Urinary tract colonization is enhanced by a plasmid that regulates uropathogenic Acinetobacter baumannii chromosomal genes

Venanzio, Gisela Di; Flores-Mireles, Ana L.; Calix, Juan J.; Haurat, M. Florencia; Scott, Nichollas E.; Palmer, Lauren D.; Potter, Robert F.; Hibbing, Michael E.; Friedman, Laura; Wang, Bin; Dantas, Gautam; Skaar, Eric P.; Hultgren, Scott J.; Feldman, Mario F.

doi:10.1038/s41467-019-10706-y

Cited by 105 publications

(147 citation statements)

References 77 publications

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“…Although research on A. baumannii infections has primarily focused on pneumonia and bloodstream infections, recent claims are that one in five A. baumannii strains are isolated from urinary sites [51]. A. baumannii occasionally causes urinary tract infections (UTIs), especially with indwelling urinary catheters [4], and was responsible for 1.6% of ICU-acquired UTIs in one study [52].…”

Section: Urinary Tract Infectionsmentioning

confidence: 99%

Insights into Acinetobacter baumannii: A Review of Microbiological, Virulence, and Resistance Traits in a Threatening Nosocomial Pathogen

2020

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Being a multidrug-resistant and an invasive pathogen, Acinetobacter baumannii is one of the major causes of nosocomial infections in the current healthcare system. It has been recognized as an agent of pneumonia, septicemia, meningitis, urinary tract and wound infections, and is associated with high mortality. Pathogenesis in A. baumannii infections is an outcome of multiple virulence factors, including porins, capsules, and cell wall lipopolysaccharide, enzymes, biofilm production, motility, and iron-acquisition systems, among others. Such virulence factors help the organism to resist stressful environmental conditions and enable development of severe infections. Parallel to increased prevalence of infections caused by A. baumannii, challenging and diverse resistance mechanisms in this pathogen are well recognized, with major classes of antibiotics becoming minimally effective. Through a wide array of antibiotic-hydrolyzing enzymes, efflux pump changes, impermeability, and antibiotic target mutations, A. baumannii models a unique ability to maintain a multidrug-resistant phenotype, further complicating treatment. Understanding mechanisms behind diseases, virulence, and resistance acquisition are central to infectious disease knowledge about A. baumannii. The aims of this review are to highlight infections and disease-producing factors in A. baumannii and to touch base on mechanisms of resistance to various antibiotic classes.

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Section: Urinary Tract Infectionsmentioning

confidence: 99%

Insights into Acinetobacter baumannii: A Review of Microbiological, Virulence, and Resistance Traits in a Threatening Nosocomial Pathogen

2020

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“…One subset of strains secretes Hcp under standard laboratory conditions, indicating that they possess a constitutively active (or offensive) T6SS. A second subset of strains possess a silenced T6SS because they harbor a family of multidrug-resistance plasmids named large conjugative plasmids (LCPs), which transcriptionally repress the T6SS locus (40)(41)(42). The final subset of A. baumannii strains expresses T6SS-related genes and does not harbor an LCP but does not secrete Hcp under standard laboratory conditions (39,(43)(44)(45).…”

mentioning

confidence: 99%

The Tip of the VgrG Spike Is Essential to Functional Type VI Secretion System Assembly in Acinetobacter baumannii

