Potential enhancement of osteoclastogenesis by severe acute respiratory syndrome coronavirus 3a/X1 protein

Abstract

Severe acute respiratory syndrome coronavirus (SARS-CoV) causes a lung disease with high mortality. In addition, osteonecrosis and bone abnormalities with reduced bone density have been observed in patients following recovery from SARS, which were partly but not entirely explained by the short-term use of steroids. Here, we demonstrate that human monocytes, potential precursors of osteoclasts, partly express angiotensin converting enzyme 2 (ACE2), a cellular receptor of SARS-CoV, and that expression of an accessory protein of SARS-CoV, 3a/X1, in murine macrophage cell line RAW264.7 cells, enhanced NF-kappaB activity and differentiation into osteoclast-like cells in the presence of receptor activator of NF-kappaB ligand (RANKL). Furthermore, human epithelial A549 cells expressed ACE2, and expression of 3a/X1 in these cells up-regulated TNF-alpha, which is known to accelerate osteoclastogenesis. 3a/X1 also enhanced RANKL expression in mouse stromal ST2 cells. These findings indicate that SARS-CoV 3a/X1 might promote osteoclastogenesis by direct and indirect mechanisms.

Bat Severe Acute Respiratory Syndrome-Like Coronavirus WIV1 Encodes an Extra Accessory Protein, ORFX, Involved in Modulation of the Host Immune Response

“…All these results suggested that ORFX participates in the modulation of the IFN response. Previous studies showed that SARS-CoV ORF3a and ORF7a activate NF-B and upregulate IL-8 and CCL5 pro- duction (22,23). In our study, we also found through a dualluciferase assay that overexpressed ORFX can activate NF-B (Fig.…”

“…The SARS-CoV ORF3a, ORF3b, and ORF6 have been reported to inhibit the host interferon (IFN) response during virus infection and contribute to pathogenesis (20,21). ORF3a and ORF7a activate NF-B and upregulate interleukin-8 (IL-8) and CCL5 production (22,23). Bat SL-CoVs display great genetic diversity and share overall nucleotide sequence identities of 88 to 97% with human SARS-CoV (2)(3)(4)(5)(6)(7)(8)(9)(10)(11).…”

The Role of Severe Acute Respiratory Syndrome (SARS)-Coronavirus Accessory Proteins in Virus Pathogenesis

“…The lung and small intestines are, however, not the only tissue targets for SARS-CoV. One of the cellular receptors for SARS-CoV, angiotensin-converting enzyme 2 (ACE2) [38,39,40], is also expressed by a certain population of peripheral CD14+ monocytes, from which osteoclasts are derived [41]. Interestingly, the expression of ORF3a in a murine macrophage osteoclast precursor cell line enhances osteoclast differentiation, and may explain why many recovered SARS patients suffer from reduced bone density [41].…”

“…Overexpression of ORF3a in several different cell culture models has demonstrated that it induces apoptosis [29,48,49,50], upregulates mRNA and protein levels of fibrinogen in lung epithelial cells [51], activates C-Jun N-terminal kinase (JNK) and the transcription factor nuclear factor kappa B (NF-kappaB), which is involved in the activation of pro-inflammatory genes [20,41,52] and downstream from that, up-regulates the production of pro-inflammatory cytokines and chemokines such as interleukin 8 (IL-8) and RANTES (CCL5) [52]. Taken together, these changes to host cellular homeostasis imply a role for ORF3a in the pathogenesis of SARS.…”

Functional Immune Deficiency Syndrome via Intestinal Infection in COVID-19

“…139 From a clinical perspective, some patients recovered from SARS showed joint pain and bone damage. Consequently, the study conducted by Obitsu et al 140 showed that ORF3a is able to induce osteoclastogenesis and thus bone abnormalities observed in SARS survivors. Further, some patients developed pulmonary thrombosis during SARS-CoV-1 infection 141 , while ORF3a was reported to increase expression of all subunits of fibrinogen.…”