AMPK/Drp1 pathway mediates Streptococcus uberis-Induced mitochondrial dysfunction.

Excessive production of reactive oxygen species (ROS) leads to oxidative stress in host cells and affects the progress of disease. Mitochondria are an important source of ROS and their dysfunction is closely related to ROS production. S. uberis is a common causative agent of mastitis. The expression of key enzymes of the mitochondrial apoptotic pathway is increased in mammary epithelial cells after S. uberis stimulation, while expression of proteins related to mitochondrial function is decreased. Drp1, a key protein associated with mitochondrial function, is activated upon infection. Accompanied by mitochondria-cytosol translocation of Drp1, Fis1 expression is significantly upregulated while Mfn1 expression is downregulated implying that the balance of mitochondrial dynamics is disrupted. This leads to mitochondrial fragmentation, decreased mitochondrial membrane potential, higher levels of mROS and oxidative injury. The AMPK activator AICAR inhibits the increased phosphorylation of Drp1 and the translocation of Drp1 to mitochondria by salvaging mitochondrial function in an AMPK/Drp1 dependent manner, which has a similar effect to Drp1 inhibitor Mdivi-1. These data show that AMPK, as an upstream negative regulator of Drp1, ameliorates mitochondrial dysfunction induced by S. uberis infection.

CLINICAL CHARACTERISTICS AND VISUAL OUTCOMES IN ENDOPHTHALMITIS AFTER KERATOPROSTHESIS IMPLANTATION.

PURPOSE: To describe the presentation, microbiology, management, and prognosis of eyes with endophthalmitis after Boston keratoprosthesis implantation. METHODS: Retrospective case series with history, diagnostics, management, and outcomes data in endophthalmitis after keratoprosthesis implantation presenting to a tertiary center between 2009 and 2020. RESULTS: Of 137 keratoprosthesis-implanted eyes, 7 eyes of 7 patients (5%) developed endophthalmitis. On presentation, 6 (86%) reported decreased visual acuity, and only 1 (14%) reported pain. Peripheral corneal ulcers were present in 2 eyes (29%). Seidel testing was negative in all cases. Six eyes (86%) had retroprosthetic membranes. One (14%) underwent initial pars plana vitrectomy with mechanical vitreous biopsy, whereas 6 (86%) received a needle vitreous tap-half of which were dry. Organisms were isolated after vitreous tap in two eyes: Streptococcus intermedius and Mycobacterium abscessus. The mean visual acuity preendophthalmitis, at presentation, and at 6 months were 20/267, 20/5,944, and 20/734, respectively. The visual acuity improved 9.08 ± 11.78 Early Treatment Diabetic Retinopathy Study lines from presentation to 6 months. Six-month visual acuity was correlated with preendophthalmitis visual acuity (r = 0.92, P = 0.003) but not presenting visual acuity (P = 0.838). CONCLUSION: Visual acuity at 6 months is correlated with preendophthalmitis visual acuity, not presenting visual acuity. Endophthalmitis should be considered in the differential diagnosis of painless intraocular inflammation any time after keratoprosthesis implantation, even if Seidel negative.

Streptococcal infection in childhood Henoch-Schönlein purpura: a 5-year retrospective study from a single tertiary medical center in China, 2015-2019.

BACKGROUND: The present study focuses on the associations of streptococcal infection with the clinical phenotypes, relapse/recurrence and renal involvement in Henoch-Schönlein purpura (HSP) children. METHODS: Two thousand seventy-four Chinese children with HSP were recruited from January 2015 to December 2019. Patients' histories associated with HSP onset were obtained by interviews and questionnaires. Laboratory data of urine tests, blood sample and infectious agents were collected. Renal biopsy was performed by the percutaneous technique. RESULTS: (1) Streptococcal infection was identified in 393 (18.9%) HSP patients, and served as the most frequent infectious trigger. (2) Among the 393 cases with streptococcal infection, 43.0% of them had arthritis/arthralgia, 32.1% had abdominal pain and 29.3% had renal involvement. (3) 26.1% of HSP patients relapsed or recurred more than 1 time within a 5-year observational period, and the relapse/recurrence rate in streptococcal infectious group was subjected to a 0.4-fold decrease as compared with the non-infectious group. (4) No significant differences in renal pathological damage were identified among the streptococcal infectious group, the other infectious group and the non-infectious group. CONCLUSIONS: Streptococcal infection is the most frequent trigger for childhood HSP and does not aggravate renal pathological damage; the possible elimination of streptococcal infection helps relieve the relapse/recurrence of HSP.

