[Community-Acquired Bacterial Meningoencephalitis: The New Guideline]. / Ambulant erworbene bakterielle Meningoenzephalitis: Die neue Leitlinie.

Updating the vaccination recommendations against meningococci and pneumococci, in particular the introduction of the B vaccine as the standard vaccination for infants from January 2024 and the adaptation of the pneumococcal vaccination strategy for infants and adults aged 60 and over with the latest conjugate vaccines (PCV13, PCV15, PCV20).Emphasis on the need for rapid diagnostic lumbar puncture and simultaneous serum and cerebrospinal fluid analysis to increase diagnostic precision. The introduction of procalcitonin (PCT) in serum as an additional biomarker to differentiate between bacterial and viral meningitis.The use of multiplex PCR as a supplement, not a replacement, for standard diagnostics to speed up pathogen identification.Adaptation of antibiotic recommendations based on the current resistance situation, in particular for meningococcal meningitis, consideration of penicillin G only after resistance testing.Clarification of the areas and duration of use of dexamethasone in bacterial meningitis, particularly in pneumococcal meningitis and the controversial data situation in Listeria meningitis.New findings on the safe use of heparin in septic sinus thrombosis without increased risk of hemorrhage.

A 48-year-old man with fever, nauseous, vomiting, and dizzy: A CARE case report.

RATIONALE: Listeria monocytogenes (LM) is an important foodborne bacterium, and LM meningoencephalitis is rare in clinical practice, with poor prognosis in severe patients. It is prone to misdiagnosis in clinical practice. We first reported a case of severe LM meningoencephalitis with muscle lesions and evaluated the comprehensive condition. PATIENT CONCERNS: A 48-year-old man had a fever and was admitted to the neurology department due to dizziness, nausea, and vomiting for 20 days. DIAGNOSES: LM meningoencephalitis complicated with muscle lesions. INTERVENTIONS: We used moxifloxacin 0.4 g, qd, meropenem 2 g, q8h, and dexamethasone 10 mg, qd to reduce exudation and adhesion. Then due to consideration of side effects, we increased the dose of ampicillin by 2 g, q4h, stopped using meropenem and moxifloxacin, and turned to maintenance treatment with dexamethasone and ampicillin. We comprehensively managed his vital signs and physical organ functions, we also controlled some comorbidities. During the hospitalization period thereafter, we used intravenous anti-infection treatment with moxifloxacin 0.4 g, qd, ampicillin 0.5 g, q4h. OUTCOMES: Half a year later, the reexamination showed only protein elevation in cerebrospinal fluid and hydrocephalus in MRI. Afterward, the symptoms did not recur again. The patient recovered well after discharge. LESSONS: LM meningoencephalitis complicated with lower limb muscle lesions is clinically rare. This report focuses on relevant treatment plans, which provide value for the examination and comprehensive management of patients with LM infection in the future.

Disseminated tuberculosis complicated by intramuscular abscesses, meningoencephalitis, and hemophagocytic lymphohistiocytosis: a case report.

BACKGROUND: As disseminated extrapulmonary tuberculosis infection can involve multiple systems and result in atypical clinical manifestations that mimic other diseases, the diagnosis may be difficult, especially in elderly patients. Delaying treatment can adversely affect the prognosis. And to achieve better prognosis, early detection and diagnosis are necessary, as well as early initiation of comprehensive treatment. CASE PRESENTATION: We present the case of a 78-year-old man with disseminated tuberculosis who developed the uncommon complication of urinary retention due to a psoas abscess, meningoencephalitis, and the rare secondary hemophagocytic lymphohistiocytosis syndrome. The patient achieved a favorable outcome following targeted therapy with antitubercular medications. CONCLUSIONS: This case highlights that disseminated extrapulmonary tuberculosis infection can present with a variety of manifestations, and may exhibit many rare and complex clinical presentations. Prompt and accurate diagnosis and treatment play a crucial role in improving prognosis for the patients with persistent fever.

A rare case report of meningoencephalitis caused by Streptococcus porcinus.

