Neonatal overfeeding attenuates microgliosis and hippocampal damage in an infant rat model of pneumococcal meningitis.

Background: Pneumococcal meningitis (PM) triggers apoptotic neuronal and progenitor cell death in the hippocampal dentate gyrus (DG), resulting in subsequent cognitive impairment. Microglia play a crucial role in PM-induced hippocampal damage. While the lasting effects of neonatal nutrition on health are well documented, the influence of early-life overfeeding on the host response to neuroinfections remains uncertain. This study aimed to examine whether neonatal overfeeding affects the outcome of PM in the hippocampus (HC). Material and methods: Overfeeding was induced by adjusting litter size immediately after birth. On the eleventh day of life, rats were intracisternally injected with Streptococcus pneumoniae or saline, followed by euthanasia after 24 hours for brain dissection. Histological analysis evaluated apoptosis in the DG and the extent of inflammatory infiltrate in the hippocampal fissure, while microgliosis was assessed by immunohistochemistry. The hippocampal transcriptome was analyzed using RNAseq, and the mRNA levels of specific inflammatory biomarkers were evaluated via RT-qPCR. Results: Overfed rats exhibited 40.5% greater body mass compared to their normal-fed counterparts. Intriguingly, PM-induced apoptosis in the DG was 50% lower in overfed rats. This effect was accompanied by significant alterations in the hippocampal transcriptional profile, particularly the lack of activation of the Programmed cell death pathway in overfed infected animals. RT-qPCR analysis of Aif1 and examination of Iba1-immunostained cells revealed mild microgliosis in the HC of infected-overfed animals. This reduced microglial reaction may be attributed to the diminished activation of interferon signaling pathways, as disclosed by the transcriptome analysis, potentially preventing microglial priming. Additionally, evidence of reduced neuroinflammation in overfed rats with PM was observed through the milder activation of pathways associated with Toll-like receptors, interleukins, and chemokine signaling. Furthermore, overfed animals exhibited increased transcription of proinflammatory Il6 and anti-inflammatory Il10 genes, with the latter showing higher expression even in the absence of PM, suggesting a priming effect of overfeeding on hippocampal immune cells. Conclusion: This study sheds light on the complex interplay between early-life overfeeding, immune response, and neuroprotection in infant rats with PM. The findings demonstrate the neuroprotective impact of early-life overfeeding in the context of PM, linked to the modulation of microglial function.

IL-10-Mediated Regulation of Microglial Inflammation in Brain Meningitis: Novel Insights and Therapeutic Potential.

BACKGROUND: Inflammation is a key pathological process in bacterial meningitis, and the transforming growth factor-beta-activated kinase 1 (TAK1)/nuclear factor-kappa B (NF-κB) pathway is implicated in the activation of microglia and the production of inflammatory factors. Interleukin (IL)-10 is an anti-inflammatory cytokine acting in an autocrine fashion in macrophages to limit inflammatory responses by decreasing the production of pro-inflammatory cytokines. This paper investigates how IL-10 can inhibit microglia activation and reduce the inflammatory response of nervous system diseases. METHODS: This study used a pneumococcal-induced in Pneumococcal meningitis (PM) C57BL/6 mice and BV-2 cells model of microglial activation, assessing the effects of IL-10 on the TAK1/NF-κB pathway. The impact of IL-10 on microglial autophagy was investigated through western blot and immunofluorescence. The effects of IL-10 were evaluated by examining cellular activation markers and the activity of molecular signaling pathways (such as phosphorylation levels of TAK1 and NF-κB). RESULTS: Pneumococcus induced the activation of microglia and reduced IL-10. IL-10 inhibited the TAK1/NF-κB pathway, reducing the pneumococcal-induced inflammatory response in microglia. IL-10 ameliorated pneumococcal infection-induced microglial injury by inhibiting autophagy. Animal experiment results also showed that IL-10 inhibited inflammation and autophagy during Pneumococcal meningitis in mice. CONCLUSION: Our study demonstrates that IL-10 reduces the inflammatory response of microglia by inhibiting the TAK1/NF-κB pathway. Additionally, IL-10 ameliorates pneumococcal infection-induced microglial injury by inhibiting the process of autophagy. These results provide a new theoretical basis and offer new insights for developing strategies to treat bacterial meningitis.