Clinical significance of Epstein-Barr virus in the cerebrospinal fluid of immunocompetent patients.

INTRODUCTION: Polymerase chain reaction (PCR)-based testing of cerebrospinal fluid (CSF) samples has greatly facilitated the diagnosis of central nervous system (CNS) infections. However, the clinical significance of Epstein-Barr virus (EBV) DNA in CSF of individuals with suspected CNS infection remains unclear. We wanted to gain a better understanding of EBV as an infectious agent in immunocompetent patients with CNS disorders. METHODS: We identified cases of EBV-associated CNS infections and reviewed their clinical and laboratory characteristics. The study population was drawn from patients with EBV PCR positivity in CSF who visited Pusan National University Hospital between 2010 and 2019. RESULTS: Of the 780 CSF samples examined during the 10-year study period, 42 (5.4 %) were positive for EBV DNA; 9 of the patients (21.4 %) were diagnosed with non-CNS infectious diseases, such as optic neuritis, Guillain-Barré syndrome, and idiopathic intracranial hypotension, and the other 33 cases were classified as CNS infections (22 as encephalitis and 11 as meningitis). Intensive care unit admission (13/33 patients, 39.3 %) and presence of severe neurological sequelae at discharge (8/33 patients, 24.2 %) were relatively frequent. In 10 patients (30.3 %), the following pathogens were detected in CSF in addition to EBV: varicella-zoster virus (n = 3), cytomegalovirus (n = 2), herpes simplex virus 1 (n = 1), herpes simplex virus 2 (n = 1), Streptococcus pneumomiae (n = 2), and Enterococcus faecalis (n = 1). The EBV-only group (n = 23) and the co-infection group (n = 10) did not differ in age, gender, laboratory data, results of brain imaging studies, clinical manifestations, or prognosis; however, the co-infected patients had higher CSF protein levels. CONCLUSION: EBV DNA in CSF is occasionally found in the immunocompetent population; the virus was commonly associated with encephalitis and poor prognosis, and frequently found together with other microbes in CSF.

Integrin α5ß1, as a Receptor of Fibronectin, Binds the FbaA Protein of Group A Streptococcus To Initiate Autophagy during Infection.

Group A Streptococcus (GAS), one of the most common extracellular pathogens, has been reported to invade epithelial and endothelial cells. Our results reveal that M1 GAS strain SF370 can be effectively eliminated by respiratory epithelial cells. Emerging evidence indicates that autophagy is an important strategy for nonphagocytes to eliminate intracellular bacteria. Upon pathogen recognition, cell surface receptors can directly trigger autophagy, which is a critical step in controlling infection. However, the mechanisms of how cells sense invading bacteria and use this information specifically to trigger autophagy remain unclear. In this study, we stimulated cells and infected mice with M and FbaA mutants of M1 GAS strain SF370 or with purified M and FbaA proteins (two critical surface structural proteins of GAS), and found that only FbaA protein was involved in autophagy induction. Furthermore, the FbaA protein induced autophagy independent of common pattern recognition receptors (such as Toll-like receptors); rather, it relies on binding to integrin α5ß1 expressed on the cell surface, which is mediated by extracellular matrix protein fibronectin (Fn). The FbaA-Fn-integrin α5ß1 complex activates Beclin-1 through the mTOR-ULK1-Beclin-1 pathway, which enables the Beclin-1/Vps34 complex to recruit Rab7 and, ultimately, to promote the formation of autophagosomes. By knocking down integrin α5ß1, Fn, Atg5, Beclin-1, and ULK1 in Hep2 cells and deleting Atg5 or integrin α5ß1 in mice, we reveal a novel role for integrin α5ß1 in inducing autophagy. Our study demonstrates that integrin α5ß1, through interacting with pathogen components, initiates effective host innate immunity against invading intracellular pathogens.IMPORTANCE Autophagy is generally considered a strategy used by the innate immune system to eliminate invasive pathogens through capturing and transferring them to lysosomes. Currently, researchers pay more attention to how virulence factors secreted by GAS regulate the autophagic process. Here, we provide the first evidence that the structural protein FbaA of M1 GAS strain SF370 is a potent inducer of autophagy in epithelial cells. Furthermore, we demonstrate that integrin α5ß1 in epithelial cells in vitro and in vivo acts as a receptor to initiate the signaling for inducing autophagy by binding to FbaA of M1 GAS strain SF370 via Fn. Our study reveals the underlying mechanisms by which pathogens induce Fn-integrin α5ß1 to trigger autophagy in a conserved pattern in epithelial cells.

