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ACE2 and SCARF Expression in Human Dorsal Root Ganglion Nociceptors: Implications for SARS-Cov-2 Virus Neurological Effects Stephanie Shiersa, Pradipta R

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ACE2 and SCARF Expression in Human Dorsal Root Ganglion Nociceptors: Implications for SARS-Cov-2 Virus Neurological Effects Stephanie Shiersa, Pradipta R Research Paper ACE2 and SCARF expression in human dorsal root ganglion nociceptors: implications for SARS-CoV-2 virus neurological effects Stephanie Shiersa, Pradipta R. Raya, Andi Wangzhoua, Ishwarya Sankaranarayanana, Claudio Esteves Tatsuib, Laurence D. Rhinesb, Yan Lic, Megan L. Uhelskic, Patrick M. Doughertyc, Theodore J. Pricea,* Abstract SARS-CoV-2 has created a global crisis. COVID-19, the disease caused by the virus, is characterized by pneumonia, respiratory distress, and hypercoagulation and can be fatal. An early sign of infection is loss of smell, taste, and chemesthesis—loss of chemical sensation. Other neurological effects of the disease have been described, but not explained. It is now apparent that many of these neurological effects (for instance joint pain and headache) can persist for at least months after infection, suggesting a sensory neuronal involvement in persistent disease. We show that human dorsal root ganglion (DRG) neurons express the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 at the RNA and protein level. We also demonstrate that SARS-CoV-2 and coronavirus- associated factors and receptors are broadly expressed in human DRG at the lumbar and thoracic level as assessed by bulk RNA sequencing. ACE2 mRNA is expressed by a subset of nociceptors that express MRGPRD mRNA, suggesting that SARS-CoV-2 may gain access to the nervous system through entry into neurons that form free nerve endings at the outermost layers of skin and luminal organs. Therefore, DRG sensory neurons are a potential target for SARS-CoV-2 invasion of the peripheral nervous system, and viral infection of human nociceptors may cause some of the persistent neurological effects seen in COVID-19. Keywords: ACE2, MRGPRD, NPPB, Nociceptor, Viral infection, COVID-19 1. Introduction epithelium.6 This is sometimes accompanied by loss of chemical 21 The SARS-CoV-2 virus that causes COVID-19 enters cells sensation, chemesthesis. This chemesthesis includes loss of capsaicin and menthol sensitivity,21 sensations that are mediated by through the angiotensin-converting enzyme 2 (ACE2) receptor. 4 32,33 nociceptive sensory neurons. Other neurological effects of SARS- The spike protein of the virus binds to ACE2 and can be 13 8 CoV-2 associated with nociceptors have been described, including primed by a number of proteases (TMPRSS2 and Furin ) that 16,18,36 37 headache and nerve pain, and may be involved in neuro- are sometimes coexpressed by ACE2-positive cells. A set of 25 genes that are involved in the response to SARS-CoV-2, SARS- immune interactions in the lung. Finally, as the pandemic has CoV-2 and coronavirus-associated factors and receptors progressed, it is now clear that many patients do not have a 27 complete recovery from COVID-19 and experience continuing (SCARFs), have emerged allowing for assessment of virus 7 effects on tissues through analysis of RNA sequencing or other symptoms such as dyspnea, joint pain, chest pain, and cough, all of high-throughput data sets. which are mediated, at least in part, by nociceptors. In addition, Neurological symptoms are common in patients with COVID-19. severe central nervous system effects such as encephalopathies and delirium have also been observed in patients with COVID- Loss of smell (anosmia) and taste is an early symptom which is 10,22 explained by non-neuronal ACE2 expression within the olfactory 19. Molecular mechanisms underlying these effects are not currently known, although studies with human brain organoids demonstrate the ACE2-dependent neuroinvasive potential of the 28 Sponsorships or competing interests that may be relevant to content are disclosed SARS-CoV-2 virus. at the end of this article. Bulk RNA sequencing data sets support the conclusion that a Department of Neuroscience and Center for Advanced Pain Studies, University of ACE2 is expressed in human DRG,20,23 but cellular resolution is b Texas at Dallas, Richardson, TX, United States, Department of Neurosurgery, lacking. Single-cell sequencing experiments from mouse DRG show University of Texas MD Anderson Cancer Center, Houston, TX, United States, c Department of Anesthesia and Pain Medicine, University of Texas MD Anderson weak Ace2 expression in a subset of neurons that also express the Cancer Center, Houston, TX, United States Mrgprd and Nppb genes.30 MrgprD is selectively expressed in a 38 *Corresponding author. Address: University of Texas at Dallas, Department of nociceptor population that forms free nerve endings in the skin, Neuroscience and Center for Advanced Pain Studies, 800 W Campbell RD, BSB cornea, and luminal organs such as the colon12 as well as the 14.102, Richardson TX 75080, United States. E-mail address: Theodore.price@ 31 utdallas.edu (T.J. Price). meninges. We tested the hypothesis that ACE2 mRNA is Supplemental digital content is available for this article. Direct URL citations appear expressed in a subset of human DRG neurons using tissues in the printed text and are provided in the HTML and PDF versions of this article on obtained from organ donors or vertebrectomy surgery based on the journal’s Web site (www.painjournalonline.com). RNAscope in situ hybridization. Our findings support the conclusion PAIN 161 (2020) 2494–2501 that approximately a quarter of human DRG neurons express ACE2 © 2020 International Association for the Study of Pain mRNA and that ACE2 protein is also found in the human DRG. Most http://dx.doi.org/10.1097/j.pain.0000000000002051 of these ACE2 mRNA–expressing neurons are nociceptors that likely 2494 S. Shiers et al.