SBi4211阻断HIV-1 gp41促进新生隐球菌对人脑微血管内皮细胞的黏附作用
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摘要
【背景】目前艾滋病和新型隐球菌性脑膜炎共病因素导致其高发病率和死亡率的机制尚不明确。【目的】探索S100B抑制剂SBi4211对HIV-1 gp41促进新生隐球菌黏附人脑微血管内皮细胞的影响和可能机制。【方法】黏附实验分析SBi4211是否能阻断HIV-1 gp41诱导下新生隐球菌黏附人脑微血管内皮细胞。使用免疫印迹方法进一步检测在此过程中SBi4211对脑微血管内皮细胞上新生隐球菌透明质酸受体CD44表达的影响。【结果】SBi4211可显著抑制HIV-1gp41对新生隐球菌黏附脑微血管内皮细胞的增强作用,且呈时间、剂量效应(P<0.05);免疫印迹结果显示SBi4211可抑制新生隐球菌和/或HIV-1 gp41增加脑微血管内皮细胞上新生隐球菌透明质酸受体CD44的表达。【结论】SBi4211可通过下调受体CD44来阻断HIV-1 gp41对新生隐球菌黏附人脑微血管内皮细胞的增强效应,这为了解HIV-1与新生隐球菌共病机制及其防治策略提供了新思路。
[Background] The prevalence of neuroAIDS and Cryptococcus neoformans meningitis has significantly increased and the mechanism remains unclear. [Objective] To study the inhibitory effect of SBi4211 on adhesion of C. neoformans to human brain microvascular endothelial cells(HBMEC) induced by HIV-1 gp41. [Methods] The adhesion experiments were carried out to determine whether SBi4211 could block C. neoformans adhesion. Furthermore, the expression of hyaluronic acid CD44 was analyzed by the Western Blot method(WB) during the adhesion process. [Results] SBi4211 could significantly inhibit the HIV-1 gp41-enhanced adhesion of C. neoformans to HBMEC in a dose-and time-dependent manner(P<0.05).Meanwhile expression of the C. neoformans hyaluronic acid receptor CD44 on HBMEC is down regulated.[Conclusion] Our study suggested SBi4211 could block HIV-1 gp41-enhanced adhesion of C. neoformans to HBMEC by reducing expression of receptor CD44, which might provide novel insights into understanding the mechanisms of C. neoformans and HIV-1 associated comorbidity besides its prevention and treatment.
[Background] The prevalence of neuroAIDS and Cryptococcus neoformans meningitis has significantly increased and the mechanism remains unclear. [Objective] To study the inhibitory effect of SBi4211 on adhesion of C. neoformans to human brain microvascular endothelial cells(HBMEC) induced by HIV-1 gp41. [Methods] The adhesion experiments were carried out to determine whether SBi4211 could block C. neoformans adhesion. Furthermore, the expression of hyaluronic acid CD44 was analyzed by the Western Blot method(WB) during the adhesion process. [Results] SBi4211 could significantly inhibit the HIV-1 gp41-enhanced adhesion of C. neoformans to HBMEC in a dose-and time-dependent manner(P<0.05).Meanwhile expression of the C. neoformans hyaluronic acid receptor CD44 on HBMEC is down regulated.[Conclusion] Our study suggested SBi4211 could block HIV-1 gp41-enhanced adhesion of C. neoformans to HBMEC by reducing expression of receptor CD44, which might provide novel insights into understanding the mechanisms of C. neoformans and HIV-1 associated comorbidity besides its prevention and treatment.
引文
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[19]Zhang B,Yu JY,Liu LQ,et al.Alpha7 nicotinic acetylcholine receptor is required for blood-brain barrier injury-related CNSdisorders caused by Cryptococcus neoformans and HIV-1associated comorbidity factors[J].BMC Infectious Diseases,2015,15:352
[20]Jong A,Wu CH,Gonzales-Gomez I,et al.Hyaluronic acid receptor CD44 deficiency is associated with decreased Cryptococcus neoformans brain infection[J].Journal of Biological Chemistry,2012,287(19):15298-15306
[21]Huang SH,Long M,Wu CH,et al.Invasion of Cryptococcus neoformans into human brain microvascular endothelial cells is mediated through the lipid rafts-endocytic pathway via the dual specificity tyrosine phosphorylation-regulated kinase 3(DYRK3)[J].Journal of Biological Chemistry,2011,286(40):34761-34769
[22]Long M,Huang SH,Wu CH,et al.Lipid raft/caveolae signaling is required for Cryptococcus neoformans invasion into human brain microvascular endothelial cells[J].Journal of Biomedical Science,2012,19:19
[23]Sekhar GN,Georgian AR,Sanderson L,et al.Organic cation transporter 1(OCT1)is involved in pentamidine transport at the human and mouse blood-brain barrier(BBB)[J].PLoS One,2017,12(3):e0173474
[24]Cirillo C,Capoccia E,Iuvone T,et al.S100B inhibitor pentamidine attenuates reactive gliosis and reduces neuronal loss in a mouse model of Alzheimer’s disease[J].BioMed Research International,2015:508342
[2]Drummond RA.Neuro-immune mechanisms of anti-cryptococcal protection[J].Journal of Fungi,2018,4(1):4
[3]Henao-Martínez AF,Chastain DB,Franco-Paredes C.Treatment of cryptococcosis in non-HIV immunocompromised patients[J].Current Opinion in Infectious Diseases,2018,31(4):278-285
