scholarly journals Methamphetamine Enhances Cryptococcus neoformans Pulmonary Infection and Dissemination to the Brain

mBio ◽  
2013 ◽  
Vol 4 (4) ◽  
Author(s):  
Dhavan Patel ◽  
Gunjan M. Desai ◽  
Susana Frases ◽  
Radames J. B. Cordero ◽  
Carlos M. DeLeon-Rodriguez ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Respiratory Tract ◽  
Cryptococcus Neoformans ◽  
Biofilm Formation ◽  
Pulmonary Infection ◽  
Capsular Polysaccharide ◽  
Content Type ◽  
The Impact ◽  
The Brain

ABSTRACTMethamphetamine (METH) is a major addictive drug of abuse in the United States and worldwide, and its use is linked to HIV acquisition. The encapsulated fungusCryptococcus neoformansis the most common cause of fungal meningitis in patients with AIDS. In addition to functioning as a central nervous system stimulant, METH has diverse effects on host immunity. Using a systemic mouse model of infection andin vitroassays in order to critically assess the impact of METH onC. neoformanspathogenesis, we demonstrate that METH stimulates fungal adhesion, glucuronoxylomannan (GXM) release, and biofilm formation in the lungs. Interestingly, structural analysis of the capsular polysaccharide of METH-exposed cryptococci revealed that METH alters the carbohydrate composition of this virulence factor, an event of adaptation to external stimuli that can be advantageous to the fungus during pathogenesis. Additionally, we show that METH promotesC. neoformansdissemination from the respiratory tract into the brain parenchyma. Our findings provide novel evidence of the impact of METH abuse on host homeostasis and increased permissiveness to opportunistic microorganisms.IMPORTANCEMethamphetamine (METH) is a major health threat to our society, as it adversely changes people’s behavior, as well as increases the risk for the acquisition of diverse infectious diseases, particularly those that enter through the respiratory tract or skin. This report investigates the effects of METH use on pulmonary infection by the AIDS-related fungusCryptococcus neoformans. This drug of abuse stimulates colonization and biofilm formation in the lungs, followed by dissemination of the fungus to the central nervous system. Notably,C. neoformansmodifies its capsular polysaccharide after METH exposure, highlighting the fungus’s ability to adapt to environmental stimuli, a possible explanation for its pathogenesis. The findings may translate into new knowledge and development of therapeutic and public health strategies to deal with the devastating complications of METH abuse.

scholarly journals Invasion of the Central Nervous System by Cryptococcus neoformans Requires a Secreted Fungal Metalloprotease

mBio ◽  
2014 ◽  
Vol 5 (3) ◽  
Author(s):  
Kiem Vu ◽  
Rick Tham ◽  
John P. Uhrig ◽  
George R. Thompson ◽  
Sarisa Na Pombejra ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Cryptococcus Neoformans ◽  
Blood Brain Barrier ◽  
Brain Endothelium ◽  
Content Type ◽  
Extracellular Proteome ◽  
Cryptococcal Disease ◽  
The Central Nervous System ◽  
The Brain