Periprosthetic joint infection with streptococcus dysgalactiae subspecies equisimilis: Case report.

Streptococcus dysgalactiae (SD) is a common pathogen among elderly population. However, to our knowledge, there is no periprosthetic joint infection case reported that is infected with Streptococcus dysgalactiae subspecies equisimilis (SDSE) in the English literature. In this article, we report a 77-year-old male patient who had undergone total knee arthroplasty three years ago and had the diagnosis of cellulitis at his leg followed by swelling, pain and hyperemia localized at his knee. Three knee aspirations were performed and the SDSE was identified. There was no direct contact of patient to animals.

Necrotizing Soft Tissue Infections: A Focused Review of Pathophysiology, Diagnosis, Operative Management, Antimicrobial Therapy, and Pediatrics.

Background: Necrotizing fasciitis is a major health problem throughout the world. The purpose of this review is to assist providers with the care of these patients through a better understanding of the pathophysiology and management options. Methods: This is a collaborative review of the literature between members of the Surgical Infection Society of North America and World Society of Emergency Surgery. Results: Necrotizing fasciitis continues to be difficult to manage with the mainstay being early diagnosis and surgical intervention. Recognition of at-risk populations assists with the initiation of treatment, thereby impacting outcomes. Conclusions: Although there are some additional treatment strategies available, surgical debridement and antimicrobial therapy are central to the successful eradication of the disease process.

Toxic shock syndrome caused by Streptococcus dysgalactiae subsp. equisimilis in a Mexican preschool patient / Síndrome de choque tóxico por Streptococcus dysgalactiae subsp. equisimilis en un paciente preescolar mexicano

Abstract Background: Severe infections due to Streptococcus dysgalactiae subsp. equisimilis (SDSE) have been identified in adults and may cause toxic shock syndrome, although with a low frequency. Case report: A preschool-age female patient, who started with an upper respiratory tract infection developing a gradual deterioration in the following three days, is described. She was admitted to the hospital in severe conditions, with tachypnea, tachycardia (200/min), hypotension (blood pressure 68/40 mmHg), capillary refill of 7 s, and erythematous maculopapular rash in thorax, abdomen and lower extremities. She received intensive management with an inadequate response. Furthermore, she developed multiple organ failure and died 8 h after admission. The blood culture was positive for S. dysgalactiae subsp. equisimilis. Conclusions: SDSE is a rare pathogen in children. In Mexico, cases of SDSE have not been reported probably due to an inaccurate identification. Mexican pediatricians should be alert to this situation.

Resumen Introducción: En adultos, se han identificado infecciones graves por Streptococcus dysgalactiae subsp. equisimilis (SDSE), que pueden causar el síndrome de choque tóxico causado por SDSE, aunque es de baja frecuencia. Caso clínico: Paciente de sexo femenino en edad preescolar. Comenzó con una infección del tracto respiratorio superior, y desarrolló un deterioro gradual en los siguientes tres días. Ingresó en el hospital en condiciones graves, con taquipnea, taquicardia (200/min), hipotensión (tensión arterial, TA 68/40 mmHg), llenado capilar de 7 s y erupción maculopapular eritematosa en el tórax, abdomen y extremidades inferiores. Recibió manejo intensivo, sin una buena respuesta. Posteriormente, desarrolló datos de falla orgánica múltiple y murió 8 h después de su ingreso. El hemocultivo fue positivo para S. dysgalactiae subsp. equisimilis. Conclusiones: El SDSE es un patógeno raro en los niños. En México, no se han reportado casos de SDSE probablemente debido a una identificación errónea. Los pediatras mexicanos deben estar atentos a esta situación.

Fulminant gas-forming breast abscess associated with synergistic Veillonella infection.

We present a rare case of a rapidly fulminant and destructive breast abscess with gas production by the synergistic infection of Veillonella and Streptococcus species. To our knowledge, this is the first reported case of Veillonella infection in the breast. Early recognition, empiric antibiotic cover, aggressive surgical debridement, and drainage are necessary to avoid systemic septicemia. Staged reconstructive breast surgery allows for correction any resultant breast deformity.

Late-onset group B streptococcus infections and severe bronchopulmonary dysplasia in an extremely preterm born infant.

