The study, conducted at the Centre for Molecular Neurosciences, Kasturba Medical College (KMC), Manipal, has revealed why Cryptococcus neoformans, a life-threatening fungal pathogen, specifically targets neurons in the brain. The findings were recently published in Frontiers in Immunology.
A Silent but Deadly Threat
Cryptococcus neoformans is an opportunistic airborne fungus that can cause fatal meningoencephalitis, particularly in individuals with weakened immune systems. While scientists have long known that the fungus releases a toxic molecule called glucuronoxylomannan (GXM) once it enters the brain, it remained unclear why certain brain cells are more vulnerable than others. The MAHE research team, led by Dr Dinesh Upadhya, used cutting-edge human brain organoids, laboratory-grown mini-brain models derived from pluripotent stem cells, to recreate a human-like brain environment for the study. “Our study shows that GXM preferentially targets neurons over other brain cells,” said Dr Upadhya. “Brain organoids allow us to understand microbial pathogenesis in a highly human-relevant system.”
Why Neurons Are More Vulnerable
To understand the mechanism behind this selective targeting, the researchers collaborated with scientists using the Schrödinger, Inc. Materials Science Suite for advanced molecular modelling. Using atomistic simulations, the team created detailed computational models of brain cell membranes. They discovered that neurons are particularly rich in a lipid molecule called phosphatidylcholine (PC). The fungal toxin GXM shows a strong attraction to this lipid, effectively guiding it toward neurons. Once attached, GXM significantly reduced synaptophysin levels, a protein essential for neuronal communication, suggesting that the infection directly disrupts brain signalling. “This lipid-specific interaction explains why neurons are preferentially affected, leading to meningitis,” said Dr. Vishukumar Aimanianda, Professor of Biochemistry at MAHE and co-investigator of the study.
Opening New Treatment Pathways
The study sets a new benchmark in using human brain organoids to investigate fungal infections. By identifying the molecular basis of the fungus's targeting of neurons, researchers believe the findings could pave the way for more targeted therapies. “Understanding these interactions at a molecular level opens new avenues for developing treatments aimed at protecting brain function,” said Dr Kavitha Saravu, Professor of Infectious Diseases at MAHE. According to researchers, the findings not only advance knowledge in fungal pathogenesis but also demonstrate the power of combining stem-cell biology with computational molecular modelling.
About Manipal Academy of Higher Education:
Manipal Academy of Higher Education (MAHE) is an Institution of Eminence Deemed-to-be University, offering over 400 specialisations across Health Sciences, Management, Law, Humanities & Social Sciences, and Technology & Science. MAHE operates through its constituent institutions across campuses in Manipal, Mangalore, Bengaluru, Jamshedpur, and Dubai.
Renowned for its academic excellence, world-class infrastructure, and impactful research contributions, MAHE has earned strong national and international recognition. In 2020, the Ministry of Education, Government of India, conferred MAHE with the prestigious Institution of Eminence status. Currently ranked 3rd in the National Institutional Ranking Framework (NIRF), MAHE continues to be a preferred destination for students seeking a transformative learning experience and vibrant campus life, as well as for national and multinational organisations seeking top talent.
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