ABSTRACTCryptococcusspp. cause life-threatening fungal infection of the central nervous system (CNS), predominantly in patients with a compromised immune system. WhyCryptococcus neoformanshas this remarkable tropism for the CNS is not clear. Recent research on cerebral pathogenesis ofC. neoformansrevealed a predominantly transcellular migration of cryptococci across the brain endothelium; however, the identities of key fungal virulence factors that function specifically to invade the CNS remain unresolved. Here we found that a novel, secreted metalloprotease (Mpr1) that we identified in the extracellular proteome ofC. neoformans(CnMpr1) is required for establishing fungal disease in the CNS. Mpr1 belongs to a poorly characterized M36 class of fungalysins that are expressed in only some fungal species. A strain ofC. neoformanslacking the gene encoding Mpr1 (mpr1Δ) failed to breach the endothelium in anin vitromodel of the human blood-brain barrier (BBB). A mammalian host infected with thempr1Δnull strain demonstrated significant improvement in survival due to a reduced brain fungal burden and lacked the brain pathology commonly associated with cryptococcal disease. Thein vivostudies further indicate that Mpr1 is not required for fungal dissemination and Mpr1 likely targets the brain endothelium specifically. Remarkably, the sole expression of CnMPR1inSaccharomyces cerevisiaeresulted in a robust migration of yeast cells across the brain endothelium, demonstrating Mpr1’s specific activity in breaching the BBB and suggesting that Mpr1 may function independently of the hyaluronic acid-CD44 pathway. This distinct role for Mpr1 may develop into innovative treatment options and facilitate a brain-specific drug delivery platform.IMPORTANCECryptococcus neoformansis a medically relevant fungal pathogen causing significant morbidity and mortality, particularly in immunocompromised individuals. An intriguing feature is its strong neurotropism, and consequently the hallmark of cryptococcal disease is a brain infection, cryptococcal meningoencephalitis. ForC. neoformansto penetrate the central nervous system (CNS), it first breaches the blood-brain barrier via a transcellular pathway; however, the identities of fungal factors required for this transmigration remain largely unknown. In an effort to identify extracellular fungal proteins that could mediate interactions with the brain endothelium, we undertook a proteomic analysis of the extracellular proteome and identified a secreted metalloprotease (Mpr1) belonging to the M36 class of fungalysins. Here we found that Mpr1 promotes migration ofC. neoformansacross the brain endothelium and into the CNS by facilitating attachment of cryptococci to the endothelium surface, thus underscoring the critical role of M36 proteases in fungal pathogenesis.

scholarly journals Cryptococcus neoformans Promotes Its Transmigration into the Central Nervous System by Inducing Molecular and Cellular Changes in Brain Endothelial Cells

2013 ◽  
Vol 81 (9) ◽  
pp. 3139-3147 ◽  
Author(s):  
Kiem Vu ◽  
Richard A. Eigenheer ◽  
Brett S. Phinney ◽  
Angie Gelli
Keyword(s):  
Central Nervous System ◽  
Endothelial Cells ◽  
Nervous System ◽  
Human Brain ◽  
Cryptococcus Neoformans ◽  
Brain Endothelial Cells ◽  
Brain Endothelium ◽  
Content Type ◽  
The Central Nervous System ◽  
The Brain

ABSTRACTCryptococcusspp. cause fungal meningitis, a life-threatening infection that occurs predominately in immunocompromised individuals. In order forCryptococcus neoformansto invade the central nervous system (CNS), it must first penetrate the brain endothelium, also known as the blood-brain barrier (BBB). Despite the importance of the interrelation betweenC. neoformansand the brain endothelium in establishing CNS infection, very little is known about this microenvironment. Here we sought to resolve the cellular and molecular basis that defines the fungal-BBB interface during cryptococcal attachment to, and internalization by, the human brain endothelium. In order to accomplish this by a systems-wide approach, the proteomic profile of human brain endothelial cells challenged withC. neoformanswas resolved using a label-free differential quantitative mass spectrometry method known as spectral counting (SC). Here, we demonstrate that as brain endothelial cells associate with, and internalize, cryptococci, they upregulate the expression of several proteins involved with cytoskeleton, metabolism, signaling, and inflammation, suggesting that they are actively signaling and undergoing cytoskeleton remodeling via annexin A2, S100A10, transgelin, and myosin. Transmission electronic microscopy (TEM) analysis demonstrates dramatic structural changes in nuclei, mitochondria, the endoplasmic reticulum (ER), and the plasma membrane that are indicative of cell stress and cell damage. The translocation of HMGB1, a marker of cell injury, the downregulation of proteins that function in transcription, energy production, protein processing, and the upregulation of cyclophilin A further support the notion thatC. neoformanselicits changes in brain endothelial cells that facilitate the migration of cryptococci across the BBB and ultimately induce endothelial cell necrosis.