Spatio-temporal brain invasion pattern of Streptococcus pneumoniae and dynamic changes in the cellular environment in bacteremia-derived meningitis.

Streptococcus pneumoniae (the pneumococcus) is the major cause of bacterial meningitis globally, and pneumococcal meningitis is associated with increased risk of long-term neurological sequelae. These include several sensorimotor functions that are controlled by specific brain regions which, during bacterial meningitis, are damaged by a neuroinflammatory response and the deleterious action of bacterial toxins in the brain. However, little is known about the invasion pattern of the pneumococcus into the brain. Using a bacteremia-derived meningitis mouse model, we combined 3D whole brain imaging with brain microdissection to show that all brain regions were equally affected during disease progression, with the presence of pneumococci closely associated to the microvasculature. In the hippocampus, the invasion provoked microglial activation, while the neurogenic niche showed increased proliferation and migration of neuroblasts. Our results indicate that, even before the outbreak of symptoms, the bacterial load throughout the brain is high and causes neuroinflammation and cell death, a pathological scenario which ultimately leads to a failing regeneration of new neurons.

Pneumococcal Meningitis Induces Hearing Loss and Cochlear Ossification Modulated by Chemokine Receptors CX3CR1 and CCR2.

PURPOSE: Pneumococcal meningitis is a major cause of hearing loss and permanent neurological impairment despite widely available antimicrobial therapies to control infection. Methods to improve hearing outcomes for those who survive bacterial meningitis remains elusive. We used a mouse model of pneumococcal meningitis to evaluate the impact of mononuclear phagocytes on hearing outcomes and cochlear ossification by altering the expression of CX3CR1 and CCR2 in these infected mice. METHODS: We induced pneumococcal meningitis in approximately 500 C57Bl6 adult mice using live Streptococcus pneumoniae (serotype 3, 1 × 105 colony forming units (cfu) in 10 µl) injected directly into the cisterna magna of anesthetized mice and treated these mice with ceftriaxone daily until recovered. We evaluated hearing thresholds over time, characterized the cochlear inflammatory response, and quantified the amount of new bone formation during meningitis recovery. We used microcomputed tomography (microCT) scans to quantify cochlear volume loss caused by neo-ossification. We also performed perilymph sampling in live mice to assess the integrity of the blood-perilymph barrier during various time intervals after meningitis. We then evaluated the effect of CX3CR1 or CCR2 deletion in meningitis symptoms, hearing loss, macrophage/monocyte recruitment, neo-ossification, and blood labyrinth barrier function. RESULTS: Sixty percent of mice with pneumococcal meningitis developed hearing loss. Cochlear fibrosis could be detected within 4 days of infection, and neo-ossification by 14 days. Loss of spiral ganglion neurons was common, and inner ear anatomy was distorted by scarring caused by new soft tissue and bone deposited within the scalae. The blood-perilymph barrier was disrupted at 3 days post infection (DPI) and was restored by seven DPI. Both CCR2 and CX3CR1 monocytes and macrophages were present in the cochlea in large numbers after infection. Neither chemokine receptor was necessary for the induction of hearing loss, cochlear fibrosis, ossification, or disruption of the blood-perilymph barrier. CCR2 knockout (KO) mice suffered the most severe hearing loss. CX3CR1 KO mice demonstrated an intermediate phenotype with greater susceptibility to hearing loss compared to control mice. Elimination of CX3CR1 mononuclear phagocytes during the first 2 weeks after meningitis in CX3CR1-DTR transgenic mice did not protect mice from any of the systemic or hearing sequelae of pneumococcal meningitis. CONCLUSIONS: Pneumococcal meningitis can have devastating effects on cochlear structure and function, although not all mice experienced hearing loss or cochlear damage. Meningitis can result in rapid progression of hearing loss with fibrosis starting at four DPI and ossification within 2 weeks of infection detectable by light microscopy. The inflammatory response to bacterial meningitis is robust and can affect all three scalae. Our results suggest that CCR2 may assist in controlling infection and maintaining cochlear patency, as CCR2 knockout mice experienced more severe disease, more rapid hearing loss, and more advanced cochlear ossification after pneumococcal meningitis. CX3CR1 also may play an important role in the maintenance of cochlear patency.

Neuronal death in pneumococcal meningitis is triggered by pneumolysin and RrgA interactions with ß-actin.

