Abstract
Cryptococcus neoformans is a pathogenic yeast that can invade the brain and cause meningoencephalitis. Our previous in vitro studies suggested that the interaction between C. neoformans hyaluronic acid and human brain endothelial CD44 could be the initial step of brain invasion. In this report, we used a CD44 knock-out (KO or CD44(-/-)) mouse model to explore the importance of CD44 in C. neoformans brain invasion. Our results showed that C. neoformans-infected CD44 KO mice survived longer than the infected wild-type mice. Consistent with our in vitro results, the brain and cerebrospinal fluid fungal burden was reduced in CD44-deficient mice. Histopathological studies showed smaller and fewer cystic lesions in the brains of CD44 KO mice. Interestingly, the cystic lesions contained C. neoformans cells embedded within their polysaccharide capsule and were surrounded by host glial cells. We also found that a secondary hyaluronic acid receptor, RHAMM (receptor of hyaluronan-mediated motility), was present in the CD44 KO mice. Importantly, our studies demonstrated an in vivo blocking effect of simvastatin. These results suggest that the CD44 and RHAMM receptors function on membrane lipid rafts during invasion and that simvastatin may have a potential therapeutic role in C. neoformans infections of the brain.
Highlights
Previous studies suggest that the C. neoformans hyaluronic acid and host CD44 interaction could be the initial step of brain invasion
Our studies demonstrated an in vivo blocking effect of simvastatin. These results suggest that the CD44 and RHAMM receptors function on membrane lipid rafts during invasion and that simvastatin may have a potential therapeutic role in C. neoformans infections of the brain
From our previous in vitro studies [12], we found that C. neoformans uses the host CD44 as the receptor and hyaluronic acid (HA) as the ligand in their association
Summary
Previous studies suggest that the C. neoformans hyaluronic acid and host CD44 interaction could be the initial step of brain invasion. Our studies demonstrated an in vivo blocking effect of simvastatin These results suggest that the CD44 and RHAMM receptors function on membrane lipid rafts during invasion and that simvastatin may have a potential therapeutic role in C. neoformans infections of the brain. Scanning electron microscopic images reveal the course of invasion: internalization by the microvilli embrace of C. neoformans, followed by a zipper-like mechanism in which the host cell plasma membrane encompasses the invading yeasts [13]. We had used the in vitro blood-brain barrier model to demonstrate that the C. neoformans HA-HBMEC CD44 interaction plays an initial role during the fungal invasion across the blood-brain barrier [12]. The CD44Ϫ/Ϫ mouse brain contained smaller and fewer cystic lesions These results suggested that host CD44 is required for C. neoformans brain invasion. Our results suggest that simvastatin may remove receptor function on the membrane lipid raft or yet identified action(s), providing a cue for a novel anticryptococcal intervention
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