Microglia and amyloid precursor protein coordinate control of transient Candidacerebritis with memory deficits
Bloodborne infections with Candida albicans are an increasingly recognized complication of modern medicine. Here, we present a mouse model of low-grade candidemia to determine the effect of disseminated infection on cerebral function and relevant immune determinants. We show that intravenous injection of 25,000 C. albicans cells causes a highly localized cerebritis marked by the accumulation of activated microglial and astroglial cells around yeast aggregates, forming fungal-induced glial granulomas. Amyloid precursor protein accumulates within the periphery of these granulomas, while cleaved amyloid beta (Aβ) peptides accumulate around the yeast cells. CNS-localized C. albicans further activate the transcription factor NF-κB and induce production of interleukin-1β (IL-1β), IL-6, and tumor necrosis factor (TNF), and Aβ peptides enhance both phagocytic and antifungal activity from BV-2 cells. Mice infected with C. albicans display mild memory impairment that resolves with fungal clearance. Our results warrant additional studies to understand the effect of chronic cerebritis on cognitive and immune function.
https://www.nature.com/articles/s41467-018-07991-4
The researchers report in the journal Nature Communications the unexpected finding that the common yeast Candida albicans, a type of fungus, can cross the blood-brain barrier and trigger an inflammatory response that results in the formation of granuloma-type structures and temporary mild memory impairments in mice. Interestingly, the granulomas share features with plaques found in Alzheimer’s disease, supporting future studies on the long-term neurological consequences of sustained C. albicans infection.
The researchers began their investigation by developing a mouse model of a low-grade fungus infection with the common yeast C. albicans that would not cause severe disease, but might carry implications for brain function. They tested several doses and finally settled on one dose of 25,000 yeasts.
They injected C. albicans into the blood stream of mice and were surprised to discover that the yeast can cross the blood-brain barrier, a robust protective mechanism the brain employs to exclude all kinds of large and small molecules, as well as a number of microorganisms that can potentially damage the brain.
“We thought that yeast would not enter the brain, but it does,” Corry said. “In the brain, the yeast triggered the activity of microglia, a resident type of immune cell. The cells became very active ‘eating and digesting’ the yeast. They also produced a number of molecules that mediated an inflammatory response leading to the capture of the yeasts inside a granule-type structure inside the brain. We called it fungus-induced glial granuloma, or FIGG.”
Corry and his colleagues also tested the animals’ memory in both yeast-infected and non-infected mice. They found that infected mice had impaired spatial memory, which reversed when the infection cleared.
The mice cleared the yeast infection in about 10 days; however, the microglia remained active and the FIGGs persisted well past this point, out to at least day 21. Intriguingly, as the FIGGs formed, amyloid precursor proteins accumulated within the periphery and amyloid beta molecules built up around yeast cells captured at the center of FIGGs. These amyloid molecules are typically found in plaques that are the trademark of Alzheimer’s disease.
“These findings suggest that the role fungi play in human illness potentially goes well beyond allergic airway disease or sepsis,” Corry said. “The results prompted us to consider the possibility that in some cases, fungi also could be involved in the development of chronic neurodegenerative disorders, such as Alzheimer’s, Parkinson’s and multiple sclerosis. We are currently exploring this possibility.”
“For these reasons, if we better understand how our immune system deals with this kind of constant threat and what are the weaknesses in our immunological armor that occur with aging that allow fungal disease to take root, then we would likely increases the possibility of finding ways to fight back, ” Corry said.
https://neurosciencenews.com/fungi-brain-infection-memory-10428/
Bloodborne infections with Candida albicans are an increasingly recognized complication of modern medicine. Here, we present a mouse model of low-grade candidemia to determine the effect of disseminated infection on cerebral function and relevant immune determinants. We show that intravenous injection of 25,000 C. albicans cells causes a highly localized cerebritis marked by the accumulation of activated microglial and astroglial cells around yeast aggregates, forming fungal-induced glial granulomas. Amyloid precursor protein accumulates within the periphery of these granulomas, while cleaved amyloid beta (Aβ) peptides accumulate around the yeast cells. CNS-localized C. albicans further activate the transcription factor NF-κB and induce production of interleukin-1β (IL-1β), IL-6, and tumor necrosis factor (TNF), and Aβ peptides enhance both phagocytic and antifungal activity from BV-2 cells. Mice infected with C. albicans display mild memory impairment that resolves with fungal clearance. Our results warrant additional studies to understand the effect of chronic cerebritis on cognitive and immune function.
https://www.nature.com/articles/s41467-018-07991-4
The researchers report in the journal Nature Communications the unexpected finding that the common yeast Candida albicans, a type of fungus, can cross the blood-brain barrier and trigger an inflammatory response that results in the formation of granuloma-type structures and temporary mild memory impairments in mice. Interestingly, the granulomas share features with plaques found in Alzheimer’s disease, supporting future studies on the long-term neurological consequences of sustained C. albicans infection.
The researchers began their investigation by developing a mouse model of a low-grade fungus infection with the common yeast C. albicans that would not cause severe disease, but might carry implications for brain function. They tested several doses and finally settled on one dose of 25,000 yeasts.
They injected C. albicans into the blood stream of mice and were surprised to discover that the yeast can cross the blood-brain barrier, a robust protective mechanism the brain employs to exclude all kinds of large and small molecules, as well as a number of microorganisms that can potentially damage the brain.
“We thought that yeast would not enter the brain, but it does,” Corry said. “In the brain, the yeast triggered the activity of microglia, a resident type of immune cell. The cells became very active ‘eating and digesting’ the yeast. They also produced a number of molecules that mediated an inflammatory response leading to the capture of the yeasts inside a granule-type structure inside the brain. We called it fungus-induced glial granuloma, or FIGG.”
Corry and his colleagues also tested the animals’ memory in both yeast-infected and non-infected mice. They found that infected mice had impaired spatial memory, which reversed when the infection cleared.
The mice cleared the yeast infection in about 10 days; however, the microglia remained active and the FIGGs persisted well past this point, out to at least day 21. Intriguingly, as the FIGGs formed, amyloid precursor proteins accumulated within the periphery and amyloid beta molecules built up around yeast cells captured at the center of FIGGs. These amyloid molecules are typically found in plaques that are the trademark of Alzheimer’s disease.
“These findings suggest that the role fungi play in human illness potentially goes well beyond allergic airway disease or sepsis,” Corry said. “The results prompted us to consider the possibility that in some cases, fungi also could be involved in the development of chronic neurodegenerative disorders, such as Alzheimer’s, Parkinson’s and multiple sclerosis. We are currently exploring this possibility.”
“For these reasons, if we better understand how our immune system deals with this kind of constant threat and what are the weaknesses in our immunological armor that occur with aging that allow fungal disease to take root, then we would likely increases the possibility of finding ways to fight back, ” Corry said.
https://neurosciencenews.com/fungi-brain-infection-memory-10428/