Fungal Infections Of Brain Research Articles

Microglia are not protective against cryptococcal meningitis

Microglia provide protection against a range of brain infections including bacteria, viruses and parasites, but how these glial cells respond to fungal brain infections is poorly understood. We investigated the role of microglia in the context of cryptococcal meningitis, the most common cause of fungal meningitis in humans. Using a series of transgenic- and chemical-based microglia depletion methods we found that, contrary to their protective role during other infections, loss of microglia did not affect control of Cryptococcus neoformans brain infection which was replicated with several fungal strains. At early time points post-infection, we found that microglia depletion lowered fungal brain burdens, which was related to intracellular residence of C. neoformans within microglia. Further examination of extracellular and intracellular fungal populations revealed that C. neoformans residing in microglia were protected from copper starvation, whereas extracellular yeast upregulated copper transporter CTR4. However, the degree of copper starvation did not equate to fungal survival or abundance of metals within different intracellular niches. Taken together, these data show how tissue-resident myeloid cells may influence fungal phenotype in the brain but do not provide protection against this infection, and instead may act as an early infection reservoir.

Developing a chronic model of Candida albicans cerebral mycosis through gut colonization

Recent evidence suggests that Alzheimer's Disease (AD) is linked to fungal brain infections. We have previously established an acute model of cerebral mycosis by intravenously injecting the pathogenic yeast Candida albicans. The resulting infection induces mild transient memory deficits and fungal induced glial granulomas consisting of microglia and amyloid β deposits surrounding yeast aggregates. This structure essentially duplicates AD's characteristic senile plaque. AD involves numerous senile plaques and tauopathy that presumably accrue over many years potentially from chronic infection.

Absence of Bacteria Permits Fungal Gut-To-Brain Translocation and Invasion in Germfree Mice but Ageing Alone Does Not Drive Pathobiont Expansion in Conventionally Raised Mice.

Age-associated changes in the structure of the intestinal microbiome and in its interaction with the brain via the gut-brain axis are increasingly being implicated in neurological and neurodegenerative diseases. Intestinal microbial dysbiosis and translocation of microbes and microbial products including fungal species into the brain have been implicated in the development of dementias such as Alzheimer’s disease. Using germ-free mice, we investigated if the fungal gut commensal, Candida albicans, an opportunistic pathogen in humans, can traverse the gastrointestinal barrier and disseminate to brain tissue and whether ageing impacts on the gut mycobiome as a pre-disposing factor in fungal brain infection. C. albicans was detected in different regions of the brain of colonised germ-free mice in both yeast and hyphal cell forms, often in close association with activated (Iba-1+) microglial cells. Using high-throughput ITS1 amplicon sequencing to characterise the faecal gut fungal composition of aged and young SPF mice, we identified several putative gut commensal fungal species with pathobiont potential although their abundance was not significantly different between young and aged mice. Collectively, these results suggest that although some fungal species can travel from the gut to brain where they can induce an inflammatory response, ageing alone is not correlated with significant changes in gut mycobiota composition which could predispose to these events. These results are consistent with a scenario in which significant disruptions to the gut microbiota or intestinal barrier, beyond those which occur with natural ageing, are required to allow fungal escape and brain infection.

Coccidioidomycosis Meningitis in an Immunocompetent Worker: A Case Report

“If you work in the dry dust of Arizona or California central valley surely be warned about fever, or deadly head-aches from all those Cocci!!”. While pulmonary coccidiomycosis infections in the endemic places are seen very often, especially among immunocompromised people, CNS coccidiomycosis infection from environmental exposure in immunocompetent individual is not that common, but when it happens it is fatal. Risk is very high in certain occupations in endemic regions and the diagnosis may be challenging in absence of high clinical suspicions. Here, we report a case of coccidiomycosis meningitis in an immunocompetent individual, who went to Arizona for a week for his painting job. The purpose of this paper is to prevent the occupation-related dreaded incidence of fungal brain infection in endemic places with robust public health measures.

