CASP4/11 Contributes to NLRP3 Activation and COVID-19 Exacerbation

Abstract

The SARS-CoV-2 infection triggers activation of the NLRP3 inflammasome, which promotes inflammation and aggravates the severe cases of COVID-19. Here, we reported that SARS-CoV-2 induces upregulation and activation of human Caspase-4/CASP4 (mouse Caspase-11/CASP11), and this process contributes to NLRP3 activation. In vivo infections performed in transgenic hACE2 humanized mice, deficient or sufficient for Casp11, indicate that hACE2 Casp11–/– mice were protected from disease development, with the increased pulmonary parenchymal area, reduced clinical score of the disease, and reduced mortality. Assessing human samples from fatal cases of COVID-19, we found that CASP4 was expressed in patient lungs and correlated with the expression of inflammasome components and inflammatory mediators, including CASP1, IL1B, IL18, and IL6. Collectively, our data establish that CASP4/11 promotes NLRP3 activation and disease pathology, revealing a possible target for therapeutic interventions to COVID-19.

The inflammatory microenvironment of the lung at the time of infection governs innate control of SARS-CoV-2 replication

“…For example, while the SCV2 spike and envelope proteins trigger inflammation through the binding of TLR2 and blockade of TLR2 signaling extended survival in mice 83,84 , we demonstrate that TLR2 is required for optimal control of viral replication in the lungs of mice early after infection. Similarly, TNFα, IL-1 and inflammasome pathways have been implicated in the deleterious effects of cytokine storms and cell death later in disease 89,92,[104][105][106] . We found that the pro-inflammatory TNFR1 pathway is critical for early viral control of SCV2 replication in mice and that pulmonary preconditioning with recombinant TNFα potently limits SCV2 viral titers in the lung.…”

“…. Moreover,105 and is also made available for use under a CC0 license. (which was not certified by peer review) is the author/funder.…”

Pulmonary inflammation and viral replication define distinct clinical outcomes in fatal cases of COVID-19

“…From day 0 to day 5, mice were evaluated for weight, temperature, and clinical score. The clinical score was measured following the previously described [ 47 ]. At the indicated time point, mice were euthanized, and lungs were collected for following analyses.…”