Vimentin contributes to the comorbidities of Cryptococcus neoformans and HIV-1 gp120

Abstract

Abstract Cryptococcus neoformans (CN) is the most common pathogen causing fungal meningitis (CNM)in patients with acquired immunodeficiency syndrome (AIDS). Due to the ambiguity of the mechanism of comorbidity of CNM and human immunodeficiency virus (HIV)-1 encephalopathy, AIDS patients with CNM have maintained a high mortality rate. CD44 on the surface of human brain microvascular endothelial cells (HBMECs), which is a main component of the blood–brain barrier (BBB), mediates the CN adhesion and penetration across the BBB. However, the HIV-1 envelope protein gp120, which binds to vimentin (Vim), is required for the entry of virus into the target cells. Our previous study has shown that NF-κB is regulated by Vim that interacts with soluble CD44. How VIM and gp120 contributing to the comorbidity of AIDS-associated CNM remain largely unknown. In this study, we generated a Vim−/−/gp120 double transgenic mouse strain and a meningitis mouse model of CN infection. Compared with Vim+/+/gp120 mice, the number of CN in the brain, circulating brain microvascular endothelial cells (cBMECs) in the blood, and p65 and TNF-α concentrations in the cerebrospinal fluid (CSF) of Vim−/−/gp120 mice were significantly decreased. In addition, astrocyte proliferation and the degree of the neuron/BBB damage induced by CN infection were also reduced in Vim−/−/gp120 mice. In vitro experiments showed that the NF-κB inhibitor caffeic acid phenethyl ester (CAPE), Ca2+-calmodulin inhibitor trifluoperazine (TFP), and the lipid raft inhibitor Nys inhibited gp120-induced leukocyte migration. The VIM inhibitors Withaferin-A (WFA) and ginsenoside Rg3 significantly blocked VIM protein expression and gp120-induced astrocyte proliferation. Our results suggest that VIM is required for the gp120-mediated CN invasion of BBB in AIDS patients, which is closely related to the activation of the NF-κB pathway and the development of meningitis. VIM-targeting inhibitors have the potential to be developed into new drugs for the treatment of CN meningitis in AIDS patients.