indeed, RIPK3 is involved in the protection against IAV infection by several mechanisms [ 10 – 14 ]. RIPK3 kinase activity, for example, is implicated in TNF-and ZBP1-mediated necroptosis, while as a scaffold it is implicated in apoptosis upon IAV infection [ 14 ]. Beyond its involvement in the protection against IAV infection, the contribution of RIPK3 to vaccine-induced immune protection conferred by active vaccination strategies has not been addressed.…”
RIPK3 partially protects against disease caused by influenza A virus (IAV) infection in the mouse model. Here, we compared the immune protection of active vaccination with a universal influenza A vaccine candidate based on the matrix protein 2 ectodomain (M2e) and of passive immunization with anti-M2e IgG antibodies in wild type and Ripk3−/− mice. We observed that the protection against IAV after active vaccination with M2e viral antigen is lost in Ripk3−/− mice. Interestingly, M2e-specific serum IgG levels induced by M2e vaccination were not significantly different between wild type and Ripk3−/− vaccinated mice demonstrating that the at least the humoral immune response was not affected by the absence of RIPK3 during active vaccination. Moreover, following IAV challenge, lungs of M2e vaccinated Ripk3−/− mice revealed a decreased number of immune cell infiltrates and an increased accumulation of dead cells, suggesting that phagocytosis could be reduced in Ripk3−/− mice. However, neither efferocytosis nor antibody-dependent phagocytosis were affected in macrophages isolated from Ripk3−/− mice. Likewise following IAV infection of Ripk3−/− mice, active vaccination and infection resulted in decreased presence of CD8+ T-cells in the lung. However, it is unclear whether this reflects a deficiency in vaccination or an inability following infection. Finally, passively transferred anti-M2e monoclonal antibodies at higher dose than littermate wild type mice completely protected Ripk3−/− mice against an otherwise lethal IAV infection, demonstrating that the increased sensitivity of Ripk3−/− mice could be overcome by increased antibodies. Therefore we conclude that passive immunization strategies with monoclonal antibody could be useful for individuals with reduced IAV vaccine efficacy or increased IAV sensitivity, such as may be expected in patients treated with future anti-inflammatory therapeutics for chronic inflammatory diseases such as RIPK inhibitors.
BackgroundInfluenza virus (IV) is a leading cause of respiratory tract infections, eliciting responses from key innate immune cells such as Macrophages (MQs), Neutrophils, and Dendritic Cells (DCs). These cells employ diverse mechanisms to combat IV, with Inflammasomes playing a pivotal role in viral infection control. Cellular death mechanisms, including Pyroptosis, Apoptosis, and Necroptosis (collectively called PANoptosis), significantly contribute to the innate immune response.MethodsIn this updated review, we delve into the intricate relationship between PANoptosis and Inflammasomes within innate immune cells (MQs, Neutrophils, and DCs) during IV infections. We explore the strategies employed by IV to evade these immune defenses and the consequences of unchecked PANoptosis and inflammasome activation, including the potential development of severe complications such as cytokine storms and tissue damage.ResultsOur analysis underscores the interplay between PANoptosis and Inflammasomes as a critical aspect of the innate immune response against IV. We provide insights into IV's various mechanisms to subvert these immune pathways and highlight the importance of understanding these interactions to develop effective antiviral medications.ConclusionA comprehensive understanding of the dynamic interactions between PANoptosis, Inflammasomes, and IV is essential for advancing our knowledge of innate immune responses to viral infections. This knowledge will be invaluable in developing targeted antiviral therapies to combat IV and mitigate potential complications, including cytokine storms and tissue damage.
Currently, various problems are being faced in the treatment of influenza, so the development of new safe and effective drugs is crucial. Selenadiazole, an important component of selenium heterocyclic compounds, has received wide attention for its biological activity. This study aimed to verify the antiviral activity of 5-nitrobenzo [c] [1,2,5]selenadiazole (SeD-3) in vivo and in vitro. The cell counting kit-8 assay and observation of cytopathic effect verified that SeD-3 could improve the survival of influenza A(H1N1)pdm09-infected Madin-Darby canine kidney cells. Polymerase chain reaction quantification and neuraminidase assay showed that SeD-3 could inhibit the proliferation of H1N1 virus. The time of addition assay demonstrated that SeD-3 may have a direct effect on virus particles and block some stages of H1N1 life cycle after virus adsorption. Cell cycle, JC-1, Annexin V, and terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling-4′,6-diamidino-2-phenylindole (TUNEL-DAPI) assays showed that SeD-3 inhibited H1N1 infection-induced apoptosis.Cytokine detection demonstrated SeD-3 inhibited the production of proinflammatory factors after infection, including tumor necrosis factor-α (TNF-α), TNF-β, interferon-γ, interleukin 12 (IL-12), and IL-17F. In vivo experiments suggested that the pathological damage in the lungs was significantly alleviated after treatment with SeD-3 by hematoxylin and eosin staining. The TUNEL assay of lung tissues indicated that SeD-3 inhibited DNA damage during H1N1 infection. Immunohistochemical assays were performed to further explore the mechanism that SeD-3 inhibited H1N1-induced apoptosis via reactive oxygen species-mediated MAPK, AKT, and P53 signaling pathways. In conclusion, SeD-3 may become a new potential anti-H1N1 influenza virus drug due to its antiviral and anti-inflammatory activity.
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