[4]Liu ZY,Wang GQ,Zhu LP,et al.Expert consensus on the diagnosis and treatment of cryptococcal meningitis[J].Chinese Journal of Internal Medicine,2018,57(5):317-323(in Chinese)刘正印,王贵强,朱利平,等.隐球菌性脑膜炎诊治专家共识[J].中华内科杂志,2018,57(5):317-323
[5]Li WL,Devied A.Clinical analysis of 31 cases of AIDScomplicated with cryptococcal meningitis[J].Chinese Journal of Clinical Neurosciences,2001,9(2):193-194(in Chinese)李微浪,Devied A.31例艾滋病合并隐球菌脑膜炎临床分析[J].中国临床神经科学,2001,9(2):193-194
[6]Guan JL,Li YP,Cai WP.Clinical analysis on 100 cases of AIDScombined with cryptococcal meningitis[J].International Medicine and Health Guidance News,2014,20(9):1185-1188(in Chinese)关家龙,李粤平,蔡卫平.艾滋病合并新型隐球菌性脑膜炎100例临床分析[J].国际医药卫生导报,2014,20(9):1185-1188
[7]Domer JE,Carrow EW.Immunity to fungal infections[A]//Eisenstein TK,Actor P,Friedman H.Host Defenses to Intracellular Pathogens[M].Boston,MA:Springer,1983:383-406
[8]Adami C,Sorci G,Blasi E,et al.S100B expression in and effects on microglia[J].Glia,2001,33(2):131-142
[9]Sviatoha V,Tani E,Kleina R,et al.Immunohistochemical analysis of the S100A1,S100B,CD44 and Bcl-2 antigens and the rate of cell proliferation assessed by Ki-67 antibody in benign and malignant melanocytic tumours[J].Melanoma Research,2010,20(2):118-125
[10]Mc Knight LE,Raman EP,Bezawada P,et al.Structure-based discovery of a novel pentamidine-related inhibitor of the calcium-binding protein S100B[J].ACS Medicinal Chemistry Letters,2012,3(12):975-979
[11]Alasady MJ,Adipietro KA,Pierce AD,et al.Abstract 315:S100Bregulates IL-6 signaling via the p90 ribosomal S6 kinase(RSK)in malignant melanoma[J].Cancer Research,2017,77(S13):315
[12]Elsegeiny W,Marr KA,Williamson PR.Immunology of cryptococcal infections:developing a rational approach to patient therapy[J].Frontiers in Immunology,2018,9:651
[13]Chang YC,Jong A,Huang S,et al.CPS1,a homolog of the Streptococcus pneumoniae type 3 polysaccharide synthase gene,is important for the pathobiology of Cryptococcus neoformans[J].Infection and Immunity,2006,74(7):3930-3938
[14]Huang SH,Wu CH,Jiang SB,et al.HIV-1 gp41 ectodomain enhances Cryptococcus neoformans binding to human brain microvascular endothelial cells via gp41 core-induced membrane activities[J].Biochemical Journal,2011,438(3):457-466
[15]Jong A,Wu CH,Prasadarao NV,et al.Invasion of Cryptococcus neoformans into human brain microvascular endothelial cells requires protein kinase C-αactivation[J].Cellular Microbiology,2008,10(9):1854-1865
[16]Sabiiti W,May RC.Capsule independent uptake of the fungal pathogen Cryptococcus neoformans into brain microvascular endothelial cells[J].PLoS One,2012,7(4):e35455
[17]Jong A,Wu CH,Shackleford GM,et al.Involvement of human CD44 during Cryptococcus neoformans infection of brain microvascular endothelial cells[J].Cellular Microbiology,2008,10(6):1313-1326
[18]Zhang LK,Qiu JW,Liang XL,et al.Role of CD44 in monocyte transmigration across Cryptococcus neoformans-infected blood-brain barrier in vitro[J].Journal of Southern Medical University,2015,35(4):468-473(in Chinese)张立科,邱嘉文,梁晓路,等.CD44在新生隐球菌体外感染血脑屏障中对单核细胞迁移的影响[J].南方医科大学学报,2015,35(4):468-473
[19]Zhang B,Yu JY,Liu LQ,et al.Alpha7 nicotinic acetylcholine receptor is required for blood-brain barrier injury-related CNSdisorders caused by Cryptococcus neoformans and HIV-1associated comorbidity factors[J].BMC Infectious Diseases,2015,15:352
[20]Jong A,Wu CH,Gonzales-Gomez I,et al.Hyaluronic acid receptor CD44 deficiency is associated with decreased Cryptococcus neoformans brain infection[J].Journal of Biological Chemistry,2012,287(19):15298-15306
[21]Huang SH,Long M,Wu CH,et al.Invasion of Cryptococcus neoformans into human brain microvascular endothelial cells is mediated through the lipid rafts-endocytic pathway via the dual specificity tyrosine phosphorylation-regulated kinase 3(DYRK3)[J].Journal of Biological Chemistry,2011,286(40):34761-34769
[22]Long M,Huang SH,Wu CH,et al.Lipid raft/caveolae signaling is required for Cryptococcus neoformans invasion into human brain microvascular endothelial cells[J].Journal of Biomedical Science,2012,19:19
[23]Sekhar GN,Georgian AR,Sanderson L,et al.Organic cation transporter 1(OCT1)is involved in pentamidine transport at the human and mouse blood-brain barrier(BBB)[J].PLoS One,2017,12(3):e0173474
[24]Cirillo C,Capoccia E,Iuvone T,et al.S100B inhibitor pentamidine attenuates reactive gliosis and reduces neuronal loss in a mouse model of Alzheimer’s disease[J].BioMed Research International,2015:508342