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Streptococcus gallolyticus subsp. gallolyticus (Sg) has long been known to have a strong association with colorectal cancer (CRC). This knowledge has important clinical implications, and yet little is known about the role of Sg in the development of CRC. Here we demonstrate that Sg promotes human colon cancer cell proliferation in a manner that depends on cell context, bacterial growth phase and direct contact between bacteria and colon cancer cells. In addition, we observed increased level of β-catenin, c-Myc and PCNA in colon cancer cells following incubation with Sg. Knockdown or inhibition of β-catenin abolished the effect of Sg. Furthermore, mice administered with Sg had significantly more tumors, higher tumor burden and dysplasia grade, and increased cell proliferation and β-catenin staining in colonic crypts compared to mice receiving control bacteria. Finally, we showed that Sg is present in the majority of CRC patients and is preferentially associated with tumor compared to normal tissues obtained from CRC patients. These results taken together establish for the first time a tumor-promoting role of Sg that involves specific bacterial and host factors and have important clinical implications.

Necrotising myositis is a rare but devastating consequence of invasive group A streptococcal infection. Early presentation could be non-specific, and clinicians might have a low index of clinical suspicion due to the rarity of cases. Prompt recognition and early aggressive surgical management are the cornerstones of treatment to reduce morbidity and mortality. We report the case of a child aged 5 years with necrotising myositis and highlight the successes and potential pitfalls in the treatment of this life-threatening condition.

Infection with the Streptococcus suis (S. suis) epidemic strain can cause Streptococcal toxic shock-like syndrome (STSLS), which is characterized by a cytokine storm, dysfunction of multiple organs and a high incidence of mortality despite adequate treatment. Despite some progress concerning the contribution of the inflammatory response to STSLS, the precise mechanism underlying STSLS development remains elusive. Here, we use a murine model to demonstrate that caspase-1 activity is critical for STSLS development. Furthermore, we show that inflammasome activation by S. suis is mainly dependent on NLRP3 but not on NLRP1, AIM2 or NLRC4. The important role of NLRP3 activation in STSLS is further confirmed in vivo with the NLRP3 inhibitor MCC950 and nlrp3-knockout mice. By comparison of WT strain with isogenic strains with mutation of various virulence genes for inflammasome activation, Suilysin is essential for inflammasome activation, which is dependent on the membrane perforation activity to cause cytosolic K+ efflux. Moreover, the mutant strain msly (P353L) expressing mutagenic SLY without hemolytic activity was unable to activate the inflammasome and does not cause STSLS. In summary, we demonstrate that the high membrane perforation activity of the epidemic strain induces a high level of NLRP3 inflammasome activation, which is essential for the development of the cytokine storm and multi-organ dysfunction in STSLS and suggests NLRP3 inflammasome as an attractive target for the treatment of STSLS.

Infection of the genitourinary tract with Group B Streptococcus (GBS), an opportunistic gram positive pathogen, is associated with premature rupture of amniotic membrane and preterm birth. In this work, we demonstrate that GBS produces membrane vesicles (MVs) in a serotype independent manner. These MVs are loaded with virulence factors including extracellular matrix degrading proteases and pore forming toxins. Mice chorio-decidual membranes challenged with MVs ex vivo resulted in extensive collagen degradation leading to loss of stiffness and mechanical weakening. MVs when instilled vaginally are capable of anterograde transport in mouse reproductive tract. Intra-amniotic injections of GBS MVs in mice led to upregulation of pro-inflammatory cytokines and inflammation mimicking features of chorio-amnionitis; it also led to apoptosis in the chorio-decidual tissue. Instillation of MVs in the amniotic sac also resulted in intrauterine fetal death and preterm delivery. Our findings suggest that GBS MVs can independently orchestrate events at the feto-maternal interface causing chorio-amnionitis and membrane damage leading to preterm birth or fetal death.

  [...]unraveling the basis of dental plaque development will ultimately contribute to both oral and overall health. By manipulation of adhesion interactions, it may be possible to develop new protocols to block adhesive reactions, impeding development of biofilm-related oral disease such as dental caries [9], [22], [26]. [...]the presence of C. albicans in the oral environment can now be considered an additional factor that needs to be taken into account in evaluating risks to caries [18].