This case report is about a boy born extremely preterm at gestational age of 24 weeks, with extremely low birth weight, developing severe bronchopulmonary dysplasia and in need of mechanical ventilation for 155 days. He also had five recurrent infections with group B streptococcus (GBS) within 4 months from birth, and his respiratory condition clearly deteriorated with every GBS infection. It was difficult to wean him from mechanical ventilation. Finally he was extubated when he was 7 months old and kept out of mechanical ventilation after receiving high-dose methylprednisolone, given according to international recommendations. After GBS was cultured for the fifth time, he received oral rifampicin along with intravenous penicillin and after this treatment, GBS did not occur again. At the age of 22 months, the boy no longer needed any respiratory support and he was about 6 months late in his neurological development.

Antigen I/II Participates in the Interactions of Streptococcus suis Serotype 9 With Phagocytes and the Development of Systemic Disease.

Streptococcus suis is an important porcine bacterial pathogen and a zoonotic agent causing a variety of pathologies including sudden death, septic shock, and meningitis. Though serotype 2 is the most studied serotype due to its presence worldwide, serotype 9 is responsible for the greatest number of porcine cases in Spain, the Netherlands, and Germany. Regardless of its increasing importance, very few studies have investigated S. suis serotype 9 virulence factors and pathogenesis. Antigens I/II (AgI/II) are multimodal adhesion proteins implicated in host respiratory tract and oral cavity persistence of various pathogenic human streptococci. It was recently demonstrated that AgI/II is involved in various bacterial functions for serotype 9, participating in the initial steps of the pathogenesis of the infection. However, its contribution to the systemic infection remains unknown. As such, we evaluated herein the role of the S. suis serotype 9 AgI/II in the interactions with phagocytes and the development of systemic disease in a mouse model of infection. Results demonstrated that the presence of AgI/II is important for the development of clinical systemic disease by promoting bacterial survival in blood possibly due to its effect on S. suis phagocytosis, as shown with macrophages and dendritic cells. Furthermore, AgI/II directly participates in dendritic cell activation and pro-inflammatory mediator production following recognition by the Toll-like receptor pathway, which may contribute to the exacerbated systemic inflammation responsible for host death. Taken together, this study demonstrates that the S. suis serotype 9 AgI/II is important for virulence during systemic infection and development of disease. In fact, this is the first study to describe a role of an AgI/II family member in systemic bacterial disease.

Idiopathic toxic epidermal necrolysis in an adolescent.

A 10-year-old girl, suspected 2 days prior to have streptococcal pharyngitis, presented with diffuse erythema, tense bullae, Nikolsky-positive desquamation, as well as ulcerations of her oral and genital mucosa. She denied recent travel, sick contacts, or preceding and concurrent use of medications, including over-the-counter and herbal supplements. A comprehensive viral polymerase chain reaction (PCR) panel, Mycoplasma pneumoniae PCR and IgM, streptococcal molecular antigen test, urine culture, blood culture, and rheumatologic serologies were negative. Based on the patient's clinical presentation and biopsy results, she was diagnosed with idiopathic toxic epidermal necrolysis.

Streptococcal toxic shock syndrome in a returning traveller.

Background: A patient presenting with fever and purpura after a stay in the tropics tempts a physician to make a differential diagnosis mainly focusing on imported diseases. Although the importance of considering a tropical disease is obvious, the fact that cosmopolitan infections account for one third of the cases in a febrile returning traveler must not be overseen. Toxic Shock Syndrome is amongst the most notorious diseases due to the high mortality when inappropriately managed and the association with necrotizing fasciitis. Methods : We present a 60-year old female with fever, shock syndrome and progressive appearance of painful purpura on the lower legs after a 2-week holiday in Zanzibar. Results : The patient was diagnosed with Streptococcal Toxic Shock Syndrome. Treatment focusing on aggressive fluid resuscitation, prompt administration of antibiotics (ceftriaxon, doxycycline and one dose of amikacin) and adjunctive treatment by clindamycin and immunoglobulin was initiated. She was also immediately taken into surgery for a bilateral fasciotomy and surgical exploration of the lower legs. Histology appeared compatible with purpura fulminans, thereby excluding necrotizing fasciitis. No source of infection could be identified.  Conclusion: Toxic Shock Syndrome remains a challenging diagnosis and even more in a returning traveler with an extensive differential diagnosis containing both tropical and cosmopolitan diseases. Cornerstones for the treatment of Streptococcal Toxic Shock Syndrome are abrupt administration of antimicrobial therapy comprising beta-lactam antibiotics and clindamycin and surgical exploration to apply source control when indicated.

Prolonged extracorporeal membrane oxygenation for pediatric necrotizing pneumonia due to Streptococcus pneumonia and influenza H1N1 co-infection: how long should we wait for native lung recovery?

