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

Abstract

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...

A Critical Role of Zinc Importer AdcABC in Group A Streptococcus-Host Interactions During Infection and Its Implications for Vaccine Development

“…However, AdcA has an additional C-terminal ZinT-like domain and the role of the ZinT-like domain of AdcA in GAS homeostasis is yet to be elucidated. Although AdcAII/Lmb and Pht proteins contribute to streptococcal adaptive responses to zinc limitation (Bayle et al, 2011, Moulin et al, 2016, Tedde et al, 2016), the exact mechanisms by which they facilitate zinc acquisition remain unknown. Nevertheless, the significance of the AdcR signaling pathway to GAS pathogenesis is underscored by the observation that inactivation of adcR caused dysregulation of zinc homeostasis and significantly attenuated GAS virulence (Sanson et al, 2015).…”

Defining the Role of the Streptococcus agalactiae Sht-Family Proteins in Zinc Acquisition and Complement Evasion

“…Streptococcus agalactiae (group B streptococcus [GBS]) is not only a human commensal of the digestive and genital tracts but also an opportunistic pathogen that causes invasive infections, including septicemia, pneumonia, and meningitis in human neonates (5,6). Zinc acquisition is essential to these processes since our prior studies have established that zinc is required for fundamental processes, including S. agalactiae growth and morphology (7). In S. agalactiae, zinc acquisition involves the AdcCB transporter, which is comprised of the integral membrane protein, AdcB, and the nucleotide binding domain, AdcC.…”

Availability of Zinc Impacts Interactions BetweenStreptococcus sanguinisandPseudomonas aeruginosain Co-culture

“…In S. sanguinis SK36, the SSA_0136 and SSA_0137 genes encode components of an Adc zinc ATP-binding cassette (ABC) transporter, which is involved in zinc uptake in several pathogenic streptococci. The SSA_0136 and SSA_0137 genes are called adcC and adcB , respectively (42, 45). The SSA_0260 gene, also termed SsaB ( S. sanguinis adhesin B) (56), is an LraI family lipoprotein and serves as the substrate-binding protein for a Mn/Zn ABC import system (57).…”