Characterization of group B Streptococcus isolated from sterile and non-sterile specimens in China.

Group B streptococcus (GBS) is a leading cause of invasive neonatal infections and has increasingly been associated with invasive diseases in non-pregnant adults. We collected 113 GBS isolates recovered from sterile and non-sterile specimens from seven tertiary hospitals in China between October 2014 and September 2016. Medical records were retrospectively reviewed and the sequence types, serotypes, virulence, and antimicrobial resistance profiles of the isolates were characterized and correlated. Significantly higher C-reactive protein and procalcitonin levels and absolute neutrophil counts were observed in patients with invasive infections than in those with non-invasive infections (P < 0.05). The 113 isolates were grouped into 24 sequence types, 5 clonal complexes, and 6 serotypes. multivariate analysis revealed that clonal complex 17 isolates characterized by serotype iii, the surface protein gene rib, and the pilus island pi-2b were independently correlated with invasive infection (or: 6.79; 95% ci: 2.31-19.94, P < 0.001). These results suggest alternative molecular biomarkers for diagnosis and prognosis of GBS infections.

Inflammasome Activation Triggers Caspase-1-Mediated Cleavage of cGAS to Regulate Responses to DNA Virus Infection.

Viral infection triggers host innate immune responses that result in the production of various cytokines including type I interferons (IFN), activation of inflammasomes, and programmed cell death of the infected cells. Tight control of inflammatory cytokine production is crucial for the triggering of an effective immune response that can resolve the infection without causing host pathology. In examining the inflammatory response of Asc-/- and Casp1-/- macrophages, we found that deficiency in these molecules resulted in increased IFN production upon DNA virus infection, but not RNA virus challenge. Investigation of the underlying mechanism revealed that upon canonical and non-canonical inflammasome activation, caspase-1 interacted with cyclic GMP-AMP (cGAMP) synthase (cGAS), cleaving it and dampening cGAS-STING-mediated IFN production. Deficiency in inflammasome signaling enhanced host resistance to DNA virus in vitro and in vivo, and this regulatory role extended to other inflammatory caspases. Thus, inflammasome activation dampens cGAS-dependent signaling, suggesting cross-regulation between intracellular DNA-sensing pathways.

Cyclic (di)nucleotides: the common language shared by microbe and host.

Fluency in a common language allows individuals to convey information and carry out complex activities that otherwise would be difficult or even impossible without the benefit of shared communication. Cyclic (di)nucleotides have recently been recognized as such an accessible language understood by both microbe and the host, ever since remarkable progresses have revealed the molecular details of these nucleotide second messengers used in cellular communication systems. Though undergoing separate evolutionary pathways in prokaryotes and eukaryotes, cyclic (di)nucleotides enable microbes to influence host cells immediately and fiercely by modulating a variety of cellular activities. Here we highlight recent insights in cyclic (di)nucleotides and focus on the balancing of these indispensable signaling molecules by synthases and phosphodiesterases.

Identification and characterization of phosphodiesterases that specifically degrade 3'3'-cyclic GMP-AMP.

Cyclic dinucleotides act as intracellular second messengers, modulating a variety of cellular activities including innate immune activation. Although phosphodiesterases (PDEs) hydrolyzing c-di-GMP and c-di-AMP have been identified, no PDEs for cGAMPs have been reported. Here we identified the first three cGAMP-specific PDEs in V. cholerae (herein designated as V-cGAP1/2/3). V-cGAPs are HD-GYP domain-containing proteins and specifically break 3'3'-cGAMP, but not other forms of cGAMP. 3'3'-cGAMP is first linearized by all three V-cGAPs to produce 5'-pApG, which is further hydrolyzed into 5'-ApG by V-cGAP1. In this two-step reaction, V-cGAP1 functions as both a PDE and a 5'-nucleotidase. In vivo experiments demonstrated that V-cGAPs play non-redundant roles in cGAMP degradation. The high specificity of V-cGAPs on 3'3'-cGAMP suggests the existence of specific PDEs for other cGAMPs, including 2'3'-cGAMP in mammalian cells. The absolute requirement of the GYP motif for 3'3'-cGAMP degradation suggests that HD domain-containing PDEs in eukaryotes are probably unable to hydrolyze cGAMPs. The fact that all V-cGAPs attack 3'3'-cGAMP on one specific phosphodiester bond suggests that PDEs for other cGAMPs would utilize a similar strategy. These results will provide valuable information for identification and characterization of mammalian 2'3'-cGAMP-specific PDEs in future studies.