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New NIH Grant to Study the Effect of Alcohol on Sepsis

Dr. Vachharajani and her team will study the immuno-metabolic mechanisms that trigger dysfunction in alcohol consumption with sepsis to identify new therapeutic targets for expanded treatments.

11/08/2021




Vidula Vachharajani, MD, has received a five-year, nearly $2 million grant from the National Institutes of Health to study how alcohol represses immune responses during sepsis.   

Sepsis and septic shock are the leading causes of death in hospitalized patients in the United States. Risk factors for sepsis include obesity and alcohol consumption, which are the top two co-morbidities for the disease, followed by diet and age.  

“Currently there are no molecular-based therapies for sepsis,” said Dr. Vachharajani, a critical care physician and research staff in the Department of Inflammation & Immunity. “We have supportive care but not specific therapies because the immune response to sepsis is very dynamic and complicated.” 

The primary goal of the study is to understand how alcohol consumption changes the energy sources that immune cells use to power themselves and how they respond to pathogen invasion during sepsis. It will build on Dr. Vachharajani’s previous research—done in collaboration with Laura Nagy, PhD, and the Northern Ohio Alcohol Center—which revealed that alcohol consumption affects survival in preclinical sepsis models. Interestingly, they also found that mice that consumed alcohol showed increased SIRT2 expression along with a muted immune response to sepsis.   

In previous studies, Dr. Vachharajani found that immunosuppression in obese mice with late sepsis was associated with increased expression of the molecule SIRT2 (sirtuin 2). She published results in PLoS ONE showing that SIRT2 does indeed modulate inflammation in obese mice with sepsis and in Cells outlining the detrimental effects of increased SIRT2 expression in high fat-exposed immune cells called macrophages.   

The secondary goal of the new project is to further understand the role of SIRT2 and how it drives immune cell behavior. The team will use mouse and cell models of sepsis to test the hypothesis that SIRT2 acts as an immune repressor in alcohol-drinking mice. 

“The study itself is about immune-metabolism, which is ultimately what immune cells use as a fuel-substrate. This ‘food’ affects how cells behave, react to pathogens and whether they are pro-inflammatory or anti-inflammatory,” said. Dr. Vachharajani. “We will continue to study their metabolic responses and pathways with the goal of finding new therapies to treat sepsis.”  




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