Fungal brain infection modelled in a human-neurovascular-unit-on-a-chip with a functional blood-brain barrier.

The neurovascular unit, which consists of vascular cells surrounded by astrocytic end-feet and neurons, controls cerebral blood flow and the permeability of the blood-brain barrier (BBB) to maintain homeostasis in the neuronal milieu. Studying how some pathogens and drugs can penetrate the human BBB and disrupt neuronal homeostasis requires in vitro microphysiological models of the neurovascular unit. Here we show that the neurotropism of Cryptococcus neoformans-the most common pathogen causing fungal meningitis-and its ability to penetrate the BBB can be modelled by the co-culture of human neural stem cells, brain microvascular endothelial cells and brain vascular pericytes in a human-neurovascular-unit-on-a-chip maintained by a stepwise gravity-driven unidirectional flow and recapitulating the structural and functional features of the BBB. We found that the pathogen forms clusters of cells that penetrate the BBB without altering tight junctions, suggesting a transcytosis-mediated mechanism. The neurovascular-unit-on-a-chip may facilitate the study of the mechanisms of brain infection by pathogens, and the development of drugs for a range of brain diseases.

Fungal brain infection\u2014no longer a death sentence

The aim of this case series was to provide a modern cohort of patients with cerebral aspergillosis and show the effectiveness of modern treatment concepts. In a 10-year period from January 2009 to January 2019, we identified 10 patients (6 male, 4 female) who received surgery or frameless stereotactic drainage of a cerebral aspergilloma at our center. Patients’ and disease characteristics were recorded. The median age was 65 (range 45 to 83). We conducted 133 cranial surgeries in 100 patients due to cerebral brain abscess (BA) during that time, which leads to a percentage of 10% of aspergilloma within BAs in our patient sample. We performed 3.1 surgeries per patient followed by antifungal treatment for 6 months (= median) according to the microbiological findings. Regarding comorbidities, the mean Charlson comorbidity index (CCI) at the time of admission was 5, representing an estimated 10-year survival of 21%. Six (60%) of 10 patients showed conditions of immunosuppression, one suffered endocarditis after replacement of aortic valves. Four patients showed associated frontobasal bone destruction, mycotic aneurysms, or thromboses. The mean duration of hospital stay was 37 days. Mortality was much lower than in literature. Sixty percent of the patients died during the follow-up period. The outcome of the two immunocompetent patients was more favorable. Cerebral aspergillosis is a rare, but still life-threatening, condition, which predominantly occurs in immunosuppressive conditions. Due to radical surgical and antifungal therapy for several months, mortality can be reduced dramatically.

Sensitive bioluminescence imaging of fungal dissemination to the brain in mouse models of cryptococcosis.

ABSTRACTCryptococcus neoformans is a leading cause of fungal brain infection, but the mechanism of dissemination and dynamics of cerebral infection following pulmonary disease are poorly understood. To address these questions, non-invasive techniques that can study the dynamic processes of disease development and progression in living animal models or patients are required. As such, bioluminescence imaging (BLI) has emerged as a powerful tool to evaluate the spatial and temporal distribution of infection in living animals. We aimed to study the time profile of the dissemination of cryptococcosis from the lung to the brain in murine models by engineering the first bioluminescent C. neoformans KN99α strain, expressing a sequence-optimized red-shifted luciferase. The high pathogen specificity and sensitivity of BLI was complemented by the three-dimensional anatomical information from micro-computed tomography (μCT) of the lung and magnetic resonance imaging (MRI) of the brain. These non-invasive imaging techniques provided longitudinal readouts on the spatial and temporal distribution of infection following intravenous, intranasal or endotracheal routes of inoculation. Furthermore, the imaging results correlated strongly with the fungal load in the respective organs. By obtaining dynamic and quantitative information about the extent and timing of brain infections for individual animals, we found that dissemination to the brain after primary infection of the lung is likely a late-stage event with a timeframe that is variable between animals. This novel tool in Cryptococcus research can aid the identification of host and pathogen factors involved in this process, and supports development of novel preventive or therapeutic approaches.

