Expression of the α7 nAChR Subunit Duplicate Form (CHRFAM7A) Was Down-Regulated in Patients with Intracranial Infection and Reduced Inflammation in in vitro Model by p38 MAPK.

OBJECTIVE: In this study, we investigated that the effects and possible mechanisms of the α7 nAChR subunit duplicate form (CHRFAM7A) affected inflammation in the model of intracranial infection. METHODS: Mice of the model group were injected (intracranial injection) with Staphylococcus aureus. Mouse microglial BV2 cell was exposed with 200 ng of LPS for 4 h. RESULTS: CHRFAM7A mRNA expressions were reduced in patients with intracranial infection. CHRFAM7A mRNA and protein expressions were suppressed in mice with intracranial infection in a time-dependent manner. CHRFAM7A reduced inflammation in mice with intracranial infection. The inhibition of CHRFAM7A reduced inflammation in mice with intracranial infection. CHRFAM7A suppressed p38 MAPK in mice with intracranial infection. The inhibition of p38 MAPK shows the effects of CHRFAM7A in intracranial infection. CONCLUSION: Our data demonstrate that the expression of the CHRFAM7A was down-regulated in patients with intracranial infection and reduced inflammation in in vitro model by p38 MAPK, which suggests the potential role of CHRFAM7A as a diagnostic biomarker for intracranial infection.

Sequential infection of Epstein-Barr virus and cryptococcal encephalitis after umbilical cord blood transplantation in a child with X-linked adrenoleukodystrophy.

Dual infection with two pathogens can be found in few cases of encephalitis. Cases of sequential infection with EBV and cryptococcal encephalitis in post-transplant patients are rare. We describe a 5-year-old boy with X-linked adrenoleukodystrophy who presented sequential infection with EBV and cryptococcal encephalitis after umbilical cord blood transplant. The patient showed fever, vomiting and emotional agitation with EBV DNA detected in CSF on day 100. The child underwent 3 doses of intravenous rituximab with a good response. However, the child presented with right facial paralysis, headache, and fever on day 130 after 2 weeks of clinical stability. Brain MRI demonstrated chronic granuloma formed with ring enhancement. FilmArray ME PCR confirmed the existence of Cryptococcus neoformans/gattii in the CSF. The child underwent sequential treatment with amphotericin liposome B and flucytosine. Maintenance treatment with fluconazole was administered for 1 year. Facial paralysis was on longer present on day 260. Cryptococcus neoformans/gattii was not detected on day 310. The biochemistry and cell count of the CSF were completely normal on day 520. Follow-up 2.5 years after presentation, brain MRI changes showed near complete resolution of the lesions. The child survived for 3 years to the last following-up. Invasive cryptococcal encephalitis is rare and life-threatening complication of transplantation. It is important to recognize dual infections, and perform treatment quickly to improve the prognosis of encephalitis after transplantation.

Analysis of Multiple Risk Factors for Seronegative Rate of Anti-Tick-Borne Encephalitis Virus Immunization in Human Serum.

Background and objectives: Tick-borne encephalitis virus (TBEV) infections have been the cause of threatening outbreaks for many years. Apart from several physical and chemical methods to prevent tick bites, active vaccination of people highly exposed to infection is still the most important strategy of prevention. However, in some subjects, the lack of or low response to TBEV antigens is observed. The aim of the current study was to assess the prevalence of seronegative rate for anti-TBEV antibodies and the risk factors for waning immunity. Materials and Methods: 2315 at least primary vaccinated subjects from the high risk group for TBEV infections participated in this study. A commercial enzyme-linked immunosorbent assay (ELISA) test was used for the assessment of anti-TBEV IgG serum level. Results: Data showed that 86.2% of subjects who underwent vaccination were positive for anti-TBEV antibodies within 5 years. As much as 13.8% of subjects that underwent primary or primary and booster vaccination were barely protected after vaccination. Women and subjects under 60 years underwent more effective protection but sex and older age was not a risk factor for being a subject of waning immunity. A logistic regression showed that both a longer time since the vaccination and a lower number of booster doses constantly increased the chance of lost anti-TBEV antibodies. Conclusions: This study demonstrates that the vaccination schedule should be reevaluated. The extension of the interval of booster immunization is risky and all subjects should be surrounded by care consisting of more frequent monitoring of serum antibodies by personalized schedule to adjust the frequency of subsequent doses of booster vaccination.