Neuronal damage is a major consequence of bacterial meningitis, but little is known about mechanisms of bacterial interaction with neurons leading to neuronal cell death. Streptococcus pneumoniae (pneumococcus) is a leading cause of bacterial meningitis and many survivors develop neurological sequelae after the acute infection has resolved, possibly due to neuronal damage. Here, we studied mechanisms for pneumococcal interactions with neurons. Using human primary neurons, pull-down experiments and mass spectrometry, we show that pneumococci interact with the cytoskeleton protein ß-actin through the pilus-1 adhesin RrgA and the cytotoxin pneumolysin (Ply), thereby promoting adhesion and invasion of neurons, and neuronal death. Using our bacteremia-derived meningitis mouse model, we observe that RrgA- and Ply-expressing pneumococci co-localize with neuronal ß-actin. Using purified proteins, we show that Ply, through its cholesterol-binding domain 4, interacts with the neuronal plasma membrane, thereby increasing the exposure on the outer surface of ß-actin filaments, leading to more ß-actin binding sites available for RrgA binding, and thus enhanced pneumococcal interactions with neurons. Pneumococcal infection promotes neuronal death possibly due to increased intracellular Ca2+ levels depending on presence of Ply, as well as on actin cytoskeleton disassembly. STED super-resolution microscopy showed disruption of ß-actin filaments in neurons infected with pneumococci expressing RrgA and Ply. Finally, neuronal death caused by pneumococcal infection could be inhibited using antibodies against ß-actin. The generated data potentially helps explaining mechanisms for why pneumococci frequently cause neurological sequelae.

Cerebral venous thrombosis in pneumococcal meningitis: An autopsy study.

AIMS: Cerebral venous thrombosis (CVT) is a rare but severe complication of bacterial meningitis. The histopathological features of CVT in meningitis patients have not been described. MATERIALS AND METHODS: We studied histopathology findings of brain autopsy material from 2 patients with bacterial meningitis complicated by CVT and compared findings with those in 3 CVT patients without meningitis and 1 patient with bacterial meningitis without CVT. The histological slides were re-evaluated and assessed for the presence of thrombosis, cerebral venous sinus mural inflammation and bleeding, inflammation at the thrombosis attachment point, endothelial abnormalities, and the presence of bacteria. RESULTS: The 2 patients who died of bacterial meningitis complicated by CVT showed multifocal deep intramural inflammation in the cerebral venous sinus, whereas this was absent in patients with only bacterial meningitis or CVT. Bacteria were identified within the intramural inflammation and thrombus. CONCLUSION: We observed bacterial invasion causing multifocal deep intramural inflammation and venous wall disintegration as CVT in pneumococcal meningitis.

Evaluation of Rat Brain Morphology Following the Induction of Acute Meningitis Treated with Ceftriaxone.

The soft and delicate tissue of the brain, which is the center of our coordination, is protected by its surrounding layers. The disruption of these layers results in complicated situations and serious health problems. The brain has three protective layers of bone or skull tissue, the blood tissue layer, and finally the meningeal layer. The layer of blood tissue contains the blood vessels that are located between the skull and the meningeal membranes. If germs or foreign matter enter the fluid through the blood vessels under any circumstances and cause infection, the bones that protect the meninges will break and cause tissue damage. The present study aimed to assess the histological and immunohistochemical characteristics of the brain of rats that underwent induced acute purulent pneumococcal meningitis after antibiotic therapy with Ceftriaxone. A number of 20 white adult male Wistar rats were assigned to three groups. The first group (n=5) regarded as the control were injected with a saline solution into the subarachnoid space in an equivalent amount. The second and third groups of rats (n=5 and 10, respectively) were infected with acute purulent meningitis by the injection of 10 µl of Streptococcus pneumoniae (S. pneumonia) suspension into the subarachnoid space of the brain using a 23-G needle. The various areas of the brains of rats after meningitis induced by S. pneumoniae were examined after the treatment with Ceftriaxone. The S. pneumoniae culture was injected into the subarachnoid space in the area of the rhomboid fossa. Treatment started 18 h after the injection. On day 10, a repeated puncture was performed with the analysis of cerebrospinal fluid in order to confirm the absence of meningitis; thereafter, the animals were taken out of the experiment. No signs of meningitis were found on histological examination. Mild perivascular and pericellular focal edema were revealed with signs of overload of the lymphatic system in the brain and focal ischemic changes in neurons. The investigation of expression with caspase-3 revealed a positive reaction of individual neurons. A positive reaction with antibodies to NeuN and Doublecortin was detected in most neurons; moreover, Glial fibrillary acidic protein (GFAP)-positive astrocytes and their processes were visualized in all layers of the brain substance. The reaction with neuron-specific enolase (NSE), microtubule-associated protein 2 (MAP-2), CD 31, and CD 34 was negative. Typical structure and pictures pointed to an intact brain and purulent meningitis in the first and second groups. The microscopic image and the changes revealed during immunohistochemistry by dual corticosteroid antibodies and neuronal nuclear protein were characterized by predominantly cytoplasmic and perinuclear reactions, respectively. Some neurons are positive for caspase-3 and are related to changes in the characteristic of premature aging.

