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Virulent intracellular pathogens, such as the Salmonella species, engage numerous virulence factors to subvert host defence mechanisms to induce a chronic infection that leads to typhoid or exacerbation of other chronic inflammatory conditions. Here we show the role of the forkhead transcription factor FoxO3a during infection of mice with Salmonella typhimurium (ST). Although FoxO3a signalling does not affect the development of CD8 + T cell responses to ST, FoxO3a has an important protective role, particularly during the chronic stage of infection, by limiting the persistence of oxidative stress. Furthermore, FoxO3a signalling regulates ERK signalling in macrophages, which results in the maintenance of a proinflammatory state. FoxO3a signalling does not affect cell proliferation or cell death. Thus, these results reveal mechanisms by which FoxO3a promotes host survival during infection with chronic, virulent intracellular bacteria. FoxO3a signalling has limited influence over acute bacterial infection. Here the authors show that FoxO3a promotes survival of mice in response to chronic Salmonella typhimurium infection by restraining oxidative stress and ERK signalling.

Oncolytic viruses rewire the immune system and can lead to long-lasting antitumor defenses against primary and metastatic tumors. However, results from clinical studies have shown heterogeneity in responses suggesting that multiplexed approaches may be necessary to consistently generate positive outcomes in patients. To this end, we explored the combination of oncolytic rhabdovirus VSV∆51 with vanadium(V) dipicolinate derivatives, which have already been explored for their antidiabetic properties in animal models. The combination of vanadium-based dipicolinate compounds with VSV∆51 significantly increased viral replication and cytotoxicity in the human renal cell carcinoma cell line 786-0. The effects of three vanadium(V)-dipicolinate coordination complexes ([VO2dipic]−, [VO2dipic-OH]− and [VO2dipic-Cl]− with –OH or –Cl in the para position) were compared to that of the simple salts using spectroscopy and speciation profiles. Like the vanadate salts and the vanadyl cation, all dioxovanadium(V) dipicolinate complexes tested were found to increase viral infection and cytotoxicity when used in combination with VSV∆51. Viral sensitization is dependent on the vanadium since free dipicolinate ligands exerted no effect on viral infection and viability. The ability of these complexes to interact with interfaces and the stability of the complexes were evaluated under physiological conditions. Results indicate that these complexes undergo hydrolysis in cell culture media thereby generating vanadate. The vanadium dipicolinate derivatives in the context of immunovirotherapy shares similarities with previous studies exploring the antidiabetic properties of the compounds. The synergy between vanadium compounds and the oncolytic virus suggests that these compounds may be valuable in the development of novel and effective pharmaco-viral therapies.