Galectin-3 and Galectin-9 May Differently Regulate the Expressions of Microglial M1/M2 Markers and T Helper 1/Th2 Cytokines in the Brains of Genetically Susceptible C57BL/6 and Resistant BALB/c Mice Following Peroral Infection With Toxoplasma gondii.

Toxoplasmic encephalitis (TE), an opportunistic infection, is a severe health problem in immunocompromised patients. Previous studies have revealed that C57BL/6 mice are susceptible and BALB/c mice are resistant to TE. To investigate the mechanisms involved in the immunopathogenesis of TE in susceptible C57BL/6 and resistant BALB/c mice, both strains of mice were perorally infected with the Prugniuad (Pru) strain of Toxoplasma gondii. Our results showed that compared with BALB/c mice, C57BL/6 mice infected with T. gondii Pru strain had more severe brain histopathological damage, and higher mRNA expression levels of tachyzoite-specific surface antigen 1, bradyzoite-specific antigen 1, interferon gamma (IFNγ), interleukin (IL)-10, arginase1 (Arg1) (M2 marker), galectin (Gal)-3, Gal-9, T. gondii microneme protein 1 (TgMIC1), TgMIC4, and TgMIC6 during the course of infection by using quantitative real-time reverse transcription-polymerase chain reaction. Further analysis displayed that BALB/c mice showed higher numbers of microglial cells and higher levels of IL-1ß, inducible nitric oxide synthase (iNOS) (M1 marker), and chitinase-3-like protein 3 (Ym1) (M2 marker) in the early infective stage [at day 14 or 35 post infection (p.i.)] compared with C57BL/6 mice, whereas C57BL/6 mice showed higher numbers of microglial cells and higher levels of IL-10, iNOS (M1 marker), and Ym1 (M2 marker) at days 35, 50, or 70 p.i. compared with BALB/c mice. Correlation analysis showed that significant positive correlations existed between Gal-3 and IL-4/IL-10/iNOS/Ym1 and between Gal-9 and IL-4/Ym1 in C57BL/6 mice; between Gal-3 and IFNγ/Arg1 and between Gal-9 and IFNγ/Arg1 in BALB/c mice. Together, our data demonstrated that different Gal-3 and Gal-9 expressions as well as different positive correlations were found between Gal-3 and T helper 1 (Th1)/Th2/M1/M2 cytokines or between Gal-9 and Th1/Th2/M2 cytokines in the brains of T. gondii Pru strain-infected C57BL/6 and BALB/c mice.

A case report of granulomatous amoebic encephalitis by Group 1 Acanthamoeba genotype T18 diagnosed by the combination of morphological examination and genetic analysis.

BACKGROUND: The diagnosis of granulomatous amoebic encephalitis is challenging for clinicians because it is a rare and lethal disease. Previous reports have indicated that Acanthamoeba with some specific genotypes tend to cause the majority of human infections. We report a case of granulomatous amoebic encephalitis caused by Acanthamoeba spp. with genotype T18 in an immunodeficient patient in Japan after allogenic bone marrow transplantation, along with the morphological characteristics and genetic analysis. CASE PRESENTATION: A 52-year old man, who had undergone allogenic bone marrow transplantation, suffered from rapid-growing brain masses in addition to pneumonia and died within 1 month from the onset of the symptoms including fever, headache and disorientation. Infection with Acanthamoeba in the brain and lung was confirmed by histological evaluation; immunohistochemical staining and polymerase chain reaction analysis using autopsy samples also indicated the growth of Acanthamoeba in the brain. Gene sequence analysis indicated that this is the second documented case of infection with Acanthamoeba spp. with genotype T18 in a human host. Postmortem retrospective evaluation of cerebrospinal fluid sample in our case, as well as literature review, indicated that some cases of granulomatous amoebic encephalitis caused by Acanthamoeba may be diagnosable by cerebrospinal fluid examination. CONCLUSION: This case indicates that Acanthamoeba spp. with genotype T18 can also be an important opportunistic pathogen. For pathologists as well as physicians, increased awareness of granulomatous amoebic encephalitis is important for improving the poor prognosis along with the attempt to early diagnosis with cerebrospinal fluid.

