NLRP3 Inflammasome Activation Enhanced by TRIM25 is Targeted by the NS1 Protein of 2009 Pandemic Influenza A Virus

Abstract

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.

Influenza A Virus Exacerbates Group A Streptococcus Infection and Thwarts Anti-bacterial Inflammatory Responses in Murine Macrophages

“…Interestingly, we detected for both, GAS mono-infection and superinfection an upregulation of Il1b, which suggests that the incapacity of co-infected macrophages to process and secrete IL-1β is due to a failure in the GAS-inducible activation of the NLRP3 inflammasome [86][87][88][89]. In fact, it was shown that different variants of IAV, including a 2009 pandemic strain, were capable of thwarting IL-1β maturation by interfering with NLRP3 inflammasome assembly [90][91][92], which is crucial for innate immune sensing and coordination [93]. An IAV-mediated nullification of IL-1β secretion would be of dramatic consequences during streptococcal superinfections.…”

Influenza A Virus Exacerbates Group A Streptococcus Infection and Thwarts Anti-Bacterial Inflammatory Responses in Murine Macrophages

“…Interestingly, we detected an upregulation of Il1b for both GAS mono-infection and superinfection, which suggests that the incapacity of co-infected macrophages to process and secrete IL-1β is due to a failure in the GASinducible activation of the NLRP3 inflammasome [86][87][88][89]. In fact, it was shown that different variants of IAV, including a 2009 pandemic strain, were capable of thwarting IL-1β maturation by interfering with NLRP3 inflammasome assembly [90][91][92], which is crucial for innate immune sensing and coordination [93]. An IAV-mediated nullification of IL-1β secretion would be of dramatic consequences during streptococcal superinfections.…”

Virus versus host: influenza A virus circumvents the immune responses

“…NS1 attenuates the association between pro-caspase-1 and ASC, followed by decreasing IL-1β signal transduction. Collectively, NS1 has an additional antagonistic effect on proinflammatory response to create a favorable environment for viral replication ( Figure 2E ) ( Park et al, 2021 ).…”