Evaluation of neurofilament light chain in the cerebrospinal fluid and blood as a biomarker for neuronal damage in experimental pneumococcal meningitis.

BACKGROUND: Pneumococcal meningitis (PM) remains a global public health concern and affects all age groups. If acquired during infancy or childhood, permanent neurofunctional deficits including cognitive impairment, cerebral palsy, and secondary epilepsy are typical sequelae of neuronal injury. Determination of patients at risk for the development of brain injury and subsequent neurofunctional sequelae could help to identify patients for focused management. Neurofilament light chain (NfL) is an axonal cytoskeletal protein released upon neuronal injury into the cerebrospinal fluid (CSF) and blood. As little is known about the course of neurofilament release in the course of PM, we measured CSF and serum NfL levels longitudinally in experimental PM (ePM). METHODS: Eleven-day-old infant Wistar rats were infected intracisternally with Streptococcus pneumoniae and treated with ceftriaxone. At 18 and 42 h post-infection (hpi), the blood and CSF were sampled for NfL measurements by a single molecule array technology. Inflammatory cytokines and MMP-9 in CSF were quantified by magnetic bead multiplex assay (Luminex®) and by gel zymography, respectively. RESULTS: In ePM, CSF and serum NfL levels started to increase at 18 hpi and were 26- and 3.5-fold increased, respectively, compared to mock-infected animals at 42 hpi (p < 0.0001). CSF and serum NfL correlated at 18 hpi (p < 0.05, r = 0.4716) and 42 hpi (p < 0.0001, r = 0.8179). Both CSF and serum NfL at 42 hpi strongly correlated with CSF levels of IL-1ß, TNF-α, and IL-6 and of MMP-9 depending on their individual kinetics. CONCLUSION: Current results demonstrate that during the peak inflammatory phase of ePM, NfL levels in CSF and serum are the highest among CNS disease models studied so far. Given the strong correlation of CSF versus serum NfL, and its CNS-specific signal character, longitudinal measurements to monitor the course of PM could be performed based on blood sample tests, i.e., without the need of repetitive spinal taps. We conclude that NfL in the serum should be evaluated as a biomarker in PM.

Selective Loss of Brain-Derived Neurotrophic Factor Exacerbates Brain Injury by Enhancing Neuroinflammation in Experimental Streptococcus pneumoniae Meningitis.

Streptococcus pneumoniae meningitis is a life-threatening bacterial infection of the central nervous system (CNS), and its unfavorable prognosis usually results from an intense inflammatory response. Recent studies have shown that brain-derived neurotrophic factor (BDNF) mediates anti-inflammatory and neuroprotective effects in CNS diseases; however, the distinct contribution of BDNF to pneumococcal meningitis (PM) remains unknown. In this study, we sought to investigate the effects of endogenous BDNF on the inflammatory response and brain damage in experimental PM. We used Camk2a-CreERT2 mice to delete Bdnf from the cerebral cortex and hippocampus, and meningitis was induced by intracisternal infection with S. pneumoniae. Clinical parameters were assessed during acute meningitis. At 24 h post-infection, histopathology, neutrophil granulocytes infiltration, and microglia/macrophage proliferation of brain tissues were evaluated. Additionally, cortical damage and hippocampal apoptosis were assessed using Nissl staining and terminal deoxynucleotidyl transferase dUTP-nick-end labeling (TUNEL), respectively. Pro-inflammatory cytokine levels were determined using real-time polymerase chain reaction (RT-PCR). Key molecules associated with the related signaling pathways were analyzed by RT-PCR and western blot. To investigate the role of microglia/macrophage in infected BDNF conditional knockout mice, GW2580 was used for microglia/macrophage depletion. Here, we, for the first time, found that BDNF conditional knockouts exhibited more profound clinical impairment, pathological severity, and neuron injury and enhanced microglia/macrophage proliferation than were observed in their littermate controls. Furthermore, the BDNF conditional knockouts showed an obviously increase in the expression of pro-inflammatory factors (Tnf-α, Il-1ß, and Il-6). Mechanistically, loss of BDNF activated TLR2- and NOD2-mediated downstream nuclear factor kappa B (NF-κB) p65 and p38 mitogen-activated protein kinase (MAPK) pathways associated with S. pneumoniae infection. Furthermore, targeted depletion of microglia/macrophage population decreased the resistance of mice to PM with diminishing neuroinflammation in BDNF conditional knockouts. Our findings suggest that loss of BDNF may enhance the inflammatory response and contribute to brain injury during PM at least partially by modulating TLR2- and NOD2-mediated signaling pathways, thereby providing a potential therapeutic target for future interventions in bacterial meningitis pathologies.

