The PhoPR-mediated response to phosphate limitation (PHO response) in Bacillus subtilis subsp subtilis is amplified and maintained by reducing the level of Lipid V composed of poly(glycerol phosphate), a wall teichoic acid (WTA) biosynthetic intermediate that inhibits PhoR autokinase activity. However, the reduction in Lipid V level is effected by activated PhoP∼P, raising the question of how the PHO response is first initiated. Furthermore, that WTA is composed of poly(ribitol phosphate) in Bacillus subtilis subsp spizizenii prompted an investigation of how the PHO response is regulated in that bacterium. We report that the PHO responses of B. subtilis subsp subtilis and subsp spizizenii are distinct. The PhoR kinases of the two B. subtilis subspecies are functionally equivalent and are activated either by the TagA/TarA or TagB/TarB enzyme product. However, they are inhibited by Lipid V composed of poly(glycerol phosphate) but not by Lipid V composed of poly(ribitol phosphate). Therefore, the distinctive PHO responses of these B. subtilis subspecies stem from the differential sensitivity of PhoR kinases to the polyol composition of Lipid V and from the genomic organization of WTA biosynthetic genes and the regulation of their expression.

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Background: Influenza is a global cause of morbidity and mortality and a significant risk for a future pandemic infection. Host hyperinflammation, similar to that seen in COVID-19, may occur in response to influenza virus pneumonia, with Janus kinase (JAK) signalling and proinflammatory cytokines Interleukin (IL)-1 and IL-6 involved. Immune modulation treatment of hospitalised and critically ill COVID-19 patients, including with IL-6 and JAK inhibitors, has been found to be beneficial. Significant interest exists in the use of immunomodulatory agents targeting these pathways in the treatment of severe influenza pneumonia. Methods: We conducted a review with both systematic and narrative methods to assess whether, in patients with severe influenza pneumonia, treatment with immunomodulatory agents targeting IL-1, IL-6 or JAK signalling, in comparison to no immune modulation, is beneficial and improves clinical outcomes. Results: Our systematic search screened 5409 records and found no randomised controlled trials of IL-1, IL-6 or JAK immunomodulatory agents in patients with severe influenza pneumonia. To support this systematic search, we provide a narrative review of the biological rationale, previous use of these agents, including in hospitalised patients with COVID-19, and an overview of their safety profiles. Conclusions: Although immune modulation has proven successful in treating hospitalised and critically ill patients with COVID-19 and a biological rationale exists for testing these agents in influenza, no agents targeting IL-1, IL-6 or JAK signalling have been assessed in randomised controlled trials of patients with severe influenza pneumonia. This highlights a significant evidence gap.