title: Hyaluronic acid receptor CD44 deficiency is associated with decreased Cryptococcus neoformans brain infection.
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.
authors.affiliation: Division of Hematology-Oncology, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California 90027, USA. ajong@chla.usc.edu
authors.forename: Ambrose
authors.initials: A
authors.lastname: Jong
authors.forename: Chun-Hua
authors.initials: CH
authors.lastname: Wu
authors.forename: Ignacio
authors.initials: I
authors.lastname: Gonzales-Gomez
authors.forename: Kyung J
authors.initials: KJ
authors.lastname: Kwon-Chung
authors.forename: Yun C
authors.initials: YC
authors.lastname: Chang
authors.forename: Hsiang-Kuang
authors.initials: HK
authors.lastname: Tseng
authors.forename: Wen-Long
authors.initials: WL
authors.lastname: Cho
authors.forename: Sheng-He
authors.initials: SH
authors.lastname: Huang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000382:microbiology; D003453:Cryptococcosis / Q000134:cerebrospinal fluid / Q000378:metabolism* / Q000382:microbiology; D003455:Cryptococcus neoformans / Q000378:metabolism* / Q000472:pathogenicity / Q000502:physiology; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D054884:Host-Pathogen Interactions; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D011485:Protein Binding; D034622:RNA Interference; D019821:Simvastatin / Q000494:pharmacology; D014774:Virulence
chemical_list: C476399:Cd44 protein, mouse; D016326:Extracellular Matrix Proteins; D018960:Hyaluronan Receptors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C098946:hyaluronan-mediated motility receptor; D019821:Simvastatin