Insight to Pyroptosis in Viral Infectious Diseases

Background: Pyroptosis is defined as programmed necrosis executed by gasdermin D or E (GSDMD or GSDME), which punches cellular membrane. Morphologically, pyroptosis is characterized by cell swelling and cell membrane rupture, leading to the release of cellular contents that triggers intense inflammatory response. More and more studies have found that pyroptosis may be involved in the pathogenesis of viral infection, which may be a determinant for inflammation observed in most viral diseases. Objective: This paper aims to summarize the roles of pyroptosis in the pathogenesis of viral infectious diseases and to provide potential drug targets for the treatment of viral diseases, which will contribute to medical research and public health. Measures: This paper mainly summarizes pyroptosis occurring in diseases caused by different viruses, including human immunodeficiency virus, hepatitis virus, enterovirus, influenza virus and dengue fever virus. Meanwhile, the reported mechanism underlying pyroptosis mediating pathogenesis of these viral diseases will also be described. Conclusion: Current studies have shown that pyroptosis is a double-edged sword in viral infectious diseases. On one hand, pyroptosis leads to pathogenic inflammation of many viral infectious diseases which aggravate tissue damage initiated by viral infection, and blocking proptosis usually relieves the inflammation, which exerts therapeutic effects on viral diseases. On the other hand, moderating pyroptosis can contribute to defense against pathogen infection by releasing immune epitopes and inducing antiviral immune response.

Epizootic, Endemic and Pandemic Zoonotic Viral Infections

More than 60% human infectious diseases have zoonotic origin. Cross species transmission of pathogens is a continuous, dynamic process that occurs throughout the world, giving rise to epizootic (temporary, limited infection), endemic (on-going infection limited to a defined geographic region) and pandemic viral infections (infection spreading to every part of the world) like the current COVID-19 pandemic, which depends on the existing conditions on the ground. In Nov 2021, sudden mortality of numerous migrating demoiselle cranes was reported from their resting site near Jodhpur, Rajasthan. The symptomatic cranes became gradually weak and were unable to fly. They eventually fell dead which caused concern locally, given the current prevailing SARS-CoV-2 pandemic situation the world over. By the end of Dec 2021, the number of cranes with mortality and morbidity reduced, making it a temporary “epizootic infection”. Molecular diagnosis carried out at a specialized laboratory identified the etiological agent to be the highly pathogenic Avian Influenza Virus H5N1 (HPAIV), which has been responsible for morbidity of avian species from different parts of the world. There was no report of spreading the H5N1 AIV infection from the infected migratory cranes to nearby chicken farms or pig farms for now. In the absence of vaccines against the highly pathogenic H5N1 AIVs, and the inherent ability of influenza viruses, both avian AIV and human IAVs to constantly mutate its envelope gene or the surface antigens, resulting from the error-prone nature of the viral RNA Polymerase enzyme are the roadblocks for development of a universal, broad-spectrum influenza vaccine. Even when such a universal vaccine against H5N1 is available, vaccinating a large number of wild migratory cranes would be difficult. However, it is possible and indeed necessary to vaccinate chickens in poultry farms and pigs in farms that raise pigs for human consumption.

3D engineered tissue models for studying human-specific infectious viral diseases

Viral infections cause damage to various organ systems by inducing organ-specific symptoms or systemic multi-organ damage.Depending on the infection route and virus type,infectious diseases are classified as respiratory,nervous,immune,digestive,or skin infections.Since these infectious diseases can widely spread in the com-munity and their catastrophic effects are severe,identification of their causative agent and mechanisms un-derlying their pathogenesis is an urgent necessity.Although infection-associated mechanisms have been studied in two-dimensional(2D)cell culture models and animal models,they have shown limitations in organ-specific or human-associated pathogenesis,and the development of a human-organ-mimetic system is required.Recently,three-dimensional(3D)engineered tissue models,which can present human organ-like physiology in terms of the 3D structure,utilization of human-originated cells,recapitulation of physiological stimuli,and tight cell–cell interactions,were developed.Furthermore,recent studies have shown that these models can recapitulate infection-associated pathologies.In this review,we summarized the recent advances in 3D engineered tissue models that mimic organ-specific viral infections.First,we briefly described the limitations of the current 2D and animal models in recapitulating human-specific viral infection pathology.Next,we provided an overview of recently reported viral infection models,focusing particularly on organ-specific infection pathologies.Finally,a future perspective that must be pursued to reconstitute more human-specific infectious diseases is presented.