The Akt Pathway Inhibitor Degeulin Prevents Staphylococcal Enterotoxin B Induced Splenocyte Proliferation and Inflammation

Abstract

Staphylococcal Enterotoxin B (SEB) is considered a potential biological weapon. It is toxic by both inhalation and ingestion. Effects of ingestion include fever, vomiting and diarrhoea, while inhalation may additionally result in chest pain, dyspnoea, pulmonary oedema and respiratory failure. Severe exposure may be fatal and treatment relies on symptomatic support. At a cellular level, SEB up-regulates T-cell proliferation leading to a pathological inflammatory response. Deguelin, a rotenoid isolated from the African plant Mundulea sericea (Leguminosae), has been shown to reduce cellular proliferation by inhibiting the phosphoinositide 3-kinase/Akt (PI3K/Akt) signalling pathway. Using isolated murine splenocytes, we have demonstrated that treatment with deguelin reduces SEB inducing T cell proliferation by 60%. Deguelin treatment also decreased IL-2 and CCL2 secretion by splenocytes exposed to SEB. We demonstrate that targeting cellular proliferation can significantly reduce inflammation after SEB exposure and suggest that antiproliferatives may have a role as potential generic medical counter measures if superantigens are used as biological weapons.

Repurposing inhibitors of phosphoinositide 3-kinase as adjuvant therapeutics for bacterial infections

“…With these infections, inflammation and toxic damage can be mitigated by using PI3K inhibitors. For example, the natural PI3K inhibitor deguelin reduces Staphylococcal Enterotoxin B induction of T-cell proliferation toxicity (Whitfeild SJ et al, 2017) (Figure 5C). However, more work is needed to understand all the potential effects of PI3K treatment for bacterial infections.…”