Acute pyogenic meningitis is a medical emergency. Bacteria are the major causative agents of pyogenic meningitis with Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis being the most common. Here, we describe a case of bacterial meningoencephalitis caused by Streptococcus porcinus. To our knowledge this is the first case described in literature. The patient was treated with ceftriaxone and supportive treatment.

Acute Meningoencephalitis Associated with Borrelia miyamotoi, Minnesota, USA.

Borrelia miyamotoi is an emerging tickborne pathogen that has been associated with central nervous system infections in immunocompromised patients, albeit infrequently. We describe a case-patient in Minnesota, USA, who had meningeal symptoms of 1 month duration. B. miyamotoi infection was diagnosed by Gram staining on cerebrospinal fluid and confirmed by sequencing.

Granulomatous meningoencephalitis and blindness associated with Mycobacterium tuberculosis complex infection in a senile female chimpanzee (Pan troglodytes).

A 40-year old female chimpanzee (Pan troglodytes) developed hyporexia, weight loss, followed by progressive and complete blindness. Tomography demonstrated an intracranial mass in the rostroventral brain involving the optic chiasm, with a presumptive diagnosis of neoplasm. However, histopathology revealed a granulomatous meningoencephalitis, and tissue samples tested positive for Mycobacterium tuberculosis.

A multi-arm, parallel, preclinical study investigating the potential benefits of acetazolamide, candesartan, and triciribine in combination with fluconazole for the treatment of cryptococcal meningoencephalitis.

Cryptococcus neoformans, an opportunistic fungal pathogen, primarily infects immunodeficient patients frequently causing cryptococcal meningoencephalitis (CM). Increased intracranial pressure (ICP) is a serious complication responsible for increased morbidity and mortality in CM patients. Non-invasive pharmacological agents that mitigate ICP could be beneficial in treating CM patients. The objective of the study was to investigate the efficacy of acetazolamide (AZA), candesartan (CAN), and triciribine (TCBN), in combination with the antifungal fluconazole, on C. neoformans-induced endothelial, brain, and lung injury in an experimental mouse model of CM. Our study shows that C. neoformans increases the expression of brain endothelial cell (BEC) junction proteins Claudin-5 (Cldn5) and VE-Cadherin to induce pathological cell-barrier remodeling and gap formation associated with increased Akt and p38 MAPK activation. All three agents inhibited C. neoformans-induced endothelial gap formation, only CAN and TCBN significantly reduced C. neoformans-induced Cldn5 expression, and only TCBN was effective in inhibiting Akt and p38MAPK. Interestingly, although C. neoformans did not cause brain or lung edema in mice, it induced lung and brain injuries, which were significantly reversed by AZA, CAN, or TCBN. Our study provides novel insights into the direct effects of C. neoformans on BECs in vitro, and the potential benefits of using AZA, CAN, or TCBN in the management of CM patients.

Pharmacodynamics of ATI-2307 in a rabbit model of cryptococcal meningoencephalitis.

Cryptococcal meningoencephalitis (CM) is a devastating fungal disease with high morbidity and mortality. The current regimen that is standard-of-care involves a combination of three different drugs administered for up to one year. There is a critical need for new therapies due to both toxicity and inadequate fungicidal activity of the currently available antifungal drugs. ATI-2307 is a novel aryl amidine that disrupts the mitochondrial membrane potential and inhibits the respiratory chain complexes of fungi-it thus represents a new mechanism for direct antifungal action. Furthermore, ATI-2307 selectively targets fungal mitochondria via a fungal-specific transporter that is not present in mammalian cells. It has very potent in vitro anticryptococcal activity. In this study, the efficacy of ATI-2307 was tested in a rabbit model of CM. ATI-2307 demonstrated significant fungicidal activity at dosages between 1 and 2 mg/kg/d, and these results were superior to fluconazole and similar to amphotericin B treatment. When ATI-2307 was combined with fluconazole, the antifungal effect was greater than either therapy alone. While ATI-2307 has potent anticryptococcal activity in the subarachnoid space, its ability to reduce yeasts in the brain parenchyma was relatively less over the same study period. This new drug, with its unique mechanism of fungicidal action and ability to positively interact with an azole, has demonstrated sufficient anticryptococcal potential in this experimental setting to be further evaluated in clinical studies.

