The H7N9 influenza A virus infection results in lethal inflammation in the mammalian host via the NLRP3-caspase-1 inflammasome

Ren, Rongrong; Wu, Shuangyan; Cai, Jialin; Yang, Yuqin; Ren, Xu; Feng, Yinchang; Chen, Lixiang; Qin, Boyin; Xu, Chunhua; Yang, Hua; Song, Zhigang; Tian, Di; Hu, Yunwen; Zhou, Xiaohui; Meng, Guangxun

doi:10.1038/s41598-017-07384-5

Cited by 42 publications

(43 citation statements)

References 36 publications

(46 reference statements)

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“…The inflammasome, an innate signaling complex that is required for IL-1β and IL-18 secretion has been implicated in multiple studies as influenza-associated pathology [16,17]. Suppressing inflammasome activation later in infection, by targeting NLRP3 (a key component of inflammasome signaling) downstream of influenza has had positive effects on recovery in animal models [18,19]. Following inflammasome activation, secondary cytokine and chemokine signaling can lead to the recruitment of tissue-damaging neutrophil and inflammatory monocyte populations.…”

Section: How Influenza Triggers Ardsmentioning

confidence: 99%

Influenza virus-related critical illness: pathophysiology and epidemiology

2019

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Influenza virus affects the respiratory tract by direct viral infection or by damage from the immune system response. In humans, the respiratory epithelium is the only site where the hemagglutinin (HA) molecule is effectively cleaved, generating infectious virus particles. Virus transmission occurs through a susceptible individual’s contact with aerosols or respiratory fomites from an infected individual. The inability of the lung to perform its primary function of gas exchange can result from multiple mechanisms, including obstruction of the airways, loss of alveolar structure, loss of lung epithelial integrity from direct epithelial cell killing, and degradation of the critical extracellular matrix. Approximately 30–40% of hospitalized patients with laboratory-confirmed influenza are diagnosed with acute pneumonia. These patients who develop pneumonia are more likely to be < 5 years old, > 65 years old, Caucasian, and nursing home residents; have chronic lung or heart disease and history of smoking, and are immunocompromised. Influenza can primarily cause severe pneumonia, but it can also present in conjunction with or be followed by a secondary bacterial infection, most commonly by Staphylococcus aureus and Streptococcus pneumoniae . Influenza is associated with a high predisposition to bacterial sepsis and ARDS. Viral infections presenting concurrently with bacterial pneumonia are now known to occur with a frequency of 30–50% in both adult and pediatric populations. The H3N2 subtype has been associated with unprecedented high levels of intensive care unit (ICU) admission. Influenza A is the predominant viral etiology of acute respiratory distress syndrome (ARDS) in adults. Risk factors independently associated with ARDS are age between 36 and 55 years old, pregnancy, and obesity, while protective factors are female sex, influenza vaccination, and infections with Influenza A (H3N2) or Influenza B viruses. In the ICU, particularly during the winter season, influenza should be suspected not only in patients with typical symptoms and epidemiology, but also in patients with severe pneumonia, ARDS, sepsis with or without bacterial co-infection, as well as in patients with encephalitis, myocarditis, and rhabdomyolysis.

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Section: How Influenza Triggers Ardsmentioning

confidence: 99%

Influenza virus-related critical illness: pathophysiology and epidemiology

2019

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“…In the academic sector of anti-inflammatory and anti-viral pharmacology, the NLRP3 inflammasome and NF-kB signaling both play essential role in the excessive inflammatory response stimulated by various types of viruses, including RSV, and are closely related to the viral-induced lung injury (Xu et al, 2015;Tate et al, 2016;Chen et al, 2017;Coates et al, 2017;Pinar et al, 2017;Ren et al, 2017;Sarvestani and McAuley, 2017). As for the application of effective treatment strategies against inflammatory response caused by RSV invasion, there has been no research paradigm until now.…”

Section: Introductionmentioning

confidence: 99%

Rhein Suppresses Lung Inflammatory Injury Induced by Human Respiratory Syncytial Virus Through Inhibiting NLRP3 Inflammasome Activation via NF-κB Pathway in Mice

et al. 2020

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“…Over-activation of the NLRP3 inflammasome has been linked to a hyper-inflammatory state and immunopathology in viral infection with minimal effect on the viral load [36][37][38][39] . However, nothing is known about NLRP3-mediated inflammation in bats.…”

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confidence: 99%

Dampened NLRP3-mediated inflammation in bats and implications for a special viral reservoir host

et al. 2019

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ResultsActivation of NLRP3 inflammasome is dampened in bat primary immune cells. Following priming (signal 1) and activation (signal 2), NLRP3 triggers assembly of the diffuse cytosolic apoptosis-associated speck-like protein containing a CARD (ASC) protein to form ASC specks 40 . These then recruit and activate caspase-1 to promote inflammatory cell death via pyroptosis and cleavage/secretion of the potent pro-inflammatory cytokine interleukin-1β (IL-1β) ( Fig. 1a).Bats are special in their ability to host emerging viruses. As the only flying mammal, bats endure high metabolic rates yet exhibit elongated lifespans. It is currently unclear whether these unique features are interlinked. The important inflammasome sensor, NLR family pyrin domain containing 3 (NLRP3), has been linked to both viral-induced and age-related inflammation. Here, we report significantly dampened activation of the NLRP3 inflammasome in bat primary immune cells compared to human or mouse counterparts. Lower induction of apoptosis-associated speck-like protein containing a CARD (ASC) speck formation and secretion of interleukin-1β in response to both 'sterile' stimuli and infection with multiple zoonotic viruses including influenza A virus (−single-stranded (ss) RNA), Melaka virus (PRV3M, double-stranded RNA) andMiddle East respiratory syndrome coronavirus (+ssRNA) was observed. Importantly, this reduction of inflammation had no impact on the overall viral loads. We identified dampened transcriptional priming, a novel splice variant and an altered leucine-rich repeat domain of bat NLRP3 as the cause. Our results elucidate an important mechanism through which bats dampen inflammation with implications for longevity and unique viral reservoir status.

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The H7N9 influenza A virus infection results in lethal inflammation in the mammalian host via the NLRP3-caspase-1 inflammasome

Cited by 42 publications

References 36 publications

Influenza virus-related critical illness: pathophysiology and epidemiology

Influenza virus-related critical illness: pathophysiology and epidemiology

Rhein Suppresses Lung Inflammatory Injury Induced by Human Respiratory Syncytial Virus Through Inhibiting NLRP3 Inflammasome Activation via NF-κB Pathway in Mice

Dampened NLRP3-mediated inflammation in bats and implications for a special viral reservoir host

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