Balamuthia mandrillaris Granulomatous Amebic Encephalitis With Renal Dissemination in a Previously Healthy Child: Case Report and Review of the Pediatric Literature.

Balamuthia mandrillaris is a recently described ameba known to cause a subacute to chronic central nervous system infection called granulomatous amebic encephalitis. Evidence suggests that apparently immunocompetent persons are at risk for disease and show a similar nonspecific presentation to that of immunodeficient persons. However, evidence of hematogenous dissemination, which has been found in immunodeficient patients, has been lacking in immunocompetent patients. Here, we describe a previously healthy patient with B mandrillaris-associated granulomatous amebic encephalitis in whom both central nervous system and renal disease were found during autopsy, which suggests hematogenous dissemination. We also provide a comprehensive review of the pediatric literature on this disease and its clinical presentation in children.

Acanthamoeba granulomatous amoebic encephalitis after pediatric hematopoietic stem cell transplant.

Acanthamoeba encephalitis is a rare, often fatal condition, particularly after HSCT, with 9 reported cases to date in the world literature. Our case was originally diagnosed with ALL at age 3 years, and after several relapses underwent HSCT at age 9 years. At 17 years of age, he was diagnosed with secondary AML for which he underwent a second allogeneic HSCT. He presented with acute-onset worsening neurological deficits on day +226 after the second transplant and a post-mortem diagnosis of Acanthamoeba encephalitis was established, with the aid of the CDC.

Role of neuroinflammation in neurodegeneration: new insights.

Previously, the contribution of peripheral infection to cognitive decline was largely overlooked however, the past 15 years have established a key role for infectious pathogens in the progression of age-related neurodegeneration. It is now accepted that the immune privilege of the brain is not absolute, and that cells of the central nervous system are sensitive to both the inflammatory events occurring in the periphery and to the infiltration of peripheral immune cells. This is particularly relevant for the progression of Alzheimer's disease, in which it has been demonstrated that patients are more vulnerable to infection-related cognitive changes. This can occur from typical infectious challenges such as respiratory tract infections, although a number of specific viral, bacterial, and fungal pathogens have also been associated with the development of the disease. To date, it is not clear whether these microorganisms are directly related to Alzheimer's disease progression or if they are opportune pathogens that easily colonize those with dementia and exacerbate the ongoing inflammation observed in these individuals. This review will discuss the impact of each of these challenges, and examine the changes known to occur with age in the peripheral immune system, which may contribute to the age-related vulnerability to infection-induced cognitive decline.

Spinal Arachnoiditis as a Complication of Cryptococcal Meningoencephalitis in Non-HIV Previously Healthy Adults.

BACKGROUND: Cryptococcus can cause meningoencephalitis (CM) among previously healthy non-HIV adults. Spinal arachnoiditis is under-recognized, since diagnosis is difficult with concomitant central nervous system (CNS) pathology. METHODS: We describe 6 cases of spinal arachnoiditis among 26 consecutively recruited CM patients with normal CD4 counts who achieved microbiologic control. We performed detailed neurological exams, cerebrospinal fluid (CSF) immunophenotyping and biomarker analysis before and after adjunctive immunomodulatory intervention with high dose pulse corticosteroids, affording causal inference into pathophysiology. RESULTS: All 6 exhibited severe lower motor neuron involvement in addition to cognitive changes and gait disturbances from meningoencephalitis. Spinal involvement was associated with asymmetric weakness and urinary retention. Diagnostic specificity was improved by MRI imaging which demonstrated lumbar spinal nerve root enhancement and clumping or lesions. Despite negative fungal cultures, CSF inflammatory biomarkers, sCD27 and sCD21, as well as the neuronal damage biomarker, neurofilament light chain (NFL), were elevated compared to healthy donor (HD) controls. Elevations in these biomarkers were associated with clinical symptoms and showed improvement with adjunctive high dose pulse corticosteroids. CONCLUSIONS: These data suggest that a post-infectious spinal arachnoiditis is an important complication of CM in previously healthy individuals, requiring heightened clinician awareness. Despite microbiological control, this syndrome causes significant pathology likely due to increased inflammation and may be amenable to suppressive therapeutics.

