Nuwan Gamage

TL;DR: A novel immune evasion mechanism of ASFV B175L to block type I IFN signaling by targeting STING and 2'3'-cyclic GMP-AMP (2′3′-cGAMP) is reported, opening a new avenue as one of theASFV virulent genes that can contribute to the advancement of AsFV live-attenuated vaccines.

TL;DR: Researchers developed a cell-adapted live attenuated vaccine candidate (ASFV-MEC-01) against African swine fever, showing 100% protection in pigs with high immune responses and no virus detection until 28 days post-inoculation, suggesting a safe and effective vaccine option.

Abstract: Regulation of the nuclear factor-kappa B (NF-kB) signaling pathway is a major host homeostatic mechanism for controlling hyper-inflammation or chronic inflammation. Despite extensive research, the regulatory factors of NF-kB signaling required to preserve homeostasis and control inflammatory disorders are not fully understood. Moreover, the role of MARCH2 in chronic inflammation models and the regulation of MARCH2 activation remain to be elucidated. We monitored disease severity and mortality in MARCH2−/− or MARCH2+/+ mice induced experimental colitis. Susceptibility to DSS-induced experimental colitis was determined by various methods, including Swiss roll assay and fluorescein isothiocyanate (FITC)-dextran treatment, respectively. RNA-sequencing was conducted to recognize the inflammatory response-related genes in the distal colon of colitis-induced mice. Enzyme-linked immunosorbent assay (ELISA) was used to measure the cytokines and chemokines with in vitro and in vivo samples. Affinity purification and LC-MS/MS analysis were used to identify the MARCH2 interacting proteins and posttranslational modifications. The underlying mechanism was elucidated using immunoblotting, co-immunoprecipitation, ubiquitination assay, and confocal microscopy. Here, we report that MARCH2−/− mice were more susceptible to experimental inflammatory bowel disease (IBD) due to the massive production of cytokines. Stimulation by inflammatory cytokines such as TNF induces dimerization of MARCH2 at a later stage and dimerized MARCH2 undergoes K63-linked autoubiquitination at lysine 127 and 238, which promotes NEMO recognition, ubiquitination and proteasomal degradation. We also show an interaction between MARCH2 and MARCH8 in resting cells that inhibits MARCH2 activation. Taken together, these findings provide new insights into the molecular mechanism of MARCH2 and suggest a crucial role of MARCH2 in the modulation of inflammation and cellular homeostasis. Our results indicate that MARCH2 plays a critical role in regulating NEMO/IKKγ under the inflammatory and resting conditions, thereby suppressing excessive or unexpected inflammatory responses. Our findings here not only demonstrate a biological role of MARCH2 in inflammatory signaling pathways but also provide a novel insight in the underlying mechanism.

TL;DR: This study evaluates the safety, efficacy, and transmission dynamics of ASFV-MEC-01, a novel live attenuated vaccine candidate against African swine fever, demonstrating its safety, protective efficacy, and phenotypic stability in pigs.