scholarly journals Adaptation of Cryptococcus neoformans to Mammalian Hosts: Integrated Regulation of Metabolism and Virulence

2011 ◽  
Vol 11 (2) ◽  
pp. 109-118 ◽  
Author(s):  
Jim Kronstad ◽  
Sanjay Saikia ◽  
Erik David Nielson ◽  
Matthias Kretschmer ◽  
Wonhee Jung ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Cryptococcus Neoformans ◽  
Central Carbon Metabolism ◽  
Yeast Cells ◽  
Phagocytic Cells ◽  
Content Type ◽  
The Central Nervous System ◽  
Mechanisms Of Adaptation ◽  
Complex Integration

ABSTRACTThe basidiomycete fungusCryptococcus neoformansinfects humans via inhalation of desiccated yeast cells or spores from the environment. In the absence of effective immune containment, the initial pulmonary infection often spreads to the central nervous system to result in meningoencephalitis. The fungus must therefore make the transition from the environment to different mammalian niches that include the intracellular locale of phagocytic cells and extracellular sites in the lung, bloodstream, and central nervous system. Recent studies provide insights into mechanisms of adaptation during this transition that include the expression of antiphagocytic functions, the remodeling of central carbon metabolism, the expression of specific nutrient acquisition systems, and the response to hypoxia. Specific transcription factors regulate these functions as well as the expression of one or more of the major known virulence factors ofC. neoformans. Therefore, virulence factor expression is to a large extent embedded in the regulation of a variety of functions needed for growth in mammalian hosts. In this regard, the complex integration of these processes is reminiscent of the master regulators of virulence in bacterial pathogens.

scholarly journals Prion propagation in mice lacking central nervous system NF-κB signalling

2008 ◽  
Vol 89 (6) ◽  
pp. 1545-1550 ◽  
Author(s):  
C. Julius ◽  
M. Heikenwalder ◽  
P. Schwarz ◽  
A. Marcel ◽  
M. Karin ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Immune Responses ◽  
Published Data ◽  
Histopathological Changes ◽  
Prion Infection ◽  
Prion Propagation ◽  
Proliferation Regulation ◽  
The Impact ◽  
The Brain

Prions induce highly typical histopathological changes including cell death, spongiosis and activation of glia, yet the molecular pathways leading to neurodegeneration remain elusive. Following prion infection, enhanced nuclear factor-κB (NF-κB) activity in the brain parallels the first pathological changes. The NF-κB pathway is essential for proliferation, regulation of apoptosis and immune responses involving induction of inflammation. The IκB kinase (IKK) signalosome is crucial for NF-κB signalling, consisting of the catalytic IKKα/IKKβ subunits and the regulatory IKKγ subunit. This study investigated the impact of NF-κB signalling on prion disease in mouse models with a central nervous system (CNS)-restricted elimination of IKKβ or IKKγ in nearly all neuroectodermal cells, including neurons, astrocytes and oligodendrocytes, and in mice containing a non-phosphorylatable IKKα subunit (IKKα AA/AA). In contrast to previously published data, the observed results showed no evidence supporting the hypothesis that impaired NF-κB signalling in the CNS impacts on prion pathogenesis.

scholarly journals EDTA Inhibits Biofilm Formation, Extracellular Vesicular Secretion, and Shedding of the Capsular Polysaccharide Glucuronoxylomannan by Cryptococcus neoformans

2012 ◽  
Vol 78 (22) ◽  
pp. 7977-7984 ◽  
Author(s):  
Emma J. Robertson ◽  
Julie M. Wolf ◽  
Arturo Casadevall
Keyword(s):  
Cryptococcus Neoformans ◽  
Biofilm Formation ◽  
Capsular Polysaccharide ◽  
Inhibitory Effect ◽  
Antifungal Drugs ◽  
Biofilm Growth ◽  
Content Type ◽  
Sublethal Concentrations ◽  
Vesicular Secretion

