Intranasal inoculation of<i>Cryptococcus neoformans</i>in mice produces nasal infection with rapid brain dissemination

Coelho, Carolina; Camacho, Emma; Salas, Antonio; Alanio, Alexandre; Casadevall, Arturo

doi:10.1101/709204

Cited by 4 publications

(4 citation statements)

References 62 publications

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“…An interesting follow up to this study would involve using the less virulent serotype D strain in C57 mice as well as using both serotypes A and D in a more resistant mouse model such as CBA/J mice. This is an important concept because eosinophilia has been reported in human cryptococcosis cases ( 247 ) and the underlying cause of susceptibility of C57 mice to C. neoformans compared to other inbred strains such as CBA/J ( 39 , 248 , 249 ), which needs to be at the forefront of interpreting data across different strains of mice.…”

Section: Modeling Cryptococcal Infections and What Has Been Learnedmentioning

confidence: 99%

Animal Models of Cryptococcus neoformans in Identifying Immune Parameters Associated With Primary Infection and Reactivation of Latent Infection

2020

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Cryptococcus species are environmental fungal pathogens and the causative agents of cryptococcosis. Infection occurs upon inhalation of infectious particles, which proliferate in the lung causing a primary infection. From this primary lung infection, fungal cells can eventually disseminate to other organs, particularly the brain, causing lethal meningoencephalitis. However, in most cases, the primary infection resolves with the formation of a lung granuloma. Upon severe immunodeficiency, dormant cryptococcal cells will start proliferating in the lung granuloma and eventually will disseminate to the brain. Many investigators have sought to study the protective host immune response to this pathogen in search of host parameters that keep the proliferation of cryptococcal cells under control. The majority of the work assimilates research carried out using the primary infection animal model, mainly because a reactivation model has been available only very recently. This review will focus on anti-cryptococcal immunity in both the primary and reactivation models. An understanding of the differences in host immunity between the primary and reactivation models will help to define the key host parameters that control the infections and are important for the research and development of new therapeutic and vaccine strategies against cryptococcosis.

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Section: Modeling Cryptococcal Infections and What Has Been Learnedmentioning

confidence: 99%

Animal Models of Cryptococcus neoformans in Identifying Immune Parameters Associated With Primary Infection and Reactivation of Latent Infection

2020

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“…In addition to the antifungal and antivirulence activities of CMN in vitro , in vivo antifungal efficacy of CMN was evaluated in a pulmonary cryptococcosis BALB/c mouse model. − Our studies in the BALB/c mouse model indicate that CMN is efficacious in vivo . CMN treatment at an oral dose of 20 mg/kg BW significantly reduced fungal load in the mouse lung.…”

Section: Resultsmentioning

confidence: 96%

Calcimycin Inhibits Cryptococcus neoformans In Vitro and In Vivo by Targeting the Prp8 Intein Splicing

Tharappel

Zhu

et al. 2022

ACS Infect. Dis.

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Drug resistance is a significant concern in the treatment of diseases, including cryptococcosis caused by Cryptococcus neoformans (Cne) and Cryptococcus gattii (Cga). Alternative drug targets are necessary to overcome drug resistance before it attains a critical stage. Splicing of inteins from pro-protein precursors is crucial for activities of essential proteins hosting intein elements in many organisms, including human pathogens such as Cne and Cga. Through a high-throughput screening, we identified calcimycin (CMN) as a potent Prp8 intein splicing inhibitor with a minimum inhibitory concentration (MIC) of 1.5 μg/mL against the wild-type Cne-H99 (Cne-WT or Cne). In contrast, CMN inhibited the intein-less mutant strain (Cne-Mut) with a 16-fold higher MIC. Interestingly, Aspergillus fumigatus and a few Candida species were resistant to CMN. Further studies indicated that CMN reduced virulence factors such as urease activity, melanin production, and biofilm formation in Cne. CMN also inhibited Cne intracellular infection in macrophages. In a target-specific split nanoluciferase assay, the IC50 of CMN was 4.6 μg/mL. Binding of CMN to recombinant Prp8 intein was demonstrated by thermal shift assay and microscale thermophoresis. Treating Cne cells with CMN reduced intein splicing. CMN was fungistatic and showed a synergistic effect with the known antifungal drug amphotericin B. Finally, CMN treatment at 20 mg/kg body weight led to 60% reduction in lung fungal load in a cryptococcal pulmonary infection mouse model. Overall, CMN represents a potent antifungal with a novel mechanism of action to treat Cne and possibly Cga infections.

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“…Porphyromonas gingivalis could be detected within the brain parenchyma following chronic oral administration to mice, 34,35 and replication‐defective HSV is found in the brain within 3 days (see below). Intranasal or intratracheal administration of the fungus Cryptococcus neoformans in mice led to rapid dissemination into the brain as quickly as 3 h postinfection, although the titers were low (≤1% of the inoculum) 36 . Similarly, intranasal administration of a filamentous bacteriophage to mice was followed by rapid appearance in the brain 37 …”

Section: How Do Endozoites Enter the Brain? Role Of The Blood–brain Bmentioning

confidence: 99%

From conifers to cognition: Microbes, brain and behavior

Lathe

Clair

2020

Genes Brain and Behavior

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A diversity of bacteria, protozoans and viruses (“endozoites”) were recently uncovered within healthy tissues including the human brain. By contrast, it was already recognized a century ago that healthy plants tissues contain abundant endogenous microbes (“endophytes”). Taking endophytes as an informative precedent, we overview the nature, prevalence, and role of endozoites in mammalian tissues, centrally focusing on the brain, concluding that endozoites are ubiquitous in diverse tissues. These passengers often remain subclinical, but they are not silent. We address their routes of entry, mechanisms of persistence, tissue specificity, and potential to cause long‐term behavioral changes and/or immunosuppression in mammals, where rabies virus is the exemplar. We extend the discussion to Herpesviridae, Coronaviridae, and Toxoplasma, as well as to diverse bacteria and yeasts, and debate the advantages and disadvantages that endozoite infection might afford to the host and to the ecosystem. We provide a clinical perspective in which endozoites are implicated in neurodegenerative disease, anxiety/depression, and schizophrenia. We conclude that endozoites are instrumental in the delicate balance between health and disease, including age‐related brain disease, and that endozoites have played an important role in the evolution of brain function and human behavior.

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Intranasal inoculation ofCryptococcus neoformansin mice produces nasal infection with rapid brain dissemination

Cited by 4 publications

References 62 publications

Animal Models of Cryptococcus neoformans in Identifying Immune Parameters Associated With Primary Infection and Reactivation of Latent Infection

Animal Models of Cryptococcus neoformans in Identifying Immune Parameters Associated With Primary Infection and Reactivation of Latent Infection

Calcimycin Inhibits Cryptococcus neoformans In Vitro and In Vivo by Targeting the Prp8 Intein Splicing

From conifers to cognition: Microbes, brain and behavior

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