NOD2 regulates microglial inflammation through the TAK1-NF-κB pathway and autophagy activation in murine pneumococcal meningitis.

Streptococcus pneumoniae is responsible for pneumococcal meningitis, with significant mortality and morbidity worldwide. Microglial inflammation plays a vital role in meningitis. The peptidoglycan sensor NOD2 (nucleotide-binding oligomerization domain 2) has been identified to promote microglia activation, but the role in autophagy following pneumococcal meningitis remains unclear. In the present study, we investigated the role of NOD2 in microglial inflammation and autophagy, as well as related signaling pathways, during S. pneumonia infection. NOD2 expression was knocked down by the injection of lentivirus-mediated short-hairpin RNA (shRNA). Our results revealed that NOD2 promotes microglial inflammation by increasing inflammatory mediators. We also showed that the TAK1-NF-κB pathway is involved in this process. In addition, NOD2 increased the expression of autophagy-related proteins and induced autophagosome formation. Rapamycin and 3-MA were utilized to assess the role of autophagy in microglial inflammation induced by S. pneumonia. We demonstrated that autophagy serves as a cellular defense mechanism to reduce inflammatory mediators. Similar to the in vitro results, NOD2 induced inflammation and autophagy in the brain in a mouse meningitis model. Moreover, NOD2 silencing significantly reduced brain edema and improved the neurological function of pneumococcal meningitis mice. Taken together, these data demonstrate that NOD2 promotes microglial inflammation and autophagy in murine pneumococcal meningitis, and the TAK1-NF-κB pathway is involved in microglial activation.

Ribosomal Protein SA-Positive Neutrophil Elicits Stronger Phagocytosis and Neutrophil Extracellular Trap Formation and Subdues Pro-Inflammatory Cytokine Secretion Against Streptococcus suis Serotype 2 Infection.

Streptococcus suis serotype 2 (SS2), an important zoonotic pathogen that causes septicemia, arthritis, and irreversible meningitis in pigs and humans, can be transmitted to humans from pigs. S. suis causes huge economic losses to the swine industry and poses a serious threat to public health. Previously, we found that the brain tissues of mice with SS2-induced meningitis showed disrupted structural integrity and significantly enhanced polymorphonuclear neutrophil (PMN) infiltration. We showed that the brain tissues of SS2-infected mice had increased ribosomal protein SA (RPSA)-positive PMN counts. However, the inflammatory responses of RPSA+ PMNs to SS2 and their effects on the blood-brain barrier (BBB) remain unclear. Therefore, in studying the pathogenesis of SS2-induced meningitis, it is essential that we explore the functions of RPSA+ PMNs and their effects on the BBB. Herein, using flow cytometry and immunofluorescence microscopy analyses, we found that RPSA expression enhances PMN-induced phagocytosis and PMN-induced formation of neutrophil extracellular traps (NETs), which facilitate further elimination of bacteria. PMN surface expression of RPSA also alleviates local inflammation and tissue injuries by inhibiting secretion of the pro-inflammatory cytokines, TNF-α and IL-6. Moreover, the single-cell BBB model showed that RPSA disrupts BBB integrity by downregulating expression of tight junction-associated membrane proteins on PMNs. Taken together, our data suggest that PMN-surface expression of RPSA is a double-edged sword. RPSA+ PMN owns a stronger ability of bacterial cleaning and weakens inflammatory cytokines release which are useful to anti-infection, but does hurt BBB. Partly, RPSA+ PMN may be extremely useful to control the infection as a therapeutic cellular population, following novel insights into the special PMN population.