ABSTRACTThe fungal pathogenCryptococcus neoformanscan grow as a biofilm on a range of synthetic and prosthetic materials. Cryptococcal biofilm formation can complicate the placement of shunts used to relieve increased intracranial pressure in cryptococcal meningitis and can serve as a nidus for chronic infection. Biofilms are generally advantageous to pathogensin vivo, as they can confer resistance to antimicrobial compounds, including fluconazole and voriconazole in the case ofC. neoformans. EDTA can inhibit biofilm formation by several microbes and enhances the susceptibility of biofilms to antifungal drugs. In this study, we evaluated the effect of sublethal concentrations of EDTA on the growth of cryptococcal biofilms. EDTA inhibited biofilm growth byC. neoformans, and the inhibition could be reversed by the addition of magnesium or calcium, implying that the inhibitory effect was by divalent cation starvation. EDTA also reduced the amount of the capsular polysaccharide glucuronoxylomannan shed into the biofilm matrix and decreased vesicular secretion from the cell, thus providing a potential mechanism for the inhibitory effect of this cation-chelating compound. Our data imply that the growth ofC. neoformansbiofilms requires the presence of divalent metals in the growth medium and suggest that cations are required for the export of materials needed for biofilm formation, possibly including extracellular vesicles.

scholarly journals Persisting Rickettsia typhi Causes Fatal Central Nervous System Inflammation

2016 ◽  
Vol 84 (5) ◽  
pp. 1615-1632 ◽  
Author(s):  
Anke Osterloh ◽  
Stefanie Papp ◽  
Kristin Moderzynski ◽  
Svenja Kuehl ◽  
Ulricke Richardt ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Rickettsia Typhi ◽  
Content Type ◽  
Inflammatory Phenotype ◽  
Obligate Intracellular Bacteria ◽  
Immunocompromised Mice ◽  
The Brain

Rickettsioses are emerging febrile diseases caused by obligate intracellular bacteria belonging to the familyRickettsiaceae. Rickettsia typhibelongs to the typhus group (TG) of this family and is the causative agent of endemic typhus, a disease that can be fatal. In the present study, we analyzed the course ofR. typhiinfection in C57BL/6 RAG1−/−mice. Although these mice lack adaptive immunity, they developed only mild and temporary symptoms of disease and survivedR. typhiinfection for a long period of time. To our surprise, 3 to 4 months after infection, C57BL/6 RAG1−/−mice suddenly developed lethal neurological disorders. Analysis of these mice at the time of death revealed high bacterial loads, predominantly in the brain. This was accompanied by a massive expansion of microglia and by neuronal cell death. Furthermore, high numbers of infiltrating CD11b+macrophages were detectable in the brain. In contrast to the microglia, these cells harboredR. typhiand showed an inflammatory phenotype, as indicated by inducible nitric oxide synthase (iNOS) expression, which was not observed in the periphery. Having shown thatR. typhipersists in immunocompromised mice, we finally asked whether the bacteria are also able to persist in resistant C57BL/6 and BALB/c wild-type mice. Indeed,R. typhicould be recultivated from lung, spleen, and brain tissues from both strains even up to 1 year after infection. This is the first report demonstrating persistence and reappearance ofR. typhi, mainly restricted to the central nervous system in immunocompromised mice.

scholarly journals Neuropathogenesis caused by Trypanosoma brucei, still an enigma to be unveiled

2021 ◽  
Vol 8 (4) ◽  
pp. 73-76
Author(s):  
Katherine Figarella
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Immune Responses ◽  
Trypanosoma Brucei ◽  
Late Stage ◽  
Early Stage ◽  
Tropical Diseases ◽  
The Central Nervous System ◽  
The Impact ◽  
The Brain

