Abstract
Not so long ago, when we talked about cell death, we spoke of either necrosis or apoptosis, the latter being, at the time, the only known form of programmed cell death. In recent years, the cell death field has exploded to include numerous other forms of programmed cell death such as pyroptosis, NETosis, necroptosis, oxeiptosis, ferroptosis, among others. Most of these types of cell death are part of normal homeostatic or regulatory processes aimed at maintaining balance within an organism at various stages of development or within healthy versus disease states.
Historically, apoptosis has received the most attention, partly because it was the first form of programmed cell death discovered, but its relevance was enhanced when it was shown to have relevance in both the control and pathogenesis of cancer development. Within the fields of virology and viral immunology, apoptosis became a hot topic because many viruses were found to either induce or prevent apoptotic cell death as a mechanism to either promote pathogenesis or inhibit the ensuing immune response.
More recently, these various forms of cell death are beginning to be classified as either immunogenic or nonimmunogenic based on whether or not the dying cell releases antigens that would then be visible or invisible to the immune system. Probably the most immunogenic form of programmed cell death is pyroptosis, which is an inflammatory type of programmed cell death that starts with the activation and assembly of an inflammasome and ends with cell lysis and release of pro-inflammatory cytokines, such as interleukin (IL)-1β and IL-18. Pyroptosis was not discovered until 1997, and the first studies of pyroptosis in the context of virus infection were published in 2009. By 2021, there were almost 1,500 articles published on pyroptosis, and almost 400 of these involved viruses.
On the topic of virus-induced inflammasome activation and pyroptosis, many fascinating questions remain unanswered. For many years, the NLRP3 inflammasome was referred to as “the” inflammasome, because it was the most commonly studied, but we now know there are numerous other inflammasome sensors, such as AIM2, NLRP16, and NLRC4, among others. In some cases, we know that specific viral proteins, or the viral genome itself, might activate the inflammasome, but for other viruses, it is not so clear. It also appears that some viruses can activate multiple inflammasome sensors, and the old notion that RNA viruses activate NLRP3 and DNA viruses use AIM2 is now proving to be a false dichotomy with many exceptions.
Another level of complexity emerges if we consider whether there is a point of no return for inflammasome activation leading to pyroptotic cell death, that is, is pyroptosis inevitable once an inflammasome has been activated, or is cell death only the end result when inflammasomes are triggered by viruses? We also know there can be cross talk between numerous forms of programmed cell death in the context of a single virus infection, and fairly recently, the term PANoptosis has been coined to describe a situation in which pyroptosis, apoptosis, and necroptosis are all taking place simultaneously.
These many forms of programmed cell death are also active outside the realm of viruses among multiple species and in various disease states, but for this special issue, we aimed to focus on virus-induced programmed cell death. In this issue, we present a collection of articles that provide insight into topics such as PANoptosis, Toll-like receptors, severe fever with thrombocytopenia syndrome, inflammatory cytokines, programmed death 1 and IL-22 gene polymorphisms and cytokine storms in the context of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), human papilloma virus, bunya virus, as well as lymphopenia in cancer patients infected with SARS-CoV-2.
We hope that this collection of work will represent a valuable resource and spark additional interest in virus-induced cell death, and we sincerely thank all authors for their outstanding work and the reviewers for volunteering their time during this disruptive pandemic.