AdcAII of Streptococcus pneumoniae Affects Pneumococcal Invasiveness

Brown, Lindsey R.; Gunnell, Steven M.; Cassella, Adam N.; Keller, Lance E.; Scherkenbach, Lisa A.; Mann, Beth; Brown, Matthew W.; Hill, Rebecca; Fitzkee, Nicholas C.; Rosch, Jason W.; Tuomanen, Elaine; Thornton, Justin A.

doi:10.1371/journal.pone.0146785

Cited by 30 publications

(38 citation statements)

References 36 publications

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“…In S. pneumoniae, either AdcA or AdcAII is sufficient for zinc acquisition during growth in vitro and for systemic virulence in vivo, but both are necessary for optimal nasopharynx colonization (40). A recent study, again in S. pneumoniae, showed that the absence of AdcAII but not AdcA negatively affected early colonization of the nasopharynx (55). These results suggest that during infection, S. pneumoniae encounters environments with the lmb-sht promoter region carrying point mutations that destroyed an inverted repeat of the first putative AdcR-box (box 1 *), or point mutations that destroyed an inverted repeat of the second putative AdcR-box (box 2 *), or combined mutations (box 1-2 *), were constructed.…”

Section: Discussionmentioning

confidence: 99%

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The Adc/Lmb System Mediates Zinc Acquisition in Streptococcus agalactiae and Contributes to Bacterial Growth and Survival

et al. 2016

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The Lmb protein of Streptococcus agalactiae is described as an adhesin that binds laminin, a component of the human extracellular matrix. In this study, we revealed a new role for this protein in zinc uptake. We also identified two Lmb homologs, AdcA and AdcAII, redundant binding proteins that combine with the AdcCB translocon to form a zinc-ABC transporter. Expression of this transporter is controlled by the zinc concentration in the medium through the zinc-dependent regulator AdcR. Triple deletion of lmb, adcA, and adcAII, or that of the adcCB genes, impaired growth and cell separation in a zinc-restricted environment. Moreover, we found that this Adc zinc-ABC transporter promotes S. agalactiae growth and survival in some human biological fluids, suggesting that it contributes to the infection process. These results indicated that zinc has biologically vital functions in S. agalactiae and that, under the conditions tested, the Adc/Lmb transporter constitutes the main zinc acquisition system of the bacterium. IMPORTANCEA zinc transporter, composed of three redundant binding proteins (Lmb, AdcA, and AdcAII), was characterized in Streptococcus agalactiae. This system was shown to be essential for bacterial growth and morphology in zinc-restricted environments, including human biological fluids. S treptococcus agalactiae (group B streptococcus [GBS]) is aGram-positive commensal bacterium of the human gastrointestinal and uro-genital tracts. GBS carriage is mostly asymptomatic in healthy adults, and this bacterium is detected in the vagina of approximatively 30% of pregnant women. Maternal carriage is the main source of transmission to neonates, in which S. agalactiae can cause invasive infections (pneumonia, septicemia, and meningitis), with an overall mortality rate of approximately 10% (1, 2). GBS is also an emergent pathogen among the elderly and in adults with underlying diseases (1, 3).The ability of GBS to colonize different niches and cause infection is multifactorial, and many virulence-associated proteins have been identified (4, 5). Binding of GBS adhesins to components of the extracellular matrix constitutes a crucial first step in the process of infection (6-9). Among them, the Lmb protein has been identified as a GBS receptor for laminin, a glycosylated multidomain protein found in all human tissues (10). The gene encoding Lmb is located on a transposon with the scpB and sht genes, which encode a C5a peptidase and a histidine triad protein, respectively (11, 12). The lmb promoter region is a hot spot for the integration of two mobile genetic elements. One of them is associated with increased expression of lmb, resulting in increased binding of strains harboring the transposon to laminin (13). It has also been shown that Lmb may promote bacterial invasion in human brain microvascular endothelial cell lines (14).Lmb is clustered by sequence homology as a metal-binding receptor. Indeed, Lmb has strong homology with the zinc-binding proteins AdcA and Lbp of other streptococcal species (15, 16). Th...

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Section: Discussionmentioning

confidence: 99%

“…It may be informative to test purified recombinant Lmb, AdcA, and AdcAII proteins for their binding ability, as previously done for the Lmb protein of S. agalactiae or Lbp of S. pyogenes (15,18,56). However, a recent study on Lmb homologs of S. pneumoniae also failed to show any binding to laminin (55).…”

Section: Figmentioning

confidence: 99%

The Adc/Lmb System Mediates Zinc Acquisition in Streptococcus agalactiae and Contributes to Bacterial Growth and Survival

et al. 2016

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“…Streptococcus pneumoniae , pneumococcus, is a Gram-positive commensal of the human nasopharynx and is the leading cause of community acquired pneumonia worldwide (11). Zinc transport systems and the zinc-dependent AdcR regulon of the pneumococcus have been characterized in detail (12-15). However, it remains unknown if other zinc-sensitive transporters exist.…”