Trypanosoma brucei is one of the protozoa parasites that can enter the brain and cause injury associated with toxic effects of parasite-derived molecules or with immune responses against infection. Other protozoa parasites with brain tropism include Toxoplasma, Plasmodium, Amoeba, and, eventually, other Trypano-somatids such as T. cruzi and Leishmania. Together, these parasites affect billions of people worldwide and are responsible for more than 500.000 deaths annually. Factors determining brain tropism, mechanisms of in-vasion as well as processes ongoing inside the brain are not well understood. But, they depend on the par-asite involved. The pathogenesis caused by T. brucei initiates locally in the area of parasite inoculation, soon trypanosomes rich the blood, and the disease enters in the so-called early stage. The pathomecha-nisms in this phase have been described, even mole-cules used to combat the disease are effective during this period. Later, the disease evolves towards a late-stage, characterized by the presence of parasites in the central nervous system (CNS), the so-called meningo-encephalitic stage. This phase of the disease has not been sufficiently examined and remains a matter of investigation. Here, I stress the importance of delve into the study of the neuropathogenesis caused by T. brucei, which will enable the identification of path-ways that may be targeted to overcome parasites that reached the CNS. Finally, I highlight the impact that the application of tools developed in the last years in the field of neuroscience will have on the study of neglect-ed tropical diseases.

COVID-19, the Brain, and the Future: Is Infection by the Novel Coronavirus a Harbinger of Neurodegeneration?

2021 ◽  
Vol 21 ◽  
Author(s):  
Adejoke Onaolapo ◽  
Olakunle Onaolapo
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Severe Acute Respiratory Syndrome ◽  
Neurodegenerative Diseases ◽  
Central Nervous System Involvement ◽  
The Novel ◽  
Novel Coronavirus ◽  
The Impact ◽  
The Brain

: The possible impact of viral infections on the development or pathogenesis of neurodegenerative disorders remains largely unknown. However, there have been reports associating the influenza virus pandemic and long-term infection with the Japanese encephalitis virus with the development of post-encephalitic Parkinsonism or von Economo encephalitis. In the last one year plus, there has been a worldwide pandemic arising from infection with the novel coronavirus or severe acute respiratory syndrome coronavirus (SARS-CoV)-2 which causes a severe acute respiratory syndrome that has become associated with central nervous system symptoms or complications. Its possible central nervous system involvement is in line with emerging scientific evidence which shows that the human respiratory coronaviruses can enter the brain, infect neural cells, persist in the brain, and cause activation of myelin-reactive T cells. Currently, there is a dearth of scientific information on the acute or possible long-term impact of infection with SARS-CoV-2 on the development of dementias and/or neurodegenerative diseases. This is not unrelated to the fact that the virus is ‘new’, and its effects on humans are still being studied. This narrative review examines extant literature for the impact of corona virus infections on the brain; as it considers the possibility that coronavirus disease 2019 (COVID-19) could increase the risk for the development of neurodegenerative diseases or hasten their progression.

scholarly journals Sepsis-induced alterations in sleep of rats

2011 ◽  
Vol 301 (5) ◽  
pp. R1467-R1478 ◽  
Author(s):  
Francesca Baracchi ◽  
Ashley M. Ingiosi ◽  
Richard M. Raymond ◽  
Mark R. Opp
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Brain Stem ◽  
Brain Temperature ◽  
Sleep Stage ◽  
Cecal Ligation ◽  
Clinical Problem ◽  
Sepsis Induction ◽  
The Impact ◽  
The Brain

