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Phospholipase B Is Critical for Cryptococcus neoformans Survival in the Central Nervous System. | LitMetric

AI Article Synopsis

  • - *Cryptococcus neoformans is a yeast-like fungus that causes severe brain infections, particularly in individuals with HIV, and has various virulence factors, including the enzyme phospholipase B (PLB1).* - *Research using PLB1 mutant strains showed that infected mice had better survival rates, lower fungal loads, and less brain damage compared to those infected with the standard strain, indicating the enzyme's role in pathogenicity.* - *The study highlights the importance of PLB1 in worsening brain infections and its implications for conditions like dementia, suggesting that better understanding of this enzyme could lead to improved treatments for cryptococcal meningoencephalitis.*

Article Abstract

Cryptococcus neoformans () is an opportunistic, encapsulated, yeast-like fungus that causes severe meningoencephalitis, especially in countries with high HIV prevalence. In addition to its well-known polysaccharide capsule, has other virulence factors such as phospholipases, a heterogeneous group of enzymes that hydrolyze ester linkages in glycerophospholipids. Phospholipase B (PLB1) has been demonstrated to play a key role in pathogenicity. In this study, we used a PLB1 mutant () and its reconstituted strain (Rec1) to assess the importance of this enzyme on brain infection and . Mice infected with the strain survive significantly longer, have lower peripheral and central nervous system (CNS) fungal loads, and have fewer and smaller cryptococcomas or biofilm-like brain lesions compared to H99- and Rec1-infected animals. PLB1 causes extensive brain tissue damage and changes microglia morphology during cryptococcal disease, observations which can have important implications in patients with altered mental status or dementia as these manifestations are related to poorer survival outcomes. cryptococci are significantly more phagocytosed and killed by NR-9460 microglia-like cells. cells have altered capsular polysaccharide biophysical properties which impair their ability to stimulate glial cell responses or morphological changes. Here, we provide significant evidence demonstrating that PLB1 is an important virulence factor for fungal colonization of and survival in the CNS as well as in the progression of cryptococcal meningoencephalitis. These findings may potentially help fill in a gap of knowledge in our understanding of cerebral cryptococcosis and provide novel research avenues in pathogenesis. Cryptococcal meningoencephalitis (CME) is a serious disease caused by infection by the neurotropic fungal pathogen Cryptococcus neoformans. Due to the increasing number of cases in HIV-infected individuals, as well as the limited therapies available, investigation into potential targets for new therapeutics has become critical. Phospholipase B is an enzyme synthesized by that confers virulence to the fungus through capsular enlargement, immunomodulation, and intracellular replication. In this study, we examined the properties of PLB1 by comparing infection of a PLB1 mutant strain with both the wild-type and a PLB1-reconstituted strain. We show that PLB1 augments the survival and proliferation of the fungus in the CNS and strengthens virulence by modulating the immune response and enhancing specific biophysical properties of the fungus. PLB1 expression causes brain tissue damage and impacts glial cell functions, which may be responsible for the dementia observed in patients which may persist even after resolving from CME. The implications of PLB1 inhibition reveal its involvement in infection and suggest that it may be a possible molecular target in the development of antifungal therapies. The results of this study support additional investigation into the mechanism of PLB1 to further understand the intricacies of cerebral infection.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10127605PMC
http://dx.doi.org/10.1128/mbio.02640-22DOI Listing

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