Immunological Analysis of Cryptococcal Meningoencephalitis in a Murine Model.

Cryptococcal meningoencephalitis (CM), caused by the fungal pathogen Cryptococcus neoformans species complex, can lead to high mortality or severe neurological sequelae in survivors that are associated with excessive inflammation in the central nervous system (CNS), especially in those who develop immune reconstitution inflammatory syndrome (IRIS) or postinfectious immune response syndrome (PIIRS). While the means to establish a cause-and-effect relationship of a specific pathogenic immune pathway during CM by human studies are limited, mouse models allow dissection of the potential mechanistic links within the CNS immunological network. In particular, these models are useful for separating pathways contributing predominantly to immunopathology from those important for fungal clearance. In this protocol, we described methods to induce a robust, physiologically relevant murine model of C. neoformans CNS infection that reproduces multiple aspects of human cryptococcal disease immunopathology and subsequent detailed immunological analysis. Combined with tools including gene knockout mice, antibody blockade, cell adoptive transfer, as well as high throughput techniques such as single-cell RNA sequencing, studies using this model will provide new insights regarding the cellular and molecular processes that elucidate the pathogenesis of cryptococcal CNS diseases in order to develop more effective therapeutic strategies.

Rapport de cas Mononuclear pleocytosis and meningoencephalitis caused by Listeria monocytogenes in an adult horse.

Clinical disease caused by infection with Listeria monocytogenes is rare in adult horses, and there is a paucity of ante-mortem clinicopathologic changes for this species reported in the literature. Confirmatory diagnosis is difficult and often requires post-mortem sampling of the brainstem. This report details a case of meningoencephalitis caused by Listeria monocytogenes in an adult American quarter horse gelding presenting with central neurologic signs. Pre-mortem analysis of the cerebrospinal fluid revealed a mononuclear, primarily lymphocytic, pleocytosis, which is a reported finding in other species with listeriosis. Post-mortem histopathologic changes of the brainstem were characteristic of listeriosis, and infection was confirmed with immunohistochemical labeling and bacterial culture. Key clinical message: Listeriosis should be included as a differential diagnosis in neurologic horses with mononuclear pleocytosis identified on cerebrospinal fluid analysis.

Pléocytose mononucléaire et méningo-encéphalite causées par Listeria monocytogenes chez un cheval adulte. La maladie clinique causée par une infection à L. monocytogenes est rare chez les chevaux adultes, et il y a peu de changements clinico-pathologiques ante-mortem rapportés dans la littérature pour cette espèce. Le diagnostic de confirmation est difficile et nécessite souvent un prélèvement post-mortem du tronc cérébral. Ce rapport détaille un cas de méningo-encéphalite causée par L. monocytogenes chez un hongre quarter horse américain adulte présentant des signes neurologiques centraux. L'analyse pré-mortem du liquide céphalo-rachidien a révélé une pléocytose mononucléaire, principalement lymphocytaire, qui est une trouvaille rapportée chez d'autres espèces atteintes de listériose. Les modifications histopathologiques post-mortem du tronc cérébral étaient caractéristiques de la listériose et l'infection a été confirmée par un marquage immunohistochimique et une culture bactérienne.Message clinique clé :La listériose doit être incluse comme diagnostic différentiel chez les chevaux avec signes neurologiques présentant une pléocytose mononucléaire identifiée lors de l'analyse du liquide céphalo-rachidien.(Traduit par Dr Serge Messier).

Population pharmacokinetics and CSF penetration of flucytosine in adults with HIV-associated cryptococcal meningoencephalitis.

