title: CD44-mediated monocyte transmigration across Cryptococcus neoformans-infected brain microvascular endothelial cells is enhanced by HIV-1 gp41-I90 ectodomain.
abstract: BACKGROUND
  Cryptococcus neoformans (Cn) is an important opportunistic pathogen in the immunocompromised people, including AIDS patients, which leads to fatal cryptococcal meningitis with high mortality rate. Previous researches have shown that HIV-1 gp41-I90 ectodomain can enhance Cn adhesion to and invasion of brain microvascular endothelial cell (BMEC), which constitutes the blood brain barrier (BBB). However, little is known about the role of HIV-1 gp41-I90 in the monocyte transmigration across Cn-infected BBB. In the present study, we provide evidence that HIV-1 gp41-I90 and Cn synergistically enhance monocytes transmigration across the BBB in vitro and in vivo. The underlying mechanisms for this phenomenon require further study.
  
  
  METHODS
  In this study, the enhancing role of HIV-1 gp41-I90 in monocyte transmigration across Cn-infected BBB was demonstrated by performed transmigration assays in vitro and in vivo.
  
  
  RESULTS
  Our results showed that the transmigration rate of monocytes are positively associated with Cn and/or HIV-1 gp41-I90, the co-exposure (HIV-1 gp41-I90 + Cn) group showed a higher THP-1 transmigration rate (P < 0.01). Using CD44 knock-down HBMEC or CD44 inhibitor Bikunin in the assay, the facilitation of transmigration rates of monocyte enhanced by HIV-1 gp41-I90 was significantly suppressed. Western blotting analysis and biotin/avidin enzyme-linked immunosorbent assays (BA-ELISAs) showed that Cn and HIV-1 gp41-I90 could increase the expression of CD44 and ICAM-1 on the HBMEC. Moreover, Cn and/or HIV-1 gp41-I90 could also induce CD44 redistribution to the membrane lipid rafts. By establishing the mouse cryptococcal meningitis model, we found that HIV-1 gp41-I90 and Cn could synergistically enhance the monocytes transmigration, increase the BBB permeability and injury in vivo.
  
  
  CONCLUSIONS
  Collectively, our findings suggested that HIV-1 gp41-I90 ectodomain can enhance the transmigration of THP-1 through Cn-infected BBB, which may be mediated by CD44. This novel study enlightens the future prospects to elaborate the inflammatory responses induced by HIV-1 gp41-I90 ectodomain and to effectively eliminate the opportunistic infections in AIDS patients.
authors.affiliation: Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, 510515, China. 307660349@qq.com.
authors.forename: Xiaolong
authors.initials: X
authors.lastname: He
authors.affiliation: Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, 510515, China. 45317380@qq.com.
authors.forename: Xiaolu
authors.initials: X
authors.lastname: Shi
authors.affiliation: Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, 510515, China. santhoshpk73@hotmail.com.
authors.forename: Santhosh
authors.initials: S
authors.lastname: Puthiyakunnon
authors.affiliation: Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, 510515, China. 380994803@qq.com.
authors.forename: Like
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, 510515, China. macao1234@126.com.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zeng
authors.affiliation: Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, 510515, China. 924566525@qq.com.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, 510515, China. saps78in@yahoo.com.
authors.forename: Swapna
authors.initials: S
authors.lastname: Boddu
authors.affiliation: Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, 510515, China. 337958623@qq.com.
authors.forename: Jiawen
authors.initials: J
authors.lastname: Qiu
authors.affiliation: The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China. 527843549@qq.com.
authors.forename: Zhihao
authors.initials: Z
authors.lastname: Lai
authors.affiliation: The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China. 870686982@qq.com.
authors.forename: Chao
authors.initials: C
authors.lastname: Ma
authors.affiliation: The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China. xyldragon94@hotmail.com.
authors.forename: Yulong
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, 510515, China. 192388989@qq.com.
authors.forename: Min
authors.initials: M
authors.lastname: Long
authors.affiliation: Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, 510515, China. 2862511913@qq.com.
authors.forename: Lei
authors.initials: L
authors.lastname: Du
authors.affiliation: Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, 510515, China. shhuang18@hotmail.com.|Saban Research Institute, Children's Hospital Los Angeles, University of Southern California, Los Angeles, CA, 90027, USA. shhuang18@hotmail.com.
authors.forename: Sheng-He
authors.initials: SH
authors.lastname: Huang
authors.affiliation: Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, 510515, China. gzhcao@smu.edu.cn.
authors.forename: Hong
authors.initials: H
authors.lastname: Cao
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000382:microbiology / Q000821:virology; D002460:Cell Line; D003453:Cryptococcosis / Q000235:genetics / Q000378:metabolism*; D003455:Cryptococcus neoformans; D042783:Endothelial Cells / Q000378:metabolism* / Q000382:microbiology / Q000821:virology; D015700:HIV Envelope Protein gp41 / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D057705:Transendothelial and Transepithelial Migration
chemical_list: C497483:CD44 protein, human; D015700:HIV Envelope Protein gp41; D018960:Hyaluronan Receptors; C514787:gp41 protein, Human immunodeficiency virus 1