Lopez

Feldman

2020

mBio

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The type VI secretion system (T6SS) is a critical weapon in bacterial warfare between Gram-negative bacteria. Although invaluable for niche establishment, this machine represents an energetic burden to its host bacterium. Acinetobacter baumannii is an opportunistic pathogen that poses a serious threat to public health due to its high rates of multidrug resistance. In some A. baumannii strains, the T6SS is transcriptionally downregulated by large multidrug resistance plasmids. Other strains, such as the clinical isolate AbCAN2, express T6SS-related genes but lack T6SS activity under laboratory conditions, despite not harboring these plasmids. This suggests that alternative mechanisms exist to repress the T6SS. Here, we used a transposon mutagenesis approach in AbCAN2 to identify novel T6SS repressors. Our screen revealed that the T6SS of this strain is inhibited by a homolog of VgrG, an essential structural component of all T6SSs reported to date. We named this protein inhibitory VgrG (VgrGi). Biochemical and in silico analyses demonstrated that the unprecedented inhibitory capability of VgrGi is due to a single amino acid mutation in a widely conserved C-terminal domain of unknown function, DUF2345. We also show that unlike in other bacteria, the C terminus of VgrG is essential for functional T6SS assembly in A. baumannii. Our study provides insight into the architectural requirements underlying functional assembly of the T6SS of A. baumannii. We propose that T6SS-inactivating point mutations are beneficial to the host bacterium, since they eliminate the energy cost associated with maintaining a functional T6SS, which appears to be unnecessary for A. baumannii virulence. IMPORTANCE Despite the clinical relevance of A. baumannii, little is known about its fundamental biology. Here, we show that a single amino acid mutation in VgrG, a critical T6SS structural protein, abrogates T6SS function. Given that this mutation was found in a clinical isolate, we propose that the T6SS of A. baumannii is probably not involved in virulence; this idea is supported by multiple genomic analyses showing that the majority of clinical A. baumannii strains lack proteins essential to the T6SS. We also show that, unlike in other species, the C terminus of VgrG is a unique architectural requirement for functional T6SS assembly in A. baumannii, suggesting that over evolutionary time, bacteria have developed changes to their T6SS architecture, leading to specialized systems.

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“…Often, controlled drug delivery systems rely on sustained passive delivery, although this often results in exposure of bacterial pathogens to sub-lethal antimicrobial doses. Additionally, the release of antimicrobial compounds may also be hindered by the deposition of host proteins onto the catheter due to inflammatory response caused by the urinary catheterization [64,65,150,[166][167][168]. All of these together may explain why promising coating technologies in vitro yield mixed results when tested in clinical trials [102].…”

Section: Challenges In Fighting Cautismentioning

confidence: 99%

“…By understanding the host response to urinary catheterization and infection, more efficient coating and modifications can be developed. Recently, it was found that one of the host proteins released by the inflammatory response, fibrinogen, is essential for biofilm formation in vivo by several prevalent uropathogens such as enterococcal strains, methicillin-resistant S. aureus, Acinetobacter baumannii, and even the fungal pathogen C. albicans [64,65,150,[166][167][168]. The fact that different groups of pathogens use host proteins for biofilm formation suggests a common pathway for colonization in the catheterized environment.…”

Section: Challenges In Fighting Cautismentioning

confidence: 99%

Urinary Catheter Coating Modifications: The Race against Catheter-Associated Infections

Andersen

Flores-Mireles

2019

Coatings

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Urinary catheters are common medical devices, whose main function is to drain the bladder. Although they improve patients' quality of life, catheter placement predisposes the patient to develop a catheter-associated urinary tract infection (CAUTI). The catheter is used by pathogens as a platform for colonization and biofilm formation, leading to bacteriuria and increasing the risk of developing secondary bloodstream infections. In an effort to prevent microbial colonization, several catheter modifications have been made ranging from introduction of antimicrobial compounds to antifouling coatings. In this review, we discuss the effectiveness of different coatings in preventing catheter colonization in vitro and in vivo, the challenges in fighting CAUTIs, and novel approaches targeting host-catheter-microbe interactions.

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Urinary tract colonization is enhanced by a plasmid that regulates uropathogenic Acinetobacter baumannii chromosomal genes

Cited by 105 publications

References 77 publications

Insights into Acinetobacter baumannii: A Review of Microbiological, Virulence, and Resistance Traits in a Threatening Nosocomial Pathogen

Insights into Acinetobacter baumannii: A Review of Microbiological, Virulence, and Resistance Traits in a Threatening Nosocomial Pathogen

The Tip of the VgrG Spike Is Essential to Functional Type VI Secretion System Assembly in Acinetobacter baumannii

Urinary Catheter Coating Modifications: The Race against Catheter-Associated Infections

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