TY - JOUR
T1 - Heparanase Blockade as a Novel Dual-Targeting Therapy for COVID-19
AU - Xiang, Jingyu
AU - Lu, Mijia
AU - Shi, Min
AU - Cheng, Xiaogang
AU - Kwakwa, Kristin A.
AU - Davis, Jennifer L.
AU - Su, Xinming
AU - Bakewell, Suzanne J.
AU - Zhang, Yuexiu
AU - Fontana, Francesca
AU - Xu, Yalin
AU - Veis, Deborah J.
AU - DiPersio, John F.
AU - Ratner, Lee
AU - Sanderson, Ralph D.
AU - Noseda, Alessandro
AU - Mollah, Shamim
AU - Li, Jianrong
AU - Weilbaecher, Katherine N.
N1 - Funding Information:
This research was supported by awards CA100730 (L.R., X.C., K.N.W., and D.J.V.), CA154737 (K.N.W.), CA097250 (K.N.W.), and CA216840 (K.N.W.). Additional funding support was provided by grants from the St. Louis Men’s Group against Cancer, the Pat Burkhart Breast Cancer Fund, and the Siteman Cancer Center. We also thank the Hope Center Alafi Neuroimaging Lab for use of the Nanozoomer (NIH shared instrumentation grant number S10RR027552). Confocal microscopy using the Olympus FluoView1200 instrument was performed in part through the use of the Washington University Center for Cellular Imaging (WUCCI) supported by the Washington University School of Medicine, the Children’s Discovery Institute of Washington University and St. Louis Children’s Hospital (CDI-CORE-2015-505 and CDI-CORE-2019-813), and the Foundation for Barnes-Jewish Hospital (3770 and 4642).
Publisher Copyright:
© 2022 American Society for Microbiology.
PY - 2022/4
Y1 - 2022/4
N2 - The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused over 5 million deaths worldwide. Pneumonia and systemic inflammation contribute to its high mortality. Many viruses use heparan sulfate proteoglycans as coreceptors for viral entry, and heparanase (HPSE) is a known regulator of both viral entry and inflammatory cytokines. We evaluated the heparanase inhibitor Roneparstat, a modified heparin with minimum anticoagulant activity, in pathophysiology and therapy for COVID-19. We found that Roneparstat significantly decreased the infectivity of SARS-CoV-2, SARS-CoV-1, and retroviruses (human Tlymphotropic virus 1 [HTLV-1] and HIV-1) in vitro. Single-cell RNA sequencing (scRNA-seq) analysis of cells from the bronchoalveolar lavage fluid of COVID-19 patients revealed a marked increase in HPSE gene expression in CD681 macrophages compared to healthy controls. Elevated levels of HPSE expression in macrophages correlated with the severity of COVID-19 and the expression of inflammatory cytokine genes, including IL6, TNF, IL1B, and CCL2. In line with this finding, we found a marked induction of HPSE and numerous inflammatory cytokines in human macrophages challenged with SARS-CoV-2 S1 protein. Treatment with Roneparstat significantly attenuated SARS-CoV-2 S1 protein-mediated inflammatory cytokine release from human macrophages, through disruption of NF-k B signaling. HPSE knockdown in a macrophage cell line also showed diminished inflammatory cytokine production during S1 protein challenge. Taken together, this study provides a proof of concept that heparanase is a target for SARS-CoV-2-mediated pathogenesis and that Roneparstat may serve as a dual-targeted therapy to reduce viral infection and inflammation in COVID-19.
AB - The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused over 5 million deaths worldwide. Pneumonia and systemic inflammation contribute to its high mortality. Many viruses use heparan sulfate proteoglycans as coreceptors for viral entry, and heparanase (HPSE) is a known regulator of both viral entry and inflammatory cytokines. We evaluated the heparanase inhibitor Roneparstat, a modified heparin with minimum anticoagulant activity, in pathophysiology and therapy for COVID-19. We found that Roneparstat significantly decreased the infectivity of SARS-CoV-2, SARS-CoV-1, and retroviruses (human Tlymphotropic virus 1 [HTLV-1] and HIV-1) in vitro. Single-cell RNA sequencing (scRNA-seq) analysis of cells from the bronchoalveolar lavage fluid of COVID-19 patients revealed a marked increase in HPSE gene expression in CD681 macrophages compared to healthy controls. Elevated levels of HPSE expression in macrophages correlated with the severity of COVID-19 and the expression of inflammatory cytokine genes, including IL6, TNF, IL1B, and CCL2. In line with this finding, we found a marked induction of HPSE and numerous inflammatory cytokines in human macrophages challenged with SARS-CoV-2 S1 protein. Treatment with Roneparstat significantly attenuated SARS-CoV-2 S1 protein-mediated inflammatory cytokine release from human macrophages, through disruption of NF-k B signaling. HPSE knockdown in a macrophage cell line also showed diminished inflammatory cytokine production during S1 protein challenge. Taken together, this study provides a proof of concept that heparanase is a target for SARS-CoV-2-mediated pathogenesis and that Roneparstat may serve as a dual-targeted therapy to reduce viral infection and inflammation in COVID-19.
KW - COVID-19
KW - SARSCoV- 2
KW - heparanase
KW - inflammatory cytokine release
KW - macrophage
UR - http://www.scopus.com/inward/record.url?scp=85128445778&partnerID=8YFLogxK
U2 - 10.1128/jvi.00057-22
DO - 10.1128/jvi.00057-22
M3 - Article
C2 - 35319225
AN - SCOPUS:85128445778
SN - 0022-538X
VL - 96
JO - Journal of Virology
JF - Journal of Virology
IS - 7
M1 - e00057-22
ER -