Activation of the NLRP1B inflammasome by caspase-8.

Cleavage of the innate immune receptor NLRP1B by various microbial proteases causes the proteasomal degradation of its N-terminal fragment and the subsequent release of a C-terminal fragment that forms an inflammasome. We reported previously that metabolic stress caused by intracellular bacteria triggers NLRP1B activation, but the mechanism by which this occurs was not elucidated. Here we demonstrate that TLR4 signaling in metabolically stressed macrophages promotes the formation of a TRIF/RIPK1/caspase-8 complex. Caspase-8 activity, induced downstream of this TLR4 pathway or through a distinct TNF receptor pathway, causes cleavage and activation of NLRP1B, which facilitates the maturation of both pro-caspase-1 and pro-caspase-8. Thus, our findings indicate that caspase-8 and NLRP1B generate a positive feedback loop that amplifies cell death processes and promotes a pro-inflammatory response through caspase-1. The ability of NLRP1B to detect caspase-8 activity suggests that this pattern recognition receptor may play a role in the defense against a variety of pathogens that induce apoptosis.

Perspectives of Older Adults on COVID-19 and Influenza Vaccination in Ontario, Canada.

INTRODUCTION/OBJECTIVES: Addressing vaccine hesitancy has become an increasingly important public health priority in recent years. There is a paucity of studies that have focused on vaccine hesitancy among older adults, who are known to be at greater risk of complications from infections such as COVID-19. We aim to explore the attitudes and beliefs of older adults regarding COVID-19 and influenza vaccines in Toronto, Ontario. METHODS: Older adults enrolled in the Student Senior Isolation Prevention Partnership (SSIPP) program at the University of Toronto were contacted to participate in a phone survey and semi-structured interview. Survey data was analyzed descriptively, and attitude toward vaccination was compared between sociodemographic groups by using Fisher's exact test. Interview audio files were transcribed verbatim and analyzed inductively for themes and sub-themes. RESULTS: All thirty-three (100%) older adults reported that they had received the first and second doses of the COVID-19 vaccine. Twenty-six (78.8%) participants reported intent to get vaccinated against influenza or had already received the influenza vaccine that year. Notably, only 2 out 7 (28.6%) individuals who did not plan to get vaccinated against influenza believed that vaccines offered by health providers are beneficial and only 3 out of 7 (42.9%) agreed that getting vaccines is a good way to protect oneself from disease. No other significant differences in attitudes among participants were found when compared by gender, ethnicity, or education level. The qualitative data analysis of interview transcripts identified 5 themes that impact vaccine decision making: safety, trust, mistrust, healthcare experience, and information dissemination and education. CONCLUSIONS: Our data showed that older adults in the SSIPP program generally had positive views toward vaccination, especially toward the COVID-19 vaccines. However, several concerns regarding the effectiveness of the vaccines were brought up in interviews, such as the speed at which the vaccines were produced and the inconsistency in government messaging.

Canonical and noncanonical inflammasomes in intestinal epithelial cells.

Inflammasomes are cytosolic, multimeric protein complexes capable of activating pro-inflammatory cytokines such as IL-1ß and IL-18, which play a key role in host defence. Inflammasome components are highly expressed in the intestinal epithelium. In recent years, studies have begun to demonstrate that epithelial-intrinsic inflammasomes play a critical role in regulating epithelial homeostasis, both by defending the epithelium from pathogenic insult and through the regulation of the mucosal environment. However, the majority of research regarding inflammasome activation has focused on professional immune cells, such as macrophages. Here, we present an overview of the current understanding of inflammasome function in epithelial cells and at mucosal surfaces and, in particular, in the intestine.

Conserved Pbp1/Ataxin-2 regulates retrotransposon activity and connects polyglutamine expansion-driven protein aggregation to lifespan-controlling rDNA repeats.

Ribosomal DNA (rDNA) repeat instability and protein aggregation are thought to be two major and independent drivers of cellular aging. Pbp1, the yeast ortholog of human ATXN2, maintains rDNA repeat stability and lifespan via suppression of RNA-DNA hybrids. ATXN2 polyglutamine expansion drives neurodegeneration causing spinocerebellar ataxia type 2 and promoting amyotrophic lateral sclerosis. Here, molecular characterization of Pbp1 revealed that its knockout or subjection to disease-modeling polyQ expansion represses Ty1 (Transposons of Yeast) retrotransposons by respectively promoting Trf4-depedendent RNA turnover and Ty1 Gag protein aggregation. This aggregation, but not its impact on retrotransposition, compromises rDNA repeat stability and shortens lifespan by hyper-activating Trf4-dependent turnover of intergenic ncRNA within the repeats. We uncover a function for the conserved Pbp1/ATXN2 proteins in the promotion of retrotransposition, create and describe powerful yeast genetic models of ATXN2-linked neurodegenerative diseases, and connect the major aging mechanisms of rDNA instability and protein aggregation.