BACKGROUND: There are limited data describing clinical flucytosine pharmacokinetics (PK). The variability of flucytosine partitioning into the CNS is not known. We described the interindividual variability in flucytosine PK in patients with HIV-associated cryptococcal meningoencephalitis. In addition, we quantified the extent and variability of CSF partitioning of flucytosine. METHODS: A PK study was conducted in 64 patients with confirmed HIV-associated cryptococcal meningoencephalitis in Blantyre, Malawi. A four-compartment PK model was developed, and Monte Carlo simulations were performed with flucytosine administered at different doses and in different schedules. RESULTS: The estimated mean apparent volume of the central compartment was 17.50 (SD 9.99) L; mean apparent clearance was 5.88 (SD 3.35) L/h; mean apparent volume of the CNS compartment was 41.73 (SD 13.66) L. From the Bayesian posterior estimates, AUC24 values at steady state (144-168 h) with doses of 25 mg/kg q6h were median (IQR) 890.38 (603.81-1213.70) mg.h/L in plasma and 595.66 (425.69-776.64) mg.h/L in CSF. The ratio of CSF:plasma AUC24 was 0.69 (IQR 0.58-0.82). CONCLUSIONS: This study revealed significant interindividual variability in flucytosine PK in plasma and CSF in patients with HIV-associated cryptococcal meningoencephalitis. The population PK model is a first critical step for revised flucytosine regimens that maximize fungal killing and minimize toxicity and the emergence of resistance.

Phospholipase B Is Critical for Cryptococcus neoformans Survival in the Central Nervous System.

Cryptococcus neoformans (Cn) is an opportunistic, encapsulated, yeast-like fungus that causes severe meningoencephalitis, especially in countries with high HIV prevalence. In addition to its well-known polysaccharide capsule, Cn has other virulence factors such as phospholipases, a heterogeneous group of enzymes that hydrolyze ester linkages in glycerophospholipids. Phospholipase B (PLB1) has been demonstrated to play a key role in Cn pathogenicity. In this study, we used a PLB1 mutant (plb1) and its reconstituted strain (Rec1) to assess the importance of this enzyme on Cn brain infection in vivo and in vitro. Mice infected with the plb1 strain survive significantly longer, have lower peripheral and central nervous system (CNS) fungal loads, and have fewer and smaller cryptococcomas or biofilm-like brain lesions compared to H99- and Rec1-infected animals. PLB1 causes extensive brain tissue damage and changes microglia morphology during cryptococcal disease, observations which can have important implications in patients with altered mental status or dementia as these manifestations are related to poorer survival outcomes. plb1 cryptococci are significantly more phagocytosed and killed by NR-9460 microglia-like cells. plb1 cells have altered capsular polysaccharide biophysical properties which impair their ability to stimulate glial cell responses or morphological changes. Here, we provide significant evidence demonstrating that Cn PLB1 is an important virulence factor for fungal colonization of and survival in the CNS as well as in the progression of cryptococcal meningoencephalitis. These findings may potentially help fill in a gap of knowledge in our understanding of cerebral cryptococcosis and provide novel research avenues in Cn pathogenesis. IMPORTANCE Cryptococcal meningoencephalitis (CME) is a serious disease caused by infection by the neurotropic fungal pathogen Cryptococcus neoformans. Due to the increasing number of cases in HIV-infected individuals, as well as the limited therapies available, investigation into potential targets for new therapeutics has become critical. Phospholipase B is an enzyme synthesized by Cn that confers virulence to the fungus through capsular enlargement, immunomodulation, and intracellular replication. In this study, we examined the properties of PLB1 by comparing infection of a Cn PLB1 mutant strain with both the wild-type and a PLB1-reconstituted strain. We show that PLB1 augments the survival and proliferation of the fungus in the CNS and strengthens virulence by modulating the immune response and enhancing specific biophysical properties of the fungus. PLB1 expression causes brain tissue damage and impacts glial cell functions, which may be responsible for the dementia observed in patients which may persist even after resolving from CME. The implications of PLB1 inhibition reveal its involvement in Cn infection and suggest that it may be a possible molecular target in the development of antifungal therapies. The results of this study support additional investigation into the mechanism of PLB1 to further understand the intricacies of cerebral Cn infection.