Double deficiency of toll-like receptors 2 and 4 alters long-term neurological sequelae in mice cured of pneumococcal meningitis.

Toll-like receptor (TLR) 2 and 4 signalling pathways are central to the body's defence against invading pathogens during pneumococcal meningitis. Whereas several studies support their importance in innate immunity, thereby preventing host mortality, any role in protecting neurological function during meningeal infection is ill-understood. Here we investigated both the acute immunological reaction and the long-term neurobehavioural consequences of experimental pneumococcal meningitis in mice lacking both TLR2 and TLR4. The absence of these TLRs significantly impaired survival in mice inoculated intracerebroventricularly with Streptococcus pneumoniae. During the acute phase of infection, TLR2/4-deficient mice had lower cerebrospinal fluid concentrations of interleukin-1ß, and higher interferon-γ, than their wild-type counterparts. After antibiotic cure, TLR2/4 double deficiency was associated with aggravation of behavioural impairment in mice, as shown by diurnal hypolocomotion throughout the adaptation phases in the Intellicage of TLR-deficient mice compared to their wild-type counterparts. While TLR2/4 double deficiency did not affect the cognitive ability of mice in a patrolling task, it aggravated the impairment of cognitive flexibility. We conclude that TLR2 and TLR4 are central to regulating the host inflammatory response in pneumococcal meningitis, which may mediate diverse compensatory mechanisms that protect the host not only against mortality but also long-term neurological complications.

Upregulation of CBP by PLY can cause permeability of blood-brain barrier to increase meningitis.

BACKGROUND: Streptococcus pneumoniae causes many human diseases including bacterial meningitis. Previous study proposed that pneumolysin (PLY), a cytotoxin from pneumococcus, is related to the infection across blood-brain barrier (BBB). However, the mechanism of how PLY break through BBB remains elusive. The present study showed that PLY can increase the permeability of BBB both in vitro and in vivo in our experiments. RESULTS: Further we found out that PLY leads to the high expression of CERB-binding protein (CBP) which can lead to releasing of tumor necrosis factor α then enhance apoptosis of cells which is a significant factor leading to permeabilization of BBB. CONCLUSION: Our findings demonstrate that CBP plays an important role in the pneumococcus infection in the brain and could be a potential therapeutic target against pneumococcal meningitis.

Quadruple valve infective endocarditis presenting with suspected Austrian syndrome: a case report and a case series of quadruple valve infective endocarditis.

OBJECTIVES: Austrian syndrome comprises the triad of pneumonia, meningitis, and endocarditis secondary to Streptococcus pneumonia. We present what we believe to be the first reported case of Austrian syndrome with quadruple heart valve involvement and review the literature detailing cases of quadruple valve infective endocarditis. CASE PRESENTATION AND RESULTS: A case is presented of a patient with radiographic evidence of a left lower lobe pneumonia. Sequential transthoracic followed by transesophageal echocardiogram done to evaluate the presence of a cardiac murmur revealed the presence of quadruple valve vegetations. Multiple blood cultures were persistently negative. The patient went on to develop seizures secondary to proven meningitis. Microbiological diagnosis was eventually established through positive Streptococcus pneumoniae antigen (Alere BinaxNOW®) from cerebrospinal fluid, establishing a presumptive clinical diagnosis of Austrian syndrome. A computerized PubMed search for reports of quadruple valve infective endocarditis and their references was collated. A total of 22 patients were found, including our patient. The median age of presentation was 47.5 years. Five patients had a history of intravenous drug abuse, another 5 had underlying congenital heart disease, and 1 had both. Two patients (9.1%) had 2 microorganisms isolated. Staphylococcus aureus and Streptococcus viridans (3 cases, 13.6% each) were the most commonly implicated microorganism. Heart failure was the commonest complication, afflicting 11 patients (50.0%). Ten patients (45.5%) underwent surgery. Overall case fatality rate was 50.0%. Cardiac surgery was of statistical significance in predicting survival (P = 0.009). CONCLUSION: Quadruple valve endocarditis is associated with a high mortality rate, and cardiac surgery may be protective.