ImmunoglobuliN in the Treatment of Encephalitis (IgNiTE): protocol for a multicentre randomised controlled trial.

INTRODUCTION: Infectious and immune-mediated encephalitides are important but under-recognised causes of morbidity and mortality in childhood, with a 7% death rate and up to 50% morbidity after prolonged follow-up. There is a theoretical basis for ameliorating the immune response with intravenous immunoglobulin (IVIG), which is supported by empirical evidence of a beneficial response following its use in the treatment of viral and autoimmune encephalitis. In immune-mediated encephalitis, IVIG is often used after a delay (by weeks in some cases), while diagnosis is confirmed. Wider use of IVIG in infectious encephalitis and earlier use in immune-mediated encephalitis could improve outcomes for these conditions. We describe the protocol for the first ever randomised control trial of IVIG treatment for children with all-cause encephalitis. METHODS AND ANALYSIS: 308 children (6 months to 16 years) with a diagnosis of acute/subacute encephalitis will be recruited in ∼30 UK hospitals and randomised to receive 2 doses (1 g/kg/dose) of either IVIG or matching placebo, in addition to standard treatment. Recruitment will be over a 42-month period and follow-up of each participant will be for 12 months post randomisation. The primary outcome is 'good recovery' (score of 2 or lower on the Glasgow Outcome Score Extended-paediatric version), at 12 months after randomisation. Additional secondary neurological measures will be collected at 4-6 weeks after discharge from acute care and at 6 and 12 months after randomisation. Safety, radiological, other autoimmune and tertiary outcomes will also be assessed. ETHICS AND DISSEMINATION: This trial has been approved by the UK National Research Ethics committee (South Central-Oxford A; REC 14/SC/1416). Current protocol: V4.0 (10/03/2016). The findings will be presented at national and international meetings and conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBERS: NCT02308982, EudraCT201400299735 and ISRCTN15791925; Pre-results.

Expression Kinetics of RANTES and MCP-1 in the Brain of Deer Mice (Peromyscus maniculatus) Infected with Vesicular Stomatitis New Jersey Virus.

The vesicular stomatitis virus (VSV) causes encephalitis in mice when inoculated intranasally. The deer mouse (Peromyscus maniculatus), a native New World rodent, is also susceptible to VSV infection and develops similar central nervous system (CNS) lesions to those observed in other rodent species. Chemokines, such as regulated on activation, normal T-cell expressed and secreted (RANTES; CCL-5) and monocyte chemoattractant protein (MCP)-1 (CCL-2), which are important for chemotaxis and activation of inflammatory cells, are expressed during the course of VSV encephalitis. However, the role of CNS resident cells in chemokine expression is poorly characterized. Here, we show that during vesicular stomatitis New Jersey virus (VSNJV) encephalitis in deer mice, RANTES and MCP-1 are expressed only in the olfactory bulb (OB), where the virus was localized. This chemokine expression was followed by the influx of inflammatory cells to the OB later in the course of acute disease. Neurons, astrocytes and microglia expressed RANTES, while MCP-1 was expressed by neurons and astrocytes. Although astrocytes and microglia responded to VSNJV infection by expressing chemokines, neurons were the cell type that was predominantly infected. Therefore, infected neurons may have a critical role in initiating an immune response in the OB. The signalling between neurons and other CNS resident cells is most likely the mechanism by which astrocytes and microglia are activated during the course of VSV encephalitis.

Swiss national prospective surveillance of paediatric Mycoplasma pneumoniae-associated encephalitis.