Experiencia de dos años con el uso de panel de RPC múltiple de meningitis-encefalitis en pacientes pediátricos en un hospital de tercer nivel en Argentina / Two-year experience with the multiple PCR panel meningitis-encephalitis panel in children in a third level hospital in Argentina

INTRODUCCIÓN: La meningitis bacteriana aguda (MBA) y la encefalitis son infecciones graves y el retraso en el tratamiento determina mayor morbimortalidad. En 2015 la FDA. aprobó un panel de RPC múltiple, BioFire® Filmarray® meningitis-encefalitis (FA-ME), que desde el 2019 se encuentra disponible en nuestro hospital. OBJETIVOS: Estimar número de determinaciones positivas mediante FA-ME, evaluar concordancia con cultivo convencional (CC) y describir si FA-ME permitió realizar cambios en el tratamiento. MATERIAL Y MÉTODOS: Estudio retrospectivo, descriptivo, realizado durante 2019-2021 en el Hospital de Niños Pedro Elizalde. Se revisaron reportes de niños con meningitis, encefalitis y meningoencefalitis y líquido-cefalorraquídeo patológico a quienes se les realizó FA-ME. RESULTADOS: Se incluyó a 32 niños, edad promedio: 48 meses. Fueron positivas 13 determinaciones de FA-ME: siete bacterias y seis virus. En dos MBA obtuvo desarrollo mediante CC. Con FA-ME se ajustó el tratamiento en dos MBA y se acortó el tratamiento intravenoso (IV). DISCUSIÓN: Nuestro trabajo permitió conocer la etiología de cinco MBA con cultivo negativo, de las cuales dos habían recibido antimicrobianos, administrar quimioprofilaxis a contactos epidemiológicos, acortar el tratamiento IV y suministrar menos dosis de aciclovir; en concordancia con la literatura médica. CONCLUSIONES: FA-ME permitió identificar la etiología en cinco MBA que no desarrollaron en CC, ajustar tratamientos empíricos inadecuados y acortar duración del tratamiento parenteral.

BACKGROUND: Bacterial meningitis and encephalitis are life-threatening infections, a delay in its treatment is associated with high mortality. In 2015, FDA approved the Multiplex PCR FilmArray™ meningitis/encephalitis syndromic panel (FA-MEP), and it is available in our hospital since 2019. AIM: To estimate the number of positive FA-MEP, to evaluate the correlation to conventional culture (CC) results and to describe if the FA-MEP technology allowed changes in the treatment. METHODS: Retrospective analysis of children with meningitis, encephalitis and meningoencephalitis and pathological cerebrospinal fluid analysis between 2019-2021, who were subject to FA-MEP testing at the Pedro Elizalde Children's Hospital. RESULTS: 32 children, mean age: 48 months. 11 patients had positive FA-ME tests: 7 bacterial, 6 viral. 2 patients correlated with CC. Based on the FAMEP results, treatment was adjusted in 2 bacterial meningitis and the duration of intravenous treatment was shortened. DISCUSSION: Our study allowed to establish the etiology of 5 culture negative bacterial meningitis, (2 had prior antibiotics), administer chemoprophylaxis to close contacts, and to administer fewer doses of acyclovir. CONCLUSIONS: The FA-MEP allowed us to identify 5 bacterial meningitis that tested negative by CC and early adjustment of inappropriate empirical antibiotics and to shorten the duration of parenteral treatments.

Anthrax Meningoencephalitis and Intracranial Hemorrhage.

The neurological sequelae of Bacillus anthracis infection include a rapidly progressive fulminant meningoencephalitis frequently associated with intracranial hemorrhage, including subarachnoid and intracerebral hemorrhage. Higher mortality than other forms of bacterial meningitis suggests that antimicrobials and cardiopulmonary support alone may be insufficient and that strategies targeting the hemorrhage might improve outcomes. In this review, we describe the toxic role of intracranial hemorrhage in anthrax meningoencephalitis. We first examine the high incidence of intracranial hemorrhage in patients with anthrax meningoencephalitis. We then review common diseases that present with intracranial hemorrhage, including aneurysmal subarachnoid hemorrhage and spontaneous intracerebral hemorrhage, postulating applicability of established and potential neurointensive treatments to the multimodal management of hemorrhagic anthrax meningoencephalitis. Finally, we examine the therapeutic potential of minocycline, an antimicrobial that is effective against B. anthracis and that has been shown in preclinical studies to have neuroprotective properties, which thus might be repurposed for this historically fatal disease.