Blood‒Brain Barrier Pathology and CNS Outcomes in Streptococcus pneumoniae Meningitis.

Streptococcus pneumoniae is a major meningitis-causing pathogen globally, bringing about significant morbidity and mortality, as well as long-term neurological sequelae in almost half of the survivors. Subsequent to nasopharyngeal colonisation and systemic invasion, translocation across the blood‒brain barrier (BBB) by S. pneumoniae is a crucial early step in the pathogenesis of meningitis. The BBB, which normally protects the central nervous system (CNS) from deleterious molecules within the circulation, becomes dysfunctional in S. pneumoniae invasion due to the effects of pneumococcal toxins and a heightened host inflammatory environment of cytokines, chemokines and reactive oxygen species intracranially. The bacteria‒host interplay within the CNS likely determines not only the degree of BBB pathological changes, but also host survival and the extent of neurological damage. This review explores the relationship between S. pneumoniae bacteria and the host inflammatory response, with an emphasis on the BBB and its roles in CNS protection, as well as both the acute and long-term pathogenesis of meningitis.

Resveratrol Acts Anti-Inflammatory and Neuroprotective in an Infant Rat Model of Pneumococcal Meningitis by Modulating the Hippocampal miRNome.

Resveratrol (RSV) is anti-inflammatory and neuroprotective, cross the blood-brain barrier (BBB) and has a safe profile. Besides, RSV modulates the expression of some miRNAs related to neurological disorders. Thus, we hypothesized that RSV can be neuroprotective in pneumococcal meningitis by modulating the global microRNA expression profile (miRNome). Eleven-day old rats were intracysternally infected with S. pneumoniae (~ 2 × 106 c.f.u.) and were orally administered with RSV (50 mg/kg) or vehicle in pre-treatment (before infection) or post-treatment schedules (3 and 18 h p.i.). At 24 h p.i., animals were euthanized and apoptotic cells were counted in the hippocampal dentate gyrus of the right brain hemispheres. The hippocampi from left hemispheres were used for cytokines and chemokines multiplex assay and miRNome profiling with TaqMan OpenArray Rodent MicroRNA. Infected rats treated with RSV had lower apoptotic scores and IL-1ß, CCL2, and CCL3 levels when compared to the infected group receiving placebo. Seven miRNAs were down regulated, and 18 were up regulated by pneumococcal acute meningitis. Thirty-seven miRNAs were down regulated, and three were up regulated (hsa-miR-15b-5p, hsa-miR-25-3p, hsa-miR-125b-5p) by the interaction between meningitis and RSV. Pathway enriched analysis revealed that meningitis and RSV modulate the expression of miRNAs targeting critical pathways related to the pathophysiology of bacterial meningitis. Nevertheless, hsa-miR-25-3p and hsa-miR-125b-5p target the transcription factor TEF-1, for which there are binding sites in Il-1ß, Ccl2, and Ccl3 genes. RSV is anti-inflammatory and neuroprotective in an infant rat model of pneumococcal meningitis and these positive effects involve the modulation of the hippocampal miRNome.

DNA repair protein APE1 is involved in host response during pneumococcal meningitis and its expression can be modulated by vitamin B6.

BACKGROUND: The production of reactive oxygen species (ROS) during pneumococcal meningitis (PM) leads to severe DNA damage in the neurons and is the major cause of cell death during infection. Hence, the use of antioxidants as adjuvant therapy has been investigated. Previous studies have demonstrated the possible participation of apurinic/apyrimidinic endonuclease (APE1) during PM. The aims of this study were to investigate the APE1 expression in the cortical and hippocampal tissues of infant Wistar rats infected with Streptococcus pneumoniae and its association with cell death and understand the role of vitamin B6 (vitB6) as a protective factor against cell death. METHODS: APE1 expression and oxidative stress markers were analyzed at two-time points, 20 and 24 h post infection (p.i.), in the cortex (CX) and hippocampus (HC) of rats supplemented with vitB6. Statistical analyses were performed by the nonparametric Kruskal-Wallis test using Dunn's post test. RESULTS: Our results showed high protein levels of APE1 in CX and HC of infected rats. In the CX, at 20 h p.i., vitB6 supplementation led to the reduction of expression of APE1 and apoptosis-inducing factor, while no significant changes in the transcript levels of caspase-3 were observed. Furthermore, levels of carbonyl content and glutamate in the CX were reduced by vitB6 supplementation at the same time point of 20 h p.i.. Since our data showed a significant effect of vitB6 on the CX at 20 h p.i. rather than that at 24 h p.i., we evaluated the effect of administering a second dose of vitB6 at 18 h p.i. and sacrifice at 24 h p.i.. Reduction in the oxidative stress and APE1 levels were observed, although the latter was not significant. Although the levels of APE1 was not significantly changed in the HC with vitB6 adjuvant therapy, vitB6 supplementation prevented the formation of the truncated form of APE1 (34 kDa) that is associated with apoptosis. CONCLUSIONS: Our data suggest that PM affects APE1 expression, which can be modulated by vitB6. Additionally, vitB6 contributes to the reduction of glutamate and ROS levels. Besides the potential to reduce cell death and oxidative stress during neuroinflammation, vitB6 showed enhanced effect on the CX than on the HC during PM.

