Abstract
Salmonella being a successful pathogen, employs a plethora of immune evasion mechanisms. This contributes to pathogenesis, persistence and also limits the efficacy of available treatment. All these contributing factors call upon for new drug targets against Salmonella. For the first time, we have demonstrated that Salmonella upregulates sirtuin 2 (SIRT2), an NAD+ dependent deacetylase in dendritic cells (DC). SIRT2 upregulation results in translocation of NFκB p65 to the nucleus. This further upregulates NOS2 transcription and nitric oxide (NO) production. NO subsequently shows antibacterial activity and suppresses T cell proliferation. NOS2 mediated effect of SIRT2 is further validated by the absence of effect of SIRT2 inhibition in NOS2-/- mice. Inhibition of SIRT2 increases intracellular survival of the pathogen and enhances antigen presentation in vitro. However, in vivo SIRT2 inhibition shows lower bacterial organ burden and reduced tissue damage. SIRT2 knockout mice also demonstrate reduced bacterial organ burden compared to wild-type mice. Collectively, our results prove the role of SIRT2 in Salmonella pathogenesis and the mechanism of action. This can aid in designing of host-targeted therapeutics directed towards inhibition of SIRT2.
Highlights
Sirtuins are a family of proteins originally discovered in yeast as a homolog to silent information regulator 2 gene (Sir2)
Salmonella enterica is the cause of infectious diseases which ranges from self-limiting diarrhoea to fatal systemic illness like typhoid
Salmonella survives inside dendritic cells (DCs) by suppressing antigen presentation, thereby successfully evading host response
Summary
Sirtuins are a family of proteins originally discovered in yeast as a homolog to silent information regulator 2 gene (Sir). Pioneering studies on Sir in Saccharomyces cerevisiae demonstrate its deacetylase function which is essential for silencing transcription at silent mating loci, telomeres and recombination in rDNA [1]. Mammalian homologs of Sir belong to HDAC-III family and are of seven types (SIRT1-7). All SIRTs share a conserved NAD+ binding domain, a catalytic domain and a variable C- terminal domain but shows differential subcellular localization. SIRT1 shows nuclear and cytoplasmic localization, SIRT2 is predominantly present in the cytoplasm but can translocate to the nucleus upon external triggers. SIRT3, SIRT4 and SIRT5 show mitochondrial localization. SIRT6 is a chromatin-associated deacetylase and SIRT7 is present in the nucleolus. A large body of literature has suggested the role of SIRTs in aging and age-related pathologies [3]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