Sepsis is a systemic immune response to infection that may result in multiple organ failure and death. Polymicrobial infections remain a serious clinical problem, and in the hospital, sepsis is the number-one noncardiac killer. Although the central nervous system may be one of the first systems affected, relatively little effort has been made to determine the impact of sepsis on the brain. In this study, we used the cecal ligation and puncture (CLP) model to determine the extent to which sepsis alters sleep, the EEG, and brain temperature (Tbr) of rats. Sepsis increases the amount of time rats spend in non-rapid eye movement sleep (NREMS) during the dark period, but not during the light period. Rapid eye movements sleep (REMS) of septic rats is suppressed for about 24 h following CLP surgery, after which REMS increases during dark periods for at least three nights. The EEG is dramatically altered shortly after sepsis induction, as evidenced by reductions in slow-frequency components. Furthermore, sleep is fragmented, indicating that the quality of sleep is diminished. Effects on sleep, the EEG, and Tbr persist for at least 84 h after sepsis induction, the duration of our recording period. Immunohistochemical assays focused on brain stem mechanisms responsible for alterations in REMS, as little information is available concerning infection-induced suppression of this sleep stage. Our immunohistochemical data suggest that REMS suppression after sepsis onset may be mediated, in part, by the brain stem GABAergic system. This study demonstrates for the first time that sleep and EEG patterns are altered during CLP-induced sepsis. These data suggest that the EEG may serve as a biomarker for sepsis onset. These data also contribute to our knowledge of potential mechanisms, whereby infections alter sleep and other central nervous system functions.

scholarly journals Role of an Expanded Inositol Transporter Repertoire in Cryptococcus neoformans Sexual Reproduction and Virulence

mBio ◽  
2010 ◽  
Vol 1 (1) ◽  
Author(s):  
Chaoyang Xue ◽  
Tongbao Liu ◽  
Lydia Chen ◽  
Wenjun Li ◽  
Iris Liu ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Gene Family ◽  
Sexual Reproduction ◽  
Cryptococcus Neoformans ◽  
Yeast Cells ◽  
Sexual Cycle ◽  
Fungal Virulence ◽  
Content Type ◽  
Fungal Meningitis

ABSTRACTCryptococcus neoformansandCryptococcus gattiiare globally distributed human fungal pathogens and the leading causes of fungal meningitis. Recent studies reveal thatmyo-inositol is an important factor for fungal sexual reproduction. ThatC. neoformanscan utilizemyo-inositol as a sole carbon source and the existence of abundant inositol in the human central nervous system suggest that inositol is important forCryptococcusdevelopment and virulence. In accord with this central importance of inositol, an expandedmyo-inositol transporter (ITR) gene family has been identified inCryptococcus. This gene family contains two phylogenetically distinct groups, with a total of 10 or more members inC. neoformansand at least six members in the sibling speciesC. gattii. These inositol transporter genes are differentially expressed under inositol-inducing conditions based on quantitative real-time PCR analyses. Expression ofITRgenes in aSaccharomyces cerevisiaeitr1 itr2mutant lacking inositol transport can complement the slow-growth phenotype of this strain, confirming thatITRgenes arebona fideinositol transporters. Gene mutagenesis studies reveal that the Itr1 and Itr1A transporters are important formyo-inositol stimulation of mating and that functional redundancies among themyo-inositol transporters likely exist. Deletion of the inositol 1-phosphate synthase geneINO1in anitr1oritr1amutant background compromised virulence in a murine inhalation model, indicating the importance of inositol sensing and acquisition for fungal infectivity. Our study provides a platform for further understanding the roles of inositol in fungal physiology and virulence.IMPORTANCECryptococcus neoformansis an AIDS-associated human fungal pathogen that causes over 1 million cases of meningitis annually and is the leading cause of fungal meningitis in immunosuppressed patients. The initial cryptococcal infection is caused predominantly via inhalation of sexual spores or desiccated yeast cells from the environment. How this fungus completes its sexual cycle and produces infectious spores in nature and why it frequently infects the central nervous system to cause fatal meningitis are critical questions that remain to be understood. In this study, we demonstrate that inositol acquisition is important not only for fungal sexual reproduction but also for fungal virulence. We identified an expanded inositol transporter gene family that contains over 10 members, important for both fungal sexual reproduction and virulence. Our work contributes to our understanding of how fungi respond to the environmental inositol availability and its impact on sexual reproduction and virulence.

Sign in / Sign up

Export Citation Format

Share Document