Sporadic isolated congenital asplenia with fulminant pneumococcal meningitis: a case report and updated literature review.

BACKGROUND: Isolated congenital asplenia (ICA) is a rare and life-threatening condition that predisposes patients to severe bacterial infections. Most of the reported cases are familial and the mode of inheritance is usually autosomal dominant. Here, we report a case of sporadic isolated asplenia and review the literature while focusing on sporadic cases. CASE PRESENTATION: We report the case of an 11-month-old female infant who developed fulminant pneumococcal meningitis. The pneumococcal vaccine-unimmunized patient was hospitalized with fever, irritability, and purpura, and was diagnosed as having meningitis, septic shock, and disseminated intravascular coagulation. Streptococcus pneumoniae was isolated from both cerebrospinal fluid and blood. She was successfully treated with prompt antibiotic therapy. During hospitalization, abdominal ultrasonography and computed tomography findings, scintigraphy results, and Howell-Jolly body-containing red blood cells indicated the presence of asplenia without any visceroarterial anomalies. Moreover, the findings of peripheral blood smears and spleen ultrasonographic examinations of her parents were normal. CONCLUSIONS: Majority of sporadic ICA cases were detected only after the onset of overwhelming infection and had a high mortality. In cases of severe invasive pneumococcal disease, a systematic search for Howell-Jolly bodies on blood smears and the presence of asplenia on abdominal imaging are essential for detecting ICA even in the absence of any family history. After the diagnosis of ICA, patient and parent education, vaccinations, antibiotic prophylaxis, and prompt empiric treatment of febrile episode should be provided.

Inhibition of DAMP signaling as an effective adjunctive treatment strategy in pneumococcal meningitis.

BACKGROUND: Pneumococcal meningitis remains a potentially lethal and debilitating disease, mainly due to brain damage from sustained inflammation. The release of danger-associated molecular patterns (DAMPs), like myeloid-related protein 14 (MRP14) and high mobility group box 1 protein (HMGB1), plays a major role in persistence of inflammation. In this study, we evaluated if paquinimod, an MRP14-inhibitor, and an anti-HMGB1 antibody can improve clinical outcome as adjunctive therapeutics in pneumococcal meningitis. METHODS: We tested the adjuvant administration of paquinimod and the anti-HMGB1 antibody in our pneumococcal meningitis mouse model assessing clinical (clinical score, open-field-test, temperature) and pathophysiological parameters (intracranial pressure, white blood cell count in CSF, bleeding area) as well as bacterial titers in blood and brain 24 h after administration and 48 h after infection. Furthermore, we explored the interactions of these two agents with dexamethasone, the standard adjuvant treatment in pneumococcal meningitis (PM), and daptomycin, a non-bacteriolytic antibiotic preventing pathogen-associated molecular pattern (PAMP) release. RESULTS: Adjunctive inhibition of MRP14 or HMGB1 reduced mortality in mice with PM. This effect was lost when the two anti-DAMP agents were given simultaneously, possibly due to excessive immunosuppression. Combining anti-PAMP (daptomycin) and anti-DAMP treatments did not produce synergistic results; instead, the anti-DAMP treatment alone was sufficient and superior. The combination of anti-HMGB1 with dexamethasone did not diminish the effect of the former. CONCLUSIONS: DAMP inhibition possesses good potential as an adjuvant treatment approach in PM, as it improves clinical outcome and can be given together with the standard adjuvant dexamethasone without drug effect loss in experimental PM.