Eukaryotic cells can initiate several distinct programmes of self-destruction, and the nature of the cell death process (non-inflammatory or proinflammatory) instructs responses of neighbouring cells, which in turn dictates important systemic physiological outcomes. Pyroptosis, or caspase 1-dependent cell death, is inherently inflammatory, is triggered by various pathological stimuli, such as stroke, heart attack or cancer, and is crucial for controlling microbial infections. Pathogens have evolved mechanisms to inhibit pyroptosis, enhancing their ability to persist and cause disease. Ultimately, there is a competition between host and pathogen to regulate pyroptosis, and the outcome dictates life or death of the host.Cells can die through distinct biochemical pathways that produce different morphological and physiological outcomes. Apoptosis is perhaps the most widely recognized programme of cell death, and is mechanistically defined by the requirement for particular cysteinedependent aspartate-specific proteases, or caspases, which produce an orchestrated disassembly of the cell 1 . Apoptotic caspases cleave cellular substrates, resulting in the characteristic features of apoptosis, which include cytoplasmic and nuclear condensation, DNA cleavage and maintenance of an intact plasma membrane. The contents of apoptotic cells are packaged into membrane-enclosed apoptotic bodies, which are targeted for phagocytosis and removal in vivo, resulting in an absence of inflammation 2 (BOX 1).Although apoptosis was the first well-recognized programme of eukaryotic cell death, 'programmed cell death' is broadly applied to several endogenous genetically defined pathways in which the cell plays an active part in its own destruction 3 . Other cell death programmes include autophagy, oncosis and caspase 1-dependent programmed cell death (also known as pyroptosis). Pyroptosis is a more recently identified pathway of host cell death that is stimulated by a range of microbial infections (for example, Salmonella, Francisella and Legionella) and non-infectious stimuli, including host factors produced during myocardial infarction 4 . Caspase 1 was first recognized as a protease that processes the inactive precursors of interleukin 1β (IL-1β) and IL-18 into mature inflammatory cytokines, and was initially called interleukin IL-1β-converting enzyme 5 . However, caspase 1 activation can result not only in the production of activated inflammatory cytokines, but also rapid cell death characterized by plasma-membrane rupture and release of proinflammatory intracellular contents 6,7 . Caspase 1-dependent cell death is a programmed process of cellular self-destruction mediated by caspases, and therefore was not initially distinguished from apoptosis [8][9][10][11] . However, the mechanism, characteristics and outcome of caspase 1-dependent cell death are distinct from apoptosis 6,7,12 . Thus, the term pyroptosis Correspondence to B.T.C. cookson@u.washington.edu. (from the Greek 'pyro', relating to fire or fever, and 'ptosis', meanin...

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Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of an ongoing pandemic, with increasing deaths worldwide. To date, documentation of the histopathological features in fatal cases of the disease caused by SARS-CoV-2 (COVID-19) has been scarce due to sparse autopsy performance and incomplete organ sampling. We aimed to provide a clinicopathological report of severe COVID-19 cases by documenting histopathological changes and evidence of SARS-CoV-2 tissue tropism. Methods In this case series, patients with a positive antemortem or post-mortem SARS-CoV-2 result were considered eligible for enrolment. Post-mortem examinations were done on 14 people who died with COVID-19 at the King County Medical Examiner's Office (Seattle, WA, USA) and Snohomish County Medical Examiner's Office (Everett, WA, USA) in negative-pressure isolation suites during February and March, 2020. Clinical and laboratory data were reviewed. Tissue examination was done by light microscopy, immunohistochemistry, electron microscopy, and quantitative RT-PCR. Findings The median age of our cohort was 73·5 years (range 42–84; IQR 67·5–77·25). All patients had clinically significant comorbidities, the most common being hypertension, chronic kidney disease, obstructive sleep apnoea, and metabolic disease including diabetes and obesity. The major pulmonary finding was diffuse alveolar damage in the acute or organising phases, with five patients showing focal pulmonary microthrombi. Coronavirus-like particles were detected in the respiratory system, kidney, and gastrointestinal tract. Lymphocytic myocarditis was observed in one patient with viral RNA detected in the tissue. Interpretation The primary pathology observed in our cohort was diffuse alveolar damage, with virus located in the pneumocytes and tracheal epithelium. Microthrombi, where observed, were scarce and endotheliitis was not identified. Although other non-pulmonary organs showed susceptibility to infection, their contribution to the pathogenesis of SARS-CoV-2 infection requires further examination. Funding None.

SummarySalmonella enterica serovar Typhimurium invades host macrophages and induces a unique caspase-1-dependent pathway of cell death termed pyroptosis, which is activated during bacterial infection in vivo . We demonstrate DNA cleavage during pyroptosis results from caspase-1-stimulated nuclease activity. Although poly(ADP-ribose) polymerase (PARP) activation by fragmented DNA depletes cellular ATP to cause lysis during oncosis, the rapid lysis characteristic of Salmonella -infected macrophages does not require PARP activity or DNA fragmentation. Membrane pores between 1.1 and 2.4 nm in diameter form during pyroptosis of host cells and cause swelling and osmotic lysis. Pore formation requires host cell actin cytoskeleton rearrangements and caspase-1 activity, as well as the bacterial type III secretion system (TTSS); however, insertion of functional TTSS translocons into the host membrane is not sufficient to directly evoke pore formation. Concurrent with pore formation, inflammatory cytokines are released from infected macrophages. This mechanism of caspase-1-mediated cell death provides additional experimental evidence supporting pyroptosis as a novel pathway of inflammatory programmed cell death.