Cryptococcal Meningoencephalitis in an Immunocompetent Patient.

Cryptococcal meningitis (CM) is an uncommon opportunistic infection in immunocompetent hosts; and causes significant mortality and long-term morbidity. Cryptococci primarily cause disease in immunocompromised hosts, but rarely can lead to severe disease in immunocompetent individuals. A 64-year man, with no known immunosuppressive illnesses, presented in the Emergency Department with gait disturbances and lethargy for one year, which got worsened recently. After further deliberation on elevated intracranial pressure (ICP), a CT brain was performed, which showed hydrocephalus; and thus lumbar puncture (LP) was done. Fungal cultures grew cryptococcus neoformans. The patient was treated with anti-fungal medications. It is highly essential for emergency physicians and other clinicians to think of atypical neurological manifestations of meningitis in immunocompetent individuals. Key Words: Cryptococcus, Immunocompetent, Antifungal treatment, Meningitis.

Comparative miRNA transcriptomics of macaques and mice reveals MYOC is an inhibitor for Cryptococcus neoformans invasion into the brain.

Cryptococcal meningoencephalitis (CM) is emerging as an infection in HIV/AIDS patients shifted from primarily ART-naive to ART-experienced individuals, as well as patients with COVID-19 and immunocompetent hosts. This fungal infection is mainly caused by the opportunistic human pathogen Cryptococcus neoformans. Brain or central nervous system (CNS) dissemination is the deadliest process for this disease; however, mechanisms underlying this process have yet to be elucidated. Moreover, illustrations of clinically relevant responses in cryptococcosis are currently limited due to the low availability of clinical samples. In this study, to explore the clinically relevant responses during C. neoformans infection, macaque and mouse infection models were employed and miRNA-mRNA transcriptomes were performed and combined, which revealed cytoskeleton, a major feature of HIV/AIDS patients, was a centric pathway regulated in both infection models. Notably, assays of clinical immune cells confirmed an enhanced macrophage "Trojan Horse" in patients with HIV/AIDS, which could be shut down by cytoskeleton inhibitors. Furthermore, myocilin, encoded by MYOC, was found to be a novel enhancer for the macrophage "Trojan Horse," and an enhanced fungal burden was achieved in the brains of MYOC-transgenic mice. Taken together, the findings from this study reveal fundamental roles of the cytoskeleton and MYOC in fungal CNS dissemination, which not only helps to understand the high prevalence of CM in HIV/AIDS but also facilitates the development of novel therapeutics for meningoencephalitis caused by C. neoformans and other pathogenic microorganisms.

Gene Expression of Diverse Cryptococcus Isolates during Infection of the Human Central Nervous System.

Cryptococcus neoformans is a major human central nervous system (CNS) fungal pathogen causing considerable morbidity and mortality. In this study, we provide the widest view to date of the yeast transcriptome directly from the human subarachnoid space and within cerebrospinal fluid (CSF). We captured yeast transcriptomes from C. neoformans of various genotypes in 31 patients with cryptococcal meningoencephalitis as well as several Cryptococcus gattii infections. Using transcriptome sequencing (RNA-seq) analyses, we compared the in vivo yeast transcriptomes to those from other environmental conditions, including in vitro growth on nutritious media or artificial CSF as well as samples collected from rabbit CSF at two time points. We ranked gene expressions and identified genetic patterns and networks across these diverse isolates that reveal an emphasis on carbon metabolism, fatty acid synthesis, transport, cell wall structure, and stress-related gene functions during growth in CSF. The most highly expressed yeast genes in human CSF included those known to be associated with survival or virulence and highlighted several genes encoding hypothetical proteins. From that group, a gene encoding the CMP1 putative glycoprotein (CNAG_06000) was selected for functional studies. This gene was found to impact the virulence of Cryptococcus in both mice and the CNS rabbit model, in agreement with a recent study also showing a role in virulence. This transcriptional analysis strategy provides a view of regulated yeast genes across genetic backgrounds important for human CNS infection and a relevant resource for the study of cryptococcal genes, pathways, and networks linked to human disease. IMPORTANCE Cryptococcus is the most common fungus causing high-morbidity and -mortality human meningitis. This encapsulated yeast has a unique propensity to travel to the central nervous system to produce disease. In this study, we captured transcriptomes of yeasts directly out of the human cerebrospinal fluid, the most concerning site of infection. By comparing the RNA transcript levels with other conditions, we gained insights into how the basic machinery involved in metabolism and environmental responses enable this fungus to cause disease at this body site. This approach was applied to clinical isolates with diverse genotypes to begin to establish a genotype-agnostic understanding of how the yeast responds to stress. Based on these results, future studies can focus on how these genes and their pathways and networks can be targeted with new therapeutics and possibly classify yeasts with bad infection outcomes.

