Identifying host human products responsible for natural transformation of resistance traits in Acinetobacter spp

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Project summary/Abstract In recent years, a massive increase in the emergence of antibiotic resistant bacteria has been observed in clinical settings. Acinetobacter baumannii is one of the most widespread pathogens that cause these alarming infections. This bacterium is characterized by its extreme genome plasticity, facilitated by horizontal genetic transfer (HGT) processes. These characteristics are the cause of A. baumannii's remarkable ability to acquire antibiotic-resistance genes. Despite the relevance of foreign DNA acquisition to the pathobiology of A. baumannii, efforts to elucidate the mechanism/s involved in natural transformation have been scarce. We have recently demonstrated that the presence of human serum albumin (HSA) in extracellular host fluids correlates with an increase in A. baumannii natural transformation. We have also observed that the expression of the A. baumannii transcriptional regulator H-NS drops in response to HSA and that competence-associated gene expression increases in the h-ns mutant strains. This observation suggests that changes in cell's H-NS levels may play a central role in natural transformation. Hence, we hypothesize that the interaction of HSA with bacterial surface components triggers a regulatory signaling cascade that decreases H-NS expression, resulting in enhanced expression of genes involved in natural competence. To test this hypothesis, we will examine the interaction of HSA with A. baumannii cell surface proteins using the receptor activity- directed affinity tagging (re-tagging) technique (aim 1). To better understand the transcriptional response cascade responsible for HSA-mediated increase in transformation efficiency, we will determine the H-NS regulated genes associated with competence using complementary RNA-seq and ChIP-seq analyses in wild-type or h-ns mutants (aim 2). The studies proposed in this application will shed light on host adaptation processes leading to antibiotic resistance in this challenging pathogen of increasing relevance worldwide. We will provide new insights into bacterial components acting at the top of the HSA signaling cascade and H-NS's role in HSA-mediated transcriptional responses, leading to an increase in DNA-uptake. Future studies can then use these findings to develop novel approaches to treat severe Acinetobacter human infections, particularly those caused by emerging multidrug-resistant isolates.