Section: Introductionmentioning

confidence: 99%

“…However, it remains unknown if other zinc-sensitive transporters exist. Previous work from our laboratory has identified roles for zinc homeostasis in both invasion and biofilm formation of S. pneumoniae (12, 16). Here we identify zinc as an effector molecule for the regulation of a genetic locus involved in maintenance of metal homeostasis.…”

Section: Introductionmentioning

confidence: 99%

SP1433-1438 operon ofStreptococcus pneumoniaeregulates metal homeostasis and cellular metabolism during zinc-stress

Burcham

Hill

Caulkins

et al. 2018

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operon of Streptococcus pneumoniae regulates metal homeostasis and 1 cellular metabolism during zinc-stress 2 3 11 12 13 14 Running Head: S. pneumoniae metabolism altered by zinc-sensitive operon 15 16 17 Corresponding author: Justin A. Thornton, thornton@biology.msstate.edu 18 19 20 21induced during zinc-limiting conditions. This operon was found to be regulated by a zinc-47 dependent regulator (SP1433) that functions independently of the overarching AdcR regulon. 48We have additionally utilized a 2D-NMR approach to analyze the secreted metabolome and 49 have employed proteomic analysis to identify a role for these systems in the maintenance of 50 cellular metabolism. This study provides new information on how Streptococcus pneumoniae 51 responds and adapts to zinc-limiting conditions. 52 53

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“…Manganese and zinc are important metal ions for bacteria as micronutrients and their availabilities fluctuate amongst host tissue microenvironments (Jacobsen et al, 2011;McDevitt et al, 2011). These metal ions have previously been associated with the regulation of Streptococcal virulence factors (Brown et al, 2016;Eijkelkamp et al, 2015;Kadioglu et al, 2008;McDevitt et al, 2011). In S.…”

Section: Changes In the Protein Profile Of Qma0285 Cultured In Differmentioning

confidence: 99%

A pan genome reverse vaccinology approach to prevent Streptococcus agalactiae infection in farmed tilapia

Kawasaki¹

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Streptococcus agalactiae (Group B Streptococcus; GBS) is a Gram-positive pathogenic bacterium that causes disease in a wide range of animals including fish. Outbreaks of GBS in farmed fish have substantial economic impacts on the aquaculture industry, especially in tilapia production, a staple food product in tropical and subtropical low-and middle-income countries and the second most widely farmed fish after carp. Although vaccination can effectively prevent disease caused by GBS in fish it often fails after relatively short periods of use. Capsular polysaccharide (CPS) is the major protective antigen in GBS vaccines and a critical virulence factor. There are currently ten CPS serotypes of GBS and, whilst vaccination against one serotype confers protection in fish, it is not cross-protective against other serotypes. In addition, under the strong selective pressure of vaccination-driven adaptive immunity, evolution of novel serotypes can occur. To improve the serotype crossprotective efficacy of GBS vaccines for aquaculture, I employed a pan-genome reverse vaccinology approach to design candidate serotype-independent protective vaccines based on conserved proteins in fish-pathogenic GBS serotypes. Reverse vaccinology exploits recent advances in genomics to predict antigens in the genome sequence. Reverse vaccinology combined with pan-genome can identify the antigens that are conserved across a diversity of strains of a pathogen.To identify potential vaccine candidate antigens, a pan-genome was constructed for GBS comprising 82 genomes including representative isolates from wild marine fish and stingrays, farm and companion animals and from human clinical cases in Australia, along with isolates from farmed tilapia in Honduras and representative genomes from all current serotypes available via the NCBI Genbank database. Core genome single nucleotide polymorphism 3 (SNP) analysis indicated dissemination of the aquatic host-adapted ST-261 lineage in wild Australian fish from an ancestral tilapia strain, which is congruent with several introductions of tilapia into northern Australia from Israel and Malaysia during the 1970s and 1980s.Aquatic serotype Ib GBS strains have lost many virulence factors during adaptation, but six adhesins, named ST-261 adhesins, were well-conserved across the aquatic isolates and might be critical for virulence in fish and good targets for vaccine development. Three of six ST-261 adhesins were also conserved across all strains including terrestrial isolates and were chosen as vaccine candidates. Expressions of ST-261 adhesin genes were inversely co-regulated with CPS expression dependent upon carbon source and metal ions in the medium. However, gene transcription was not reflective of surface expression as serum antibodies derived in tilapia against recombinant adhesins did not detect similar variation in the level of ST-261 adhesins in whole cell ELISA or Western blot. This may be due to posttranscriptional processing causing a disconnect between gene and protein expression.To evaluate th...

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AdcAII of Streptococcus pneumoniae Affects Pneumococcal Invasiveness

Cited by 30 publications

References 36 publications

The Adc/Lmb System Mediates Zinc Acquisition in Streptococcus agalactiae and Contributes to Bacterial Growth and Survival

The Adc/Lmb System Mediates Zinc Acquisition in Streptococcus agalactiae and Contributes to Bacterial Growth and Survival

SP1433-1438 operon ofStreptococcus pneumoniaeregulates metal homeostasis and cellular metabolism during zinc-stress

A pan genome reverse vaccinology approach to prevent Streptococcus agalactiae infection in farmed tilapia

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