·161 (2020) 2494–2501 PAIN® Copyright © 2020 by the International Association for the Study of Pain. Unauthorized reproduction of this article is prohibited. November 2020· Volume 161· Number 11 www.painjournalonline.com 2495 form free nerve endings in skin or other organs, creating a potential 2.3. Tissue quality check entry point for the virus into the peripheral nervous system. All tissues were checked for RNA quality by using a positive control probe cocktail (ACD) which contains probes for high-, 2. Materials and methods medium-, and low-expressing mRNAs that are present in all cells (ubiquitin C . peptidyl-prolyl cis-trans isomerase B . DNA- 2.1. Tissue preparation directed RNA polymerase II subunit RPB1). All tissues showed All human tissue procurement procedures were approved by the signal for all 3 positive control probes (Supplementary Fig. 1, institutional review boards at the University of Texas at Dallas and available at http://links.lww.com/PAIN/B157). A negative control University of Texas MD Anderson Cancer Center. Human dorsal root probe against the bacterial DapB gene (ACD) was used to check ganglion (DRG) (at levels T4, T5, and L5) was collected, frozen on dry for nonspecific/background label. ice (L5) or liquid nitrogen (T4 and T5), and stored in a 280˚C freezer. Donor and/or patient information is provided in Table 1. The human 2.4. Image analysis DRG were gradually embedded with optical coherence tomography in a cryomold by adding small volumes of optical coherence Dorsal root ganglion sections were imaged on an Olympus tomography over dry ice to avoid thawing. All tissues were cryostat FV3000 confocal microscope at 320 or 340 magnification. For sectioned at 20 mm onto SuperFrost Plus charged slides. Sections the CALCA/P2RX3/ACE2 and SCN10A/ACE2 experiments, 3 to were only briefly thawed to adhere to the slide but were immediately 4 20X images were acquired of each human DRG section, and 3 returned to the 220˚C cryostat chamber until completion of to 4 sections were imaged per human donor. For the MRGPRD/ sectioning. The slides were then immediately used for histology. NPPB/ACE2 experiments, 8 40X images were acquired of each human DRG section, and 3 to 4 sections were imaged per donor. The sections imaged were chosen at random, but preference was 2.2. RNAscope in situ hybridization given to sections that did not have any sectioning artifact or RNAscope in situ hybridization multiplex version 1 was performed as sections that encompassed the entire DRG bulb. The acquisition instructed by Advanced Cell Diagnostics (ACD). Slides were parameters were set based on guidelines for the FV3000 removed from the cryostat and immediately transferred to cold provided by Olympus. In particular, the gain was kept at the (4˚C) 10% formalin for 15 minutes. The tissues were then dehydrated default setting 1, HV #600, offset 5 4 (based on HI-LO settings; in 50% ethanol (5 minutes), 70% ethanol (5 minutes), and 100% does not change between experiments), and laser power #10% ethanol (10 minutes) at room temperature. The slides were air dried (but generally, the laser power was #5% for our experiments). briefly, and then, boundaries were drawn around each section using The raw image files were brightened and contrasted in Olympus a hydrophobic pen (ImmEdge PAP pen; Vector Labs, Burlingame, CellSens software (v1.18) and then analyzed manually 1 cell at a CA). When hydrophobic boundaries had dried, protease IV reagent time for expression of each gene target. Cell diameters were was added to each section until fully covered and incubated for 5 measured using the polyline tool. Total neuron counts for human minutes at room temperature. The protease IV incubation period samples were acquired by counting all the probe-labeled neurons was optimized as recommended by ACD for the specific lot of and all neurons that were clearly outlined by DAPI (satellite cell) protease IV reagent. Slides were washed briefly in 1X phosphate- signal and contained lipofuscin in the overlay image. buffered saline (pH 7.4) at room temperature. Each slide was then Large globular structures and/or signal that autofluoresced in placed in a prewarmed humidity control tray (ACD) containing all 3 channels (488, 550, and 647; appears white in the 20x dampened filter paper, and a mixture of channel 1, channel 2, and RNAscope overlay images) was considered to be background channel 3 probes (50:1:1 dilution, as directed by ACD due to stock lipofuscin and was not analyzed.
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