Alpha7 nicotinic acetylcholine receptor is required for blood-brain barrier injury-related CNS disorders caused by Cryptococcus neoformans and HIV-1 associated comorbidity factors.
BACKGROUND
Cryptococcal meningitis is the most common fungal infection of the central nervous system (CNS) in HIV/AIDS. HIV-1 virotoxins (e.g., gp41) are able to induce disorders of the blood-brain barrier (BBB), which mainly consists of BMEC. Our recent study suggests that α7 nAChR is an essential regulator of inflammation, which contributes to regulation of NF-κB signaling, neuroinflammation and BBB disorders caused by microbial (e.g., HIV-1 gp120) and non-microbial [e.g., methamphetamine (METH)] factors. However, the underlying mechanisms for multiple comorbidities are unclear.


METHODS
In this report, an aggravating role of α7 nAChR in host defense against CNS disorders caused by these comorbidities was demonstrated by chemical [inhibitor: methyllycaconitine (MLA)] and genetic (α7(-/-) mice) blockages of α7 nAChR.


RESULTS
As shown in our in vivo studies, BBB injury was significantly reduced in α7(-/-) mice infected with C. neoformans. Stimulation by the gp41 ectodomain peptide (gp41-I90) and METH was abolished in the α7(-/-) animals. C. neoformans and gp41-I90 could activate NF-κB. Gp41-I90- and METH-induced monocyte transmigration and senescence were significantly inhibited by MLA and CAPE (caffeic acid phenethyl ester, an NF-κB inhibitor).


CONCLUSIONS
Collectively, our data suggest that α7 nAChR plays a detrimental role in the host defense against C. neoformans- and HIV-1 associated comorbidity factors-induced BBB injury and CNS disorders.
Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, 510515, China. zhang20051005@126.com.|Saban Research Institute of Childrens Hospital Los Angeles, Department of Pediatrics, University of Southern California, 4650 Sunset Blvd., Mailstop #51, Los Angeles, CA, 90027, USA. zhang20051005@126.com.
Bao
B
Zhang
Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, 510515, China. jyyu1001@126.com.|Saban Research Institute of Childrens Hospital Los Angeles, Department of Pediatrics, University of Southern California, 4650 Sunset Blvd., Mailstop #51, Los Angeles, CA, 90027, USA. jyyu1001@126.com.
Jing-Yi
JY
Yu
Division of Pediatric Neurology, Children's Medical Center, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China. llq91217@163.com.
Li-Qun
LQ
Liu
Saban Research Institute of Childrens Hospital Los Angeles, Department of Pediatrics, University of Southern California, 4650 Sunset Blvd., Mailstop #51, Los Angeles, CA, 90027, USA. lapeng@chla.usc.edu.|Department of Clinic Laboratory, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, China. lapeng@chla.usc.edu.
Liang
L
Peng
Saban Research Institute of Childrens Hospital Los Angeles, Department of Pediatrics, University of Southern California, 4650 Sunset Blvd., Mailstop #51, Los Angeles, CA, 90027, USA. chifeng68@gmail.com.
Feng
F
Chi
Saban Research Institute of Childrens Hospital Los Angeles, Department of Pediatrics, University of Southern California, 4650 Sunset Blvd., Mailstop #51, Los Angeles, CA, 90027, USA. CWu@chla.usc.edu.
Chun-Hua
CH
Wu
Saban Research Institute of Childrens Hospital Los Angeles, Department of Pediatrics, University of Southern California, 4650 Sunset Blvd., Mailstop #51, Los Angeles, CA, 90027, USA. ajong@chla.usc.edu.
Ambrose
A
Jong
Saban Research Institute of Childrens Hospital Los Angeles, Department of Pediatrics, University of Southern California, 4650 Sunset Blvd., Mailstop #51, Los Angeles, CA, 90027, USA. shiwang@chla.usc.edu.|Department of Children's Medical Laboratory Diagnosis Center, Qilu Children's Hospital of Shandong University, Jinan, 250022, China. shiwang@chla.usc.edu.
Shi-Fu
SF
Wang
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.
Hong
H
Cao
Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, 510515, China. shhuang@hsc.usc.edu.|Saban Research Institute of Childrens Hospital Los Angeles, Department of Pediatrics, University of Southern California, 4650 Sunset Blvd., Mailstop #51, Los Angeles, CA, 90027, USA. shhuang@hsc.usc.edu.
Sheng-He
SH
Huang
D000157:Aconitine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D060085:Coinfection; D003455:Cryptococcus neoformans; D015700:HIV Envelope Protein gp41 / Q000494:pharmacology; D015658:HIV Infections / Q000378:metabolism; D015497:HIV-1 / Q000378:metabolism; D007249:Inflammation; D016919:Meningitis, Cryptococcal / Q000235:genetics*; D008694:Methamphetamine / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000187:drug effects; D018733:Nicotinic Antagonists / Q000494:pharmacology; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000037:antagonists & inhibitors / Q000235:genetics*
D000697:Central Nervous System Stimulants; C579166:Chrna7 protein, mouse; D015700:HIV Envelope Protein gp41; D016328:NF-kappa B; D018733:Nicotinic Antagonists; D064569:alpha7 Nicotinic Acetylcholine Receptor; C514787:gp41 protein, Human immunodeficiency virus 1; C054634:methyllycaconitine; D008694:Methamphetamine; D000157:Aconitine