Salmonella escapes adaptive immune response via SIRT2 mediated modulation of innate immune response in dendritic cells

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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. Salmonella enterica is the cause of infectious diseases which ranges from self-limiting diarrhoea to fatal systemic illness like typhoid. During its pathogenesis, Salmonella survives inside dendritic cells (DCs) by suppressing antigen presentation, thereby successfully evading host response. Although, various previous studies have focused on the role of host epigenetic modification during Salmonella pathogenesis, till date, there has been no study on the role of SIRT2 in Salmonella infection. Here, we show that Salmonella upregulates SIRT2 expression in DCs, which in turn upregulates nitric oxide production by enhancing nuclear translocation of NFκB. Being a suppressor of T cell proliferation as well as an antimicrobial agent, nitric oxide regulation can affect Salmonella infection in both positive and negative ways, respectively. This study shows the trade-off made by Salmonella where, in vitro infection mediated upregulation of SIRT2 enhances antimicrobial response, but simultaneous higher intracellular NO inhibits T cell response leading to impaired antigen presentation and successful pathogenesis. Since inhibition of SIRT2 gives a fitness advantage to the infected host leading to better clearance of the pathogen, our findings may have further implications in the development of novel therapeutics.
Funding Information
  • Department of Atomic Energy, Government of India (DAE00198)

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