Spectrum of Magnetic Resonance Imaging Findings in Fungal Infections of Brain

Spectrum of Magnetic Resonance Imaging Findings in Fungal Infections of Brain

Genomic Understanding of an Infectious Brain Disease from the Desert.

Rhinocladiella mackenziei accounts for the majority of fungal brain infections in the Middle East, and is restricted to the arid climate zone between Saudi Arabia and Pakistan. Neurotropic dissemination caused by this fungus has been reported in immunocompromised, but also immunocompetent individuals. If untreated, the infection is fatal. Outside of humans, the environmental niche of R. mackenziei is unknown, and the fungus has been only cultured from brain biopsies. In this paper, we describe the whole-genome resequencing of two R. mackenziei strains from patients in Saudi Arabia and Qatar. We assessed intraspecies variation and genetic signatures to uncover the genomic basis of the pathogenesis, and potential niche adaptations. We found that the duplicated genes (paralogs) are more susceptible to accumulating significant mutations. Comparative genomics with other filamentous ascomycetes revealed a diverse arsenal of genes likely engaged in pathogenicity, such as the degradation of aromatic compounds and iron acquisition. In addition, intracellular accumulation of trehalose and choline suggests possible adaptations to the conditions of an arid climate region. Specifically, protein family contractions were found, including short-chain dehydrogenase/reductase SDR, the cytochrome P450 (CYP) (E-class), and the G-protein β WD-40 repeat. Gene composition and metabolic potential indicate extremotolerance and hydrocarbon assimilation, suggesting a possible environmental habitat of oil-polluted desert soil.

Hemispheric multiple fungal brain abscesses due to Scedosporium apiospermum following surgery

We report an interesting and rare case of hemispheric multiple brain abscesses due to Scedosporium apiospermum which developed following neurosurgery and mimicked hemiconvulsion hemiplegia epilepsy syndrome on initial scans. Interestingly all the abscesses were only on the right side of cerebral hemisphere which later on spread to the other side. All the lesions had hemorrhagic walls seen as hypointensities on susceptibility weighted imaging. The patient succumbed to this fatal fungal brain infection.

Fungal brain infections

Fungal infections of the central nervous system, once a relatively rare occurrence, are increasingly common due to the expansion of immunocompromised populations at risk, and therefore are important to recognize early and manage appropriately. The specific infectious risk posed by novel immune-modifying therapies can, in most cases, be predicted on the basis of the immune target and medication timing. In addition, major advances in noninvasive diagnostic tests (e.g. serum beta glucan and galactomannan assays), and the recent introduction of more effective antifungal therapies, have led to a dramatic improvement in clinical outcomes. The current review provides approaches to patients with suspected central nervous system fungal infections based on host-risk factors, clinical syndromes and specific pathogens.

Fungal versus bacterial brain abscesses: is diffusion-weighted MR imaging a useful tool in the differential diagnosis?

The aim of this study was to investigate the appearance of fungal brain abscesses on diffusion-weighted (DW) images, and to evaluate whether the imaging characteristics and apparent diffusion coefficient (ADC) values associated with fungal abscesses were distinct from those of bacterial abscesses. We retrospectively reviewed the MR images from nine patients with fungal brain infections, and 17 patients with pyogenic brain abscesses. All patients underwent conventional MR sequences and DW imaging on 1.5-T clinical MR scanners. ADC values of 20 fungal and 20 bacterial brain abscesses were calculated and compared using a random factor analysis of variance. Multiple lesions were present in 6 of 9 patients (67%) with fungal abscesses and in 5 of 17 patients (29%) with bacterial abscesses. On DW images, all but one bacterial brain abscess showed a homogeneous high signal, whereas the appearance of fungal abscesses on DW images was more variable: in five of nine patients with fungal abscesses, the lesions were homogeneously hyperintense, while in the remaining four patients, the lesions were of mixed signal intensity. Mean ADC values were 0.74 x 10(-3) mm(2)/s in the fungal group and 0.486 x 10(-3) mm(2)/s in the bacterial group (P< or =0.05). Our results indicate that there is a trend towards higher ADC values in fungal lesions. Additional findings that support fungal rather than bacterial cerebral infection are multiplicity, signal heterogeneity on T2-weighted and DW imaging, and involvement of deep grey-matter nuclei.