Streptococcus agalactiae (Group B Streptococcus, GBS) normally colonizes healthy adults but can cause invasive disease, such as meningitis, in the newborn. To gain access to the central nervous system, GBS must interact with and penetrate brain or meningeal blood vessels; however, the exact mechanisms are still being elucidated. Here, we investigate the contribution of BspC, an antigen I/II family adhesin, to the pathogenesis of GBS meningitis. Disruption of the bspC gene reduced GBS adherence to human cerebral microvascular endothelial cells (hCMEC), while heterologous expression of BspC in non-adherent Lactococcus lactis conferred bacterial attachment. In a murine model of hematogenous meningitis, mice infected with ΔbspC mutants exhibited lower mortality as well as decreased brain bacterial counts and inflammatory infiltrate compared to mice infected with WT GBS strains. Further, BspC was both necessary and sufficient to induce neutrophil chemokine expression. We determined that BspC interacts with the host cytoskeleton component vimentin and confirmed this interaction using a bacterial two-hybrid assay, microscale thermophoresis, immunofluorescent staining, and imaging flow cytometry. Vimentin null mice were protected from WT GBS infection and also exhibited less inflammatory cytokine production in brain tissue. These results suggest that BspC and the vimentin interaction is critical for the pathogenesis of GBS meningitis.

Group B Streptococcus (GBS) carriage by pregnant women is the primary risk factor for early-onset GBS neonatal sepsis. Intrapartum antibiotic prophylaxis (IAP) can prevent this transmission route, and two main approaches are recommended to base the selection of pregnant women to be submitted to IAP: the risk-based and the culture-based strategies. In Brazil, compliance to such recommendations is poor, and not much is known about GBS carriage. In the present study, 3,647 pregnant women living in Rio de Janeiro State, Brazil, were screened for GBS anogenital colonization, over a period of 8 years (2008-2015). GBS was detected in 956 (26.2%) of them, and presence of vaginal discharge was the only trait associated with a higher risk for GBS colonization. Serotypes Ia (257; 37.3%) and II (137; 19.9%) were the most frequent among 689 (72.1% of the total) GBS isolates evaluated, followed by NT isolates (84; 12.1%), serotype Ib (77; 11.1%), V (63; 9.1%), III (47; 6.8%) and IV (24; 3.5%). Estimated coverage of major serotype-based GBS vaccines currently under clinical trials would vary from 65.2% to 84.3%. All 689 isolates tested were susceptible to ampicillin and vancomycin. Resistance to chloramphenicol, clindamycin, erythromycin, levofloxacin, and tetracycline was observed in 5% (35), 2% (14), 14% (97), 5% (35) and 86% (592) of the isolates, respectively. No significant fluctuations in colonization rates, serotype distribution and antimicrobial susceptibility profiles were observed throughout the period of time investigated. The culture-based approach for IAP recommendation showed to be the best choice for the population investigated when compared to the risk-based, since the first did not increase the number of pregnant women submitted to antibiotic therapy and covered a larger number of women who were actually colonized by GBS. The fact the not all isolates were available for additional characterization, and serotype IX antiserum was not available for testing represent limitations of this study. Nevertheless, to the best of our knowledge, this is the largest investigation on GBS carriage among pregnant women in Brazil up to date, and results are useful for improving GBS prevention and treatment strategies.

