Identifying host human products responsible for natural transformation of resistance traits in Acinetobacter spp
Project Number5SC3GM125556-07
Former Number5SC3GM125556-04
Contact PI/Project LeaderRAMIREZ, MARIA SOLEDAD
Awardee OrganizationCALIFORNIA STATE UNIVERSITY FULLERTON
Description
Abstract Text
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.
Public Health Relevance Statement
Project Narrative
Acinetobacter baumannii has posed a serious threat to human health worldwide. This project further
expands our observation that Human Serum Albumin (HSA) plays a role in the ability of A. baumannii
to emerge as a hard pathogen to be treated and will determine the mechanistic aspect of this host
pathogen interaction. Knowledge gained from this study would potentially identify new/alternative
targets much needed for the development of novel approaches to control A. baumannii antibiotic
resistance.
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