The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, 3052, Australia.
Department of Medical Biology, University of Melbourne, Melbourne, VIC, 3050, Australia.
Cell Death Dis. 2024 Jan 30;15(1):100. doi: 10.1038/s41419-024-06471-6.
Necroptosis, a type of lytic cell death executed by the pseudokinase Mixed Lineage Kinase Domain-Like (MLKL) has been implicated in the detrimental inflammation caused by SARS-CoV-2 infection. We minimally and extensively passaged a single clinical SARS-CoV-2 isolate to create models of mild and severe disease in mice allowing us to dissect the role of necroptosis in SARS-CoV-2 disease pathogenesis. We infected wild-type and MLKL-deficient mice and found no significant differences in viral loads or lung pathology. In our model of severe COVID-19, MLKL-deficiency did not alter the host response, ameliorate weight loss, diminish systemic pro-inflammatory cytokines levels, or prevent lethality in aged animals. Our in vivo models indicate that necroptosis is dispensable in the pathogenesis of mild and severe COVID-19.
细胞程序性坏死，一种由混合谱系激酶结构域样（MLKL）伪激酶执行的溶细胞性细胞死亡方式，已被牵连到由 SARS-CoV-2 感染引起的有害炎症中。我们最小限度和最大限度地传代了单个临床 SARS-CoV-2 分离株，在小鼠中建立了轻度和重度疾病模型，使我们能够剖析程序性坏死在 SARS-CoV-2 疾病发病机制中的作用。我们感染了野生型和 MLKL 缺陷型小鼠，并未发现病毒载量或肺部病理有显著差异。在我们的严重 COVID-19 模型中，MLKL 缺陷并未改变宿主反应、减轻体重减轻、降低全身促炎细胞因子水平，或防止老年动物的致死性。我们的体内模型表明，程序性坏死在轻度和重度 COVID-19 的发病机制中是可有可无的。