Disseminated Scedosporium apiospermum infection in a previously healthy woman with HELLP syndrome

A previously healthy 33-year-old female died of disseminated infection with Scedosporium apiospermum in association with Hemolysis, Elevated Liver enzymes, and Low Platelets (HELLP) syndrome following the delivery of twins. Her postpartum course was complicated by multisystem organ failure managed with extracorporeal membrane oxygenation (ECMO). She also developed bowel and left lower extremity ischemia requiring surgical resection. Blood cultures yielded S. apiospermum, and histologic findings revealed in vivo adventitious sporulation, an unusual occurrence with this pathogen. Autopsy showed extensive fungal infection of brain, lungs, thyroid, heart, and kidneys.

Bacterial and fungal brain infections in AIDS.

Many bacterial and fungal pathogens can infect the central nervous system (CNS) in patients also infected with human immunodeficiency virus (HIV). Most of these organisms cause meningitis, and this is sometimes accompanied by focal parenchymal infection. More virulent pathogens, such as Mycobacterium tuberculosis hominis, can cause disease in individuals with mild degrees of HIV-associated immunosuppression. Less virulent pathogens, such as Cryptococcus neoformans, tend to affect individuals with more advanced immunosuppression. This review focuses on the clinical manifestations, diagnosis, and treatment of the more common bacterial and fungal CNS infections.

Multiple opportunistic infections and neoplasms in the acquired immunodeficiency syndrome

The articles by Fischl et al¹and Burkes et al²that appear elsewhere in this issue nicely illustrate the scope of infectious and neoplastic complications found in the acquired immunodeficiency syndrome (AIDS). Just two patients were reported, but between them they had no fewer than nine different infections and two malignancies, including human T-cell lymphotropic virus (HTLV-III) infection, oral candidiasis,<i>Pneumocystis carinii</i>pneumonia, cytomegalovirus infection, fungal brain infection,<i>Toxoplasma</i>brain abscesses, tuberculosis, cysticercosis, Epstein-Barr virus infection, Kaposi's sarcoma, and non-Hodgkin's lymphoma. Convincing evidence now exists that the cause of AIDS is a retrovirus, HTLV-III, and that this infection may be associated with a profound and progressive cellular immunodeficiency state.³Other data also indicate the possibility of impaired humoral defenses, but in adults, so far, this has led to comparatively few clinical sequelae.⁴Serious opportunistic infections and/or Kaposi's sarcoma dominate what appear to be the later

Multiple Opportunistic Infections and Neoplasms in the Acquired Immunodeficiency Syndrome

The articles by Fischl et al 1 and Burkes et al 2 that appear elsewhere in this issue nicely illustrate the scope of infectious and neoplastic complications found in the acquired immunodeficiency syndrome (AIDS). Just two patients were reported, but between them they had no fewer than nine different infections and two malignancies, including human T-cell lymphotropic virus (HTLV-III) infection, oral candidiasis, Pneumocystis carinii pneumonia, cytomegalovirus infection, fungal brain infection, Toxoplasma brain abscesses, tuberculosis, cysticercosis, Epstein-Barr virus infection, Kaposi's sarcoma, and non-Hodgkin's lymphoma. Convincing evidence now exists that the cause of AIDS is a retrovirus, HTLV-III, and that this infection may be associated with a profound and progressive cellular immunodeficiency state. 3 Other data also indicate the possibility of impaired humoral defenses, but in adults, so far, this has led to comparatively few clinical sequelae. 4 Serious opportunistic infections and/or Kaposi's sarcoma dominate what appear to be the later