AUTHOR=Alqahtani Maha , Ma Zhuo , Miller Jacob , Yu Jen , Malik Meenakshi , Bakshi Chandra Shekhar 

TITLE=Comparative analysis of absent in melanoma 2-inflammasome activation in Francisella tularensis and Francisella novicida

JOURNAL=Frontiers in Microbiology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2023.1188112

DOI=10.3389/fmicb.2023.1188112

ISSN=1664-302X

ABSTRACT=<p><italic>Francisella tularensis</italic> is a highly virulent Gram-negative bacterium that causes the fatal zoonotic disease tularemia. The mechanisms and signaling pathways leading to the absent in melanoma 2 (Aim2) inflammasome activation have been elegantly elucidated using <italic>Francisella novicida</italic> as a model. Although not pathogenic for humans, <italic>F</italic>. <italic>novicida</italic> can cause tularemia in mice, and the inflammatory response it triggers is the polar opposite to that observed in mice infected with <italic>F</italic>. <italic>tularensis</italic> strains. This study aimed to understand the mechanisms of Aim2 inflammasome activation in <italic>F</italic>. <italic>tularensis-</italic>infected macrophages. The results reveal that macrophages infected with the <italic>F</italic>. <italic>tularensis</italic> live vaccine strain (LVS) induce lower levels of Aim2-dependent IL-1β than those infected with <italic>F</italic>. <italic>novicida</italic>. The suppression/weak activation of Aim2 in <italic>F</italic>. <italic>tularensis</italic> LVS-infected macrophages is due to the suppression of the cGAS-STING DNA-sensing pathway. Furthermore, the introduction of exogenous <italic>F</italic>. <italic>tularensis</italic> LVS DNA into the cytosol of the <italic>F</italic>. <italic>tularensis</italic> LVS-infected macrophages, alone or in conjunction with a priming signal, failed to restore IL-1β levels similar to those observed for <italic>F</italic>. <italic>novicida-</italic>infected macrophages. These results indicated that, in addition to the bacterial DNA, DNA from some other sources, specifically from the damaged mitochondria, might contribute to the robust Aim2-dependent IL-1β levels observed in <italic>F</italic>. <italic>novicida</italic>-infected macrophages. The results indicate that <italic>F</italic>. <italic>tularensis</italic> LVS induces mitophagy that may potentially prevent the leakage of mitochondrial DNA and the subsequent activation of the Aim2 inflammasome. Collectively, this study demonstrates that the mechanisms of Aim2 inflammasome activation established for <italic>F</italic>. <italic>novicida</italic> are not operative in <italic>F</italic>. <italic>tularensis</italic>.</p>