OBJECTIVE: To assess the presence of Mycoplasma pneumoniae-associated encephalitis in children in Switzerland and its likely pathogenesis. METHODS: M. pneumoniae-associated encephalitis cases seen at a single-centre during 2010-2013 were reviewed, and the Swiss Paediatric Surveillance Unit (SPSU) prospectively conducted a nationwide surveillance 2013-2015. Case definition included confirmed, probable and possible cases. RESULTS: Seven patients (median age 8.7 years, range 4.7-10.1 years) with confirmed or possible M. pneumoniae-associated encephalitis were observed. All patients manifested prodromal respiratory symptoms over at least 5 days and five out of the six who had a chest radiograph, showed pulmonary infiltrates. M. pneumoniae DNA in cerebrospinal fluid was negative in all patients. Intrathecally synthesised M. pneumoniae-specific immunoglobulin (IgM and IgG) were investigated and found positive in one patient (confirmed case). M. pneumoniae DNA in respiratory specimens and/or M. pneumoniae-specific IgM and IgG in serum were detected in the other six patients (possible cases). One confirmed and two possible cases had neurological sequelae at 4-19 months follow-up. CONCLUSION: The lack of detectable M. pneumoniae DNA in cerebrospinal fluid of our encephalitis patients suggests a likely immune-mediated pathogenesis ignited by a respiratory inflammatory process including pneumonia.

Myalgic encephalomyelitis, chronic fatigue syndrome: An infectious disease.

The etiology of myalgic encephalomyelitis also known as chronic fatigue syndrome or ME/CFS has not been established. Controversies exist over whether it is an organic disease or a psychological disorder and even the existence of ME/CFS as a disease entity is sometimes denied. Suggested causal hypotheses have included psychosomatic disorders, infectious agents, immune dysfunctions, autoimmunity, metabolic disturbances, toxins and inherited genetic factors. Clinical, immunological and epidemiological evidence supports the hypothesis that: ME/CFS is an infectious disease; the causal pathogen persists in patients; the pathogen can be transmitted by casual contact; host factors determine susceptibility to the illness; and there is a population of healthy carriers, who may be able to shed the pathogen. ME/CFS is endemic globally as sporadic cases and occasional cluster outbreaks (epidemics). Cluster outbreaks imply an infectious agent. An abrupt flu-like onset resembling an infectious illness occurs in outbreak patients and many sporadic patients. Immune responses in sporadic patients resemble immune responses in other infectious diseases. Contagion is shown by finding secondary cases in outbreaks, and suggested by a higher prevalence of ME/CFS in sporadic patients' genetically unrelated close contacts (spouses/partners) than the community. Abortive cases, sub-clinical cases, and carrier state individuals were found in outbreaks. The chronic phase of ME/CFS does not appear to be particularly infective. Some healthy patient-contacts show immune responses similar to patients' immune responses, suggesting exposure to the same antigen (a pathogen). The chronicity of symptoms and of immune system changes and the occurrence of secondary cases suggest persistence of a causal pathogen. Risk factors which predispose to developing ME/CFS are: a close family member with ME/CFS; inherited genetic factors; female gender; age; rest/activity; previous exposure to stress or toxins; various infectious diseases preceding the onset of ME/CFS; and occupational exposure of health care professionals. The hypothesis implies that ME/CFS patients should not donate blood or tissue and usual precautions should be taken when handling patients' blood and tissue. No known pathogen has been shown to cause ME/CFS. Confirmation of the hypothesis requires identification of a causal pathogen. Research should focus on a search for unknown and known pathogens. Finding a causal pathogen could assist with diagnosis; help find a biomarker; enable the development of anti-microbial treatments; suggest preventive measures; explain pathophysiological findings; and reassure patients about the validity of their symptoms.

CD8+ T cell immunity in an encephalitis model of Toxoplasma gondii infection.

Toxoplasma gondii infection induces a robust CD8 T cell immunity in the infected host, which is critical for keeping chronic infection under control. IFNγ production and cytolytic activity exhibited by CD8 T cells are critical functions needed to prevent the reactivation of latent infection. Paradoxically, the susceptible mice infected with the parasite develop encephalitis irrespective of the presence of vigorous CD8 T cell immunity. Recent studies from our laboratory have demonstrated that these animals have defect in the memory CD8 T cell population, which become dysfunctional due to exhibition of inhibitory receptors like PD-1. Although the blockade of PD-1-PDL-1 pathway rescues the CD8 response, PD-1(hi) expressing cells are refractory to the treatment. In this review, we discuss the development of CD8 memory response during chronic infection, mechanism responsible for their dysfunctionality, and possible therapeutic measures that can be taken to reverse the process.