Burkholderia cenocepacia is an opportunistic pathogen that causes severe infections of the cystic fibrosis (CF) lung. To acquire iron, B. cenocepacia secretes the Fe(III)-binding compound, ornibactin. Genes for synthesis and utilisation of ornibactin are served by the iron starvation (IS) extracytoplasmic function (ECF) σ factor, OrbS. Transcription of orbS is regulated in response to the prevailing iron concentration by the ferric uptake regulator (Fur), such that orbS expression is repressed under iron-sufficient conditions. Here we show that, in addition to Fur-mediated regulation of orbS, the OrbS protein itself responds to intracellular iron availability. Substitution of cysteine residues in the C-terminal region of OrbS diminished the ability to respond to Fe(II) in vivo. Accordingly, whilst Fe(II) impaired transcription from and recognition of OrbS-dependent promoters in vitro by inhibiting the binding of OrbS to core RNA polymerase (RNAP), the cysteine-substituted OrbS variant was less responsive to Fe(II). Thus, the cysteine residues within the C-terminal region of OrbS contribute to an iron-sensing motif that serves as an on-board ‘anti-σ factor’ in the presence of Fe(II). A model to account for the presence two regulators (Fur and OrbS) that respond to the same intracellular Fe(II) signal to control ornibactin synthesis and utilisation is discussed.
Issue: Nov-Dec 2020 Deploying COVID-19 vaccines once they are available is going to be an unprecedented administrative and logistical challenge. This paper proposes a plan to vaccinate 80% of India’s population by December 2021. We envision this process to be divided into four main stages viz., estimating the need, securing vaccine supply, distributing the vaccines, and post-market surveillance. Broadly, we suggest that essential workers be prioritised for vaccination in the first phase followed by everyone else. We recommend that the government issue a model contract to build manufacturer trust and incentivise ramping up manufacturing capacity. Vaccines can be priced as per market rates with the government subsidising the cost to necessary recipients to ensure equitable access. Along with public private partnerships and open markets, the government must leverage administrative capacities of Election Commission of India to roll out a nationwide vaccination drive for maximising vaccine coverage. Finally, we recommend post-market vaccine surveillance strategies to obtain data on adverse events and tweak vaccine deployments, when necessary.
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