EFFECT OF NLRP3 INFLAMMASOME IN PNEUMONIA CAUSED BY INFLUENZA A VIRUS H1N1 AND MRSA

Nucleotide-binding domain and leucine-rich repeat-containing protein 3 (NLRP3) inflammasome-mediated interleukin-1 beta (IL-1β) production is one of the crucial responses in innate immunity upon infection with viruses including influenza A virus (IAV) and is modulated by both viral and host cellular proteins. Among host proteins involved, we identified tripartite motif-containing protein 25 (TRIM25) as a positive regulator of porcine NLRP3 inflammasome-mediated IL-1β production. TRIM25 achieved this function by enhancing the pro-caspase-1 interaction with apoptosis-associated speck-like protein containing caspase recruitment domain (ASC). The N-terminal RING domain, particularly residues predicted to be critical for the E3 ligase activity of TRIM25, was responsible for this enhancement. However, non-structural protein 1 (NS1) C-terminus of 2009 pandemic IAV interfered with this action by interacting with TRIM25, leading to diminished association between pro-caspase-1 and ASC. These findings demonstrate that TRIM25 promotes the IL-1β signaling, while it is repressed by IAV NS1 protein, revealing additional antagonism of the NS1 against host pro-inflammatory responses.

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The Zα2 domain of ZBP1 is a molecular switch regulating influenza-induced PANoptosis and perinatal lethality during development

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.013752 ◽

2020 ◽

Vol 295 (24) ◽

pp. 8325-8330 ◽

Cited By ~ 14

Author(s):

Sannula Kesavardhana ◽

R. K. Subbarao Malireddi ◽

Amanda R. Burton ◽

Shaina N. Porter ◽

Peter Vogel ◽

...

Keyword(s):

Cell Death ◽

Nucleic Acids ◽

Influenza A Virus ◽

Nlrp3 Inflammasome ◽

Influenza A ◽

Defense Responses ◽

Innate Immune ◽

Inflammasome Activation ◽

Perinatal Lethality

Z-DNA-binding protein 1 (ZBP1) is an innate immune sensor of nucleic acids that regulates host defense responses and development. ZBP1 activation triggers inflammation and pyroptosis, necroptosis, and apoptosis (PANoptosis) by activating receptor-interacting Ser/Thr kinase 3 (RIPK3), caspase-8, and the NLRP3 inflammasome. ZBP1 is unique among innate immune sensors because of its N-terminal Zα1 and Zα2 domains, which bind to nucleic acids in the Z-conformation. However, the specific role of these Zα domains in orchestrating ZBP1 activation and subsequent inflammation and cell death is not clear. Here we generated Zbp1ΔZα2/ΔZα2 mice that express ZBP1 lacking the Zα2 domain and demonstrate that this domain is critical for influenza A virus–induced PANoptosis and underlies perinatal lethality in mice in which the RIP homotypic interaction motif domain of RIPK1 has been mutated (Ripk1mRHIM/mRHIM). Deletion of the Zα2 domain in ZBP1 abolished influenza A virus–induced PANoptosis and NLRP3 inflammasome activation. Furthermore, deletion of the Zα2 domain of ZBP1 was sufficient to rescue Ripk1mRHIM/mRHIM mice from perinatal lethality caused by ZBP1-driven cell death and inflammation. Our findings identify the essential role of the Zα2 domain of ZBP1 in several physiological functions and establish a link between Z-RNA sensing via the Zα2 domain and promotion of influenza-induced PANoptosis and perinatal lethality.

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Decision letter for "Immunodepression induced by influenza A virus (H1N1) in lymphoid organs functions as a pathogenic mechanism"

10.1111/1440-1681.13358/v2/decision1 ◽

2020 ◽

Keyword(s):

Influenza A Virus ◽

Influenza A ◽

Lymphoid Organs ◽

Pathogenic Mechanism ◽

Virus H1n1

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Immunogenicity, Boostability, and Sustainability of the Immune Response after Vaccination against Influenza A Virus (H1N1) 2009 in a Healthy Population

Clinical and Vaccine Immunology ◽

10.1128/cvi.05046-11 ◽

2011 ◽

Vol 18 (9) ◽

pp. 1401-1405 ◽

Cited By ~ 36

Author(s):

Elisabeth Huijskens ◽

John Rossen ◽

Paul Mulder ◽

Ruud van Beek ◽

Hennie van Vugt ◽

...

Keyword(s):

Immune Response ◽

Influenza Virus ◽

Influenza A Virus ◽

Influenza A ◽

Seasonal Influenza ◽

Virus H1n1 ◽

Prospective Longitudinal Study ◽

Virus Vaccination ◽

Short Period ◽

Prospective Longitudinal

ABSTRACTThe emergence of a new influenza A virus (H1N1) variant in 2009 led to a worldwide vaccination program, which was prepared in a relatively short period of time. This study investigated the humoral immunity against this virus before and after vaccination with a 2009 influenza A virus (H1N1) monovalent MF59-adjuvanted vaccine, as well as the persistence of vaccine-induced antibodies. Our prospective longitudinal study included 498 health care workers (mean age, 43 years; median age, 44 years). Most (89%) had never or only occasionally received a seasonal influenza virus vaccine, and 11% were vaccinated annually (on average, for >10 years). Antibody titers were determined by a hemagglutination inhibition (HI) assay at baseline, 3 weeks after the first vaccination, and 5 weeks and 7 months after the second vaccination. Four hundred thirty-five persons received two doses of the 2009 vaccine. After the first dose, 79.5% developed a HI titer of ≥40. This percentage increased to 83.3% after the second dose. Persistent antibodies were found in 71.9% of the group that had not received annual vaccinations and in 43.8% of the group that had received annual vaccinations. The latter group tended to have lower HI titers (P=0.09). With increasing age, HI titers decreased significantly, by 2.4% per year. A single dose of the 2009 vaccine was immunogenic in almost 80% of the study population, whereas an additional dose resulted in significantly increased titers only in persons over 50. Finally, a reduced HI antibody response against the 2009 vaccine was found in adults who had previously received seasonal influenza virus vaccination. More studies on the effect of yearly seasonal influenza virus vaccination on the immune response are warranted.

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