Most children with severe respiratory failure require extracorporeal membrane oxygenation (ECMO) for 7-10 days. However, some may need prolonged duration ECMO (> 14 days). To date, no consensus exists on how long to wait for native lung recovery. Here we report the case of a 3-year-old boy who developed severe necrotizing pneumonia requiring venovenous (VV) ECMO after 19 days of mechanical ventilation. In the first 4 weeks of his ECMO run, he showed no lung aeration, requiring total extracorporeal support. However, after we started strategies for promoting lung recovery such as daily prone positioning and regular use of toilet bronchoscopy and inhalative DNAse to clear secretions, by week five his tidal volumes gradually increased and he was successfully decannulated after 43 days. Moreover, we decided not to proceed to a surgical removal of the necrotic lung area. At present, he is 1-year post discharge and has fully recovered. This report shows that unexpected native lung recovery is possible even after prolonged loss of lung function and that a previous healthy lung can recover from apparent irreversible lung injury.

Predictors of visual outcome and the role of early vitrectomy in streptococcal endophthalmitis.

IMPORTANCE: Streptococcal endophthalmitis has devastating sequelae. This study aims to identify factors which may be targeted to optimize patient outcomes. BACKGROUND: This study investigated characteristics influencing visual outcomes and the role of early vitrectomy. DESIGN: Retrospective observational case series of consecutive patients was conducted. PARTICIPANTS: All patients with a culture-positive diagnosis of streptococcal endophthalmitis treated at a tertiary ophthalmology referral centre between July 1997 and February 2012 were included. METHODS: Patient records were reviewed and data collected on their presentation, examination, microbiology results, procedures and final outcome. MAIN OUTCOME MEASURES: Visual acuity (VA) and enucleation/evisceration were measured. RESULTS: Of the 101 patients, 35.6% presented with a VA of hand movements and 42.6% with light perception (LP). Final VA was poor (6/60 or worse) in 77.6% and 24.7% were enucleated/eviscerated. Presenting VA of LP or worse (P = 0.008), no view of fundus (P = 0.001), large number of organisms (P < 0.001), recognition of Streptococcus on Gram stain (P = 0.010), heavy growth on culture (P < 0.001) and more intravitreal injections (P = 0.038) were significantly associated with poor visual outcome (6/60 or worse). Presenting VA of LP or worse (P = 0.042) and non-viridans Streptococcus species (P = 0.002) were significantly associated with enucleation/evisceration. Fifteen patients (14.9%) had early vitrectomy within 48 h which was not associated with poor final VA or removal of the eye (P = 1.000). CONCLUSIONS AND RELEVANCE: Early vitrectomy did not influence visual outcome in this cohort. Microbiology results were useful in predicting poor outcomes, and may allow clinicians to make early treatment decisions and provide prognostic information for patients.

Acid Stress Response Mechanisms of Group B Streptococci.

Group B streptococcus (GBS) is a leading cause of neonatal mortality and morbidity in the United States and Europe. It is part of the vaginal microbiota in up to 30% of pregnant women and can be passed on to the newborn through perinatal transmission. GBS has the ability to survive in multiple different host niches. The pathophysiology of this bacterium reveals an outstanding ability to withstand varying pH fluctuations of the surrounding environments inside the human host. GBS host pathogen interations include colonization of the acidic vaginal mucosa, invasion of the neutral human blood or amniotic fluid, breaching of the blood brain barrier as well as survival within the acidic phagolysosomal compartment of macrophages. However, investigations on GBS responses to acid stress are limited. Technologies, such as whole genome sequencing, genome-wide transcription and proteome mapping facilitate large scale identification of genes and proteins. Mechanisms enabling GBS to cope with acid stress have mainly been studied through these techniques and are summarized in the current review.

Endothelial cells are intrinsically defective in xenophagy of Streptococcus pyogenes.

Group A Streptococcus (GAS) is deleterious pathogenic bacteria whose interaction with blood vessels leads to life-threatening bacteremia. Although xenophagy, a special form of autophagy, eliminates invading GAS in epithelial cells, we found that GAS could survive and multiply in endothelial cells. Endothelial cells were competent in starvation-induced autophagy, but failed to form double-membrane structures surrounding GAS, an essential step in xenophagy. This deficiency stemmed from reduced recruitment of ubiquitin and several core autophagy proteins in endothelial cells, as demonstrated by the fact that it could be rescued by exogenous coating of GAS with ubiquitin. The defect was associated with reduced NO-mediated ubiquitin signaling. Therefore, we propose that the lack of efficient clearance of GAS in endothelial cells is caused by their intrinsic inability to target GAS with ubiquitin to promote autophagosome biogenesis for xenophagy.