CCR2 Signaling Promotes Brain Infiltration of Inflammatory Monocytes and Contributes to Neuropathology during Cryptococcal Meningoencephalitis.

Cryptococcal meningoencephalitis (CM) is a leading cause of central nervous system (CNS) infection-related mortality worldwide, with surviving patients often developing neurological deficiencies. While CNS inflammation has been implicated in the pathogenesis of CM, little is known about the relative contribution of the specific inflammatory/immune pathways to CNS pathology versus fungal clearance. Increased cerebrospinal fluid level of C-C chemokine receptor 2 (CCR2) ligand CCL2 is associated with disease deterioration in patients with CM. Using a murine model, we investigated the role of the CCR2 pathway in the development of CNS inflammation and pathology during CM. We found that CCR2-deficient mice exhibited improved 28-day survival and alleviated neurological disease scores despite a brain fungal burden higher than that of the WT mice. Reduced CM pathology in CCR2-deficient mice was accompanied by markedly decreased neuronal cell death around cryptococcal microcysts and restored expression of genes involved in neurotransmission, connectivity, and neuronal cell structure in the brains. Results show that CCR2 axis is the major pathway recruiting CD45hiCD11b+Ly6C+ inflammatory monocyte to the brain and indirectly modulates the accumulation of CD4+ T cells and CD8+ T cells. In particular, CCR2 axis promotes recruitment of interferon gamma (IFN-γ)-producing CD4+ T cells and classical activation of myeloid cells. In this context, CCR2 deletion limits the immune network dysregulation we see in CM and attenuates neuropathology. Thus, the CCR2 axis is a potential target for interventions aimed to limit inflammatory CNS pathology in CM patients. IMPORTANCE Cryptococcal meningoencephalitis (CM) causes nearly 200,000 deaths worldwide each year, and survivors frequently develop long-lasting neurological sequelae. The high rate of mortality and neurologic sequelae in CM patients indicate that antifungal therapies alone are often insufficient to control disease progression. Here, we reveal that CM disease progression in mice is accompanied by inflammatory monocytes infiltration at the periphery of the infected foci that overlap locally perturbed neuronal function and death. Importantly, we identified that CCR2 signaling is a critical pathway driving neuroinflammation, especially inflammatory monocyte recruitment, as well as CNS pathology and mortality in CM mice. Our results imply that targeting the CCR2 pathway may be beneficial as a therapy complementary to antifungal drug treatment, helping to reduce CNS damage and mortality in CM patients.

Cryptococcal meningoencephalitis: time for action.

Cryptococcal meningoencephalitis was first described over a century ago. This fungal infection is preventable and treatable yet continues to be associated with excessive morbidity and mortality. The largest burden of disease resides in people living with HIV in low-income and middle-income countries. In this group, mortality with the best antifungal induction regimen (7 days of amphotericin B deoxycholate [1·0 mg/kg per day] and flucytosine [100·0 mg/kg per day]) in a clinical trial setting was 24% at 10 weeks. The world is now at an inflection point in terms of recognition, research, and action to address the burden of morbidity and mortality from cryptococcal meningoencephalitis. However, the scope of interventional programmes needs to increase, with particular attention to implementation science that is specific to individual countries. This Review summarises causes of excessive mortality, interventions with proven survival benefit, and gaps in knowledge and practice that contribute to the ongoing high death toll from cryptococcal meningoencephalitis. TRANSLATIONS: For the Vietnamese and Chichewa translations of the abstract see Supplementary Materials section.