Summary: A new study from the University of Sydney describes how the early immune response can inadvertently help a fungus invade the brain, leading to neurocryptococcosis and cryptococcal meningitis. These findings point to potential new strategies to prevent and treat this serious infection.
Source: University of Sydney.
Published in The American Journal of Pathology, the study was led by researchers at the Westmead Institute for Medical Research and the Marie Bashir Institute for Infectious Disease and Biosecurity at the University of Sydney.
Meningitis is inflammation of the meninges, the three membranes that surround the brain and spinal cord. This inflammation can occur when infectious organisms or inflammatory cells enter the fluid spaces that surround and protect the brain. Cryptococcus neoformans, a fungal pathogen found worldwide in environments such as soil, decaying wood, tree hollows and bird droppings, is a major cause of fungal meningitis, especially in people with weakened immune systems.
The research team used experimental models to define a two-step invasion process by which Cryptococcus neoformans reaches and infects the brain. Paradoxically, the body’s early immune response — intended to control infection — plays a central role in transporting the fungus from the bloodstream into brain tissue, where it can form tumour-like lesions and trigger meningitis.
The investigators identified a specific anatomical route for this invasion. Circulating white blood cells called monocytes were observed migrating from the blood across the endothelial lining of small blood vessels known as post-capillary venules into the adjacent peri-vascular space. These monocytes act as carriers — or “Trojan horses” — ferrying cryptococci across the vessel wall and releasing them into the peri-vascular space. From that compartment the fungus can then penetrate further into brain tissue and the cerebrospinal fluid, leading to infection and inflammation of the meninges.
Key findings
Lead researcher Professor Tania Sorrell of the University of Sydney explained that the early immune response in neurocryptococcosis includes monocytes, neutrophils and lymphocytes recruited from the blood into the peri-vascular space adjacent to post-capillary venules. The study shows that blood-derived monocytes — and to a lesser extent neutrophils — act as the primary effectors that mediate invasion of the central nervous system by Cryptococcus neoformans via this route.
By pinpointing how and where white blood cells transport cryptococci across the blood vessel wall and into the brain’s peri-vascular spaces, the study highlights a crucial step in the development of cryptococcal meningitis. This discovery provides a clearer mechanistic picture of the early stages of neurocryptococcosis and identifies possible targets for therapies that could interrupt the transport process and reduce the risk of brain infection.
The researchers emphasize that understanding this complex immune-pathogen interaction is an important first step in designing new treatments. Such strategies could complement existing antifungal drugs by blocking or modulating the host pathways that the fungus exploits to reach the brain.
Cryptococcus neoformans is a common cause of fungal meningitis and can be fatal even with treatment; mortality may reach up to one third of patients in some settings. Globally, an estimated 220,000 new cases of cryptococcal meningitis occur each year, resulting in approximately 181,000 deaths. Infection begins when a person inhales microscopic fungal spores or cells; although most people who are exposed do not develop disease, those with weakened immune systems — particularly people with advanced HIV/AIDS — are at highest risk for severe, life-threatening complications.
Because cryptococcal infections are largely opportunistic, prevention efforts focus on reducing exposures in vulnerable populations and improving immune function when possible. The new mechanistic insights from this study suggest that additional approaches might aim to prevent the fungus from exploiting host immune cells as vehicles into the central nervous system, potentially reducing the burden of disease and improving outcomes in at-risk patients.
About this research
Source: Dan Gaffney, University of Sydney. Published in The American Journal of Pathology. Image in the public domain. Original research appeared in the American Journal of Pathology during the week of June 18, 2018.
Understanding the cellular routes and host responses that allow Cryptococcus neoformans to invade the brain opens the door to targeted therapies that could complement antifungal drugs and improve survival from cryptococcal meningitis.