Key Points Streptococcus pyogenes , also called group A Streptococcus (GAS), is a Gram-positive bacterial pathogen that naturally infects only humans and is the aetiological agent of several potentially fatal syndromes, including 'flesh-eating disease' (necrotizing fasciitis). The worldwide resurgence of severe invasive GAS infections over the past 30 years is correlated with the global dissemination of the GAS serotype M1T1 clone. Recent work demonstrates that the capacity of GAS serotype M1T1 to cause invasive disease is increased by selection for mutations within the covRS two-component regulator operon. This genetic alteration dramatically changes the transcriptome, resulting in the downregulation of a broad-spectrum cysteine protease, streptococcal pyrogenic exotoxin B (SpeB), and the upregulation of several virulence factors, including the nuclease extracellular streptodornase D (Sda1). Elevated Sda1 nuclease activity enhances the resistance of GAS serotype M1T1 to neutrophil-mediated killing, through the degradation of DNA-based neutrophil extracellular traps, and the absence of SpeB protease activity permits the accumulation of plasmin activity on the GAS cell surface, triggering tissue destruction and systemic spread. GAS uses a repertoire of virulence factors to thwart the host innate immune response, and several of these factors are critical for invasive disease. The switch from non-invasive to hyperinvasive GAS is triggered by particular genetic events, and our increased understanding of this switch has led to a model for the initiation of invasive GAS disease in humans. An understanding of the mechanism by which GAS causes serious invasive infections may augment the development of new-generation therapeutics and provide better health outcomes in the fight against this globally important human pathogen. Group A Streptococcus can cause devastating infections with high mortality rates. Here, Walker and colleagues describe the bacterial virulence factors that allow this species to infect tissues and escape destruction in neutrophils, and discuss how genetic changes in a two-component regulatory system promote pathogenicity. Streptococcus pyogenes is also known as group A Streptococcus (GAS) and is an important human pathogen that causes considerable morbidity and mortality worldwide. The GAS serotype M1T1 clone is the most frequently isolated serotype from life-threatening invasive (at a sterile site) infections, such as streptococcal toxic shock-like syndrome and necrotizing fasciitis. Here, we describe the virulence factors and newly discovered molecular events that mediate the in vivo changes from non-invasive GAS serotype M1T1 to the invasive phenotype, and review the invasive-disease trigger for non-M1 GAS. Understanding the molecular basis and mechanism of initiation for streptococcal invasive disease may expedite the discovery of novel therapeutic targets for the treatment and control of severe invasive GAS diseases.

Disease tolerance is a host response to infection that limits collateral damage to host tissues while having a neutral effect on pathogen fitness. Previously, we found that the pathogenic lactic acid bacterium Streptococcus pyogenes manipulates disease tolerance using its aerobic mixed-acid fermentation pathway via the enzyme pyruvate dehydrogenase, but the microbe-derived molecules that mediate communication with the host’s disease tolerance pathways remain elusive. Here we show in a murine model that aerobic mixed-acid fermentation inhibits the accumulation of inflammatory cells including neutrophils and macrophages, reduces the immunosuppressive cytokine interleukin-10, and delays bacterial clearance and wound healing. In infected macrophages, the aerobic mixed-acid fermentation end-products acetate and formate from streptococcal upregulate host acetyl-CoA metabolism and reduce interleukin-10 expression. Inhibiting aerobic mixed-acid fermentation using a bacterial-specific pyruvate dehydrogenase inhibitor reduces tissue damage during murine infection, correlating with increased interleukin-10 expression. Our results thus suggest that reprogramming carbon flow provides a therapeutic strategy to mitigate tissue damage during infection. Disease tolerance helps avoid inflammatory damages when immune system is trying to clear infection, but the mechanisms are still unclear. Here the authors show that the bacteria tap into disease tolerance by altering host cell acetyl-CoA metabolism to suppress innate cell function and cytokine production.

Background. Few cross-population studies examining the epidemiology of invasive group B streptococcal (GBS) disease have been undertaken. To identify longitudinal trends in the burden and characteristics of infections, national surveillance data on diagnoses in England and Wales from 1991 to 2010 were analyzed. Methods. A parallel review of laboratory-confirmed invasive GBS infection surveillance reports and isolates submitted to the national reference laboratory was undertaken. Cases were defined as GBS isolated from a normally sterile site. Results. A total of 21 386 reports of invasive GBS infection were made between 1991 and 2010. The annual rate of reports doubled over the 20 years from 1.48 to 2.99 per 100 000 population. Significant increases were seen in all age groups but most pronounced in adults. Rates of early-onset (0–6 days) infant disease fluctuated but showed a general rise between 2000 and 2010 from 0.28 to 0.41 per 1000 live births. Rates of late-onset (7–90 days) disease increased steadily between 1991 and 2010 from 0.11 to 0.29 per 1000 live births. Resistance to erythromycin increased markedly from 2.5% in 1991 to 15% in 2010. The distribution of serotypes varied according to patient age and over time with type III increasing among early-onset cases and decreasing in adults. Conclusions. Although risk of invasive GBS infection remains highest within the first few days of life, the relative burden of disease is shifting toward adults. The rise in incidence and antibiotic resistance makes development of an effective and safe vaccine all the more pressing.