Autoinducer 2 Signaling via the Phosphotransferase FruA Drives Galactose Utilization by Streptococcus pneumoniae , Resulting in Hypervirulence

Abstract

Communication between bacterial cells is crucial for the coordination of diverse cellular processes that facilitate environmental adaptation and, in the case of pathogenic species, virulence. This is achieved by the secretion and detection of small signaling molecules called autoinducers, a process termed quorum sensing. To date, the only signaling molecule recognized by both Gram-positive and Gram-negative bacteria is autoinducer 2 (AI-2), synthesized by the metabolic enzyme LuxS (S-ribosylhomocysteine lyase) as a by-product of the activated methyl cycle. Homologues of LuxS are ubiquitous in bacteria, suggesting a key role in interspecies, as well as intraspecies, communication. Gram-negative bacteria sense and respond to AI-2 via the Lsr ABC transporter system or by the LuxP/LuxQ phosphorelay system. However, homologues of these systems are absent from Gram-positive bacteria and the AI-2 receptor is unknown. Here we show that in the major human pathogen Streptococcus pneumoniae, sensing of exogenous AI-2 is dependent on FruA, a fructose-specific phosphoenolpyruvate-phosphotransferase system that is highly conserved in Gram-positive pathogens. Importantly, AI-2 signaling via FruA enables the bacterium to utilize galactose as a carbon source and upregulates the Leloir pathway, thereby leading to increased production of capsular polysaccharide and a hypervirulent phenotype.

Deletion of the Zinc Transporter Lipoprotein AdcAII Causes Hyperencapsulation of Streptococcus pneumoniae Associated with Distinct Alleles of the Type I Restriction-Modification System

“…Combined deletion of adcA and adcAII was also not associated with the hyperencapsulated phenotype, but the double mutation had major effects on S. pneumoniae (37), and RegM (38), as well as the conserved 5= cpsABCD (also termed wzg, wzh, wzd, and wze) genes of the cps locus (39)(40)(41). Two S. pneumoniae quorum-sensing systems (LuxS/AI-2 and the Rgg/small hydrophobic peptide system) increase capsule thickness (42)(43)(44), which can also be regulated independently of gene transcription by the supply of capsule monosaccharide precursors (45) or by increased capsule shedding mediated by LytA (12). However, our transcriptome analysis did not identify increased cps locus gene expression or any effects on the abovementioned known regulators of capsule expression in the ⌬adcAII strain.…”

Streptococcus pneumoniae: transmission, colonization and invasion

“…The various released sugars can have substantial intracellular effects by regulating carbohydrate metabolism through the catabolite repressor CcpA 102 . Sialic acid released by NanA has been shown to act as a signal, increasing bacterial loads in the nasopharynx of mice colonized with S. pneumoniae and facilitating invasion of nasal tissue and progression to pneumonia and meningitis 105,106 . Such signalling involves the two- transcriptional regulatory protein CiaR and requires sialic acid uptake by the transporter SatABC, and this results in increased pneumococcal resistance to antimicrobial reactive oxygen species 107 .…”

“…The luxS gene is of particular interest, as it is involved in the synthesis of the ubiquitous QS molecule autoinducer 2 (AI-2), which is an important regulator of bio-film formation and virulence in pneumococci 117 . Recent studies show that AI-2 accumulating in the extracellular compartment is sensed by the fructose PTS transporter subunit IIC FruA, leading to upregulation of the galactose ABC transporter and the 105 . Galactose is an important carbon source for S. pneumoniae in the respiratory tract, and AI-2-mediated QS seems to be essential for its uptake and metabolism.…”

“…Galactose is an important carbon source for S. pneumoniae in the respiratory tract, and AI-2-mediated QS seems to be essential for its uptake and metabolism. Upregulation of the Leloir pathway increases the availability of activated sugar precursors, leading to increased production of CPS and a hypervirulent phenotype 105 .…”

Ингибиторы механизмов кворум-сенсинга бактерий Streptococcus рneumoniae

“…Соединение 5-азацитидин (5-azacytidine) ингибирует синтез наиболее распространенной сигнальной молекулы QS грамположительных бактерий аутоиндуктора AI-2 [21]. Соединение 5-азацитидин является производным цитидина, которое вызывает гипометилирование ДНК и ингибирует ДНК-метилтрансферазу.…”