Biology subjects

Dabbagh, D.

Publications and source records attributed to Dabbagh, D..

4 recordsLinked to original sources

bioRxiv2025

CD34 serves as an intrinsic innate immune guardrail protecting stem cells from replicating retroviruses

Stem cells are highly resistant to viral infection compared to their differentiated progeny, and this resistance is associated with stem cell-specific restriction factors and intrinsic interferon stimulated genes (ISGs). In HIV infection, proviral DNA has been detected in certain bone marrow hematopoietic stem cells, yet widespread stem cell infection in vivo is restricted. Intriguingly, exposing bone marrow stem cells to HIV in vitro led to viral replication selectively only in the CD34- population, but not in the CD34+ cells. The mechanism dictating this CD34-based HIV restriction remained a mystery, especially since HIV has a capacity to antagonize restriction factors and ISGs. CD34 is a common marker of hematopoietic stem and progenitor cells. Here, we report the intrinsic antiviral properties of CD34. Expression of CD34 in HIV-1 producer cells results in the loss of progeny virion infectivity. Conversely, removal of CD34 using CRISPR/Cas9 knockout or stem cell differentiation cytokines promotes HIV-1 replication in stem cells. These results suggest that in addition to restriction factors and intrinsic ISGs, CD34 serves as a host innate protection preventing retrovirus replication in stem cells. Mechanistically, CD34 does not block viral entry, integration, and release. Instead, it becomes incorporated onto progeny virions, which inactivates virus infectivity. These findings offer new insights into innate immunity in stem cells, and highlight intriguing retrovirus-host interactions in evolution.

immunology↗

bioRxiv2021

Identification of the SHREK family of proteins as broad-spectrum host antiviral factors

Mucins and mucin-like molecules are highly glycosylated, high-molecular-weight cell surface proteins that possess a semi-rigid and highly extended extracellular domain. P-selectin glycoprotein ligand-1 (PSGL-1), a mucin-like glycoprotein, has recently been found to restrict HIV-1 infectivity through virion incorporation that sterically hinders virus particle attachment to target cells. Here, we report the identification of a family of antiviral cellular proteins, named the Surface-Hinged, Rigidly-Extended Killer (SHREK) family of virion inactivators (PSGL-1, CD43, TIM-1, CD34, PODXL1, PODXL2, CD164, MUC1, MUC4, and TMEM123), that share similar structural characteristics with PSGL-1. We demonstrate that SHREK proteins block HIV-1 infectivity by inhibiting virus particle attachment to target cells. In addition, we demonstrate that SHREK proteins are broad-spectrum host antiviral factors that block the infection of diverse viruses such as influenza A. Furthermore, we demonstrate that a subset of SHREKs also blocks the infectivity of a hybrid alphavirus-SARS-CoV-2 virus-like particle. These results suggest that SHREK proteins may be a part of host innate immunity against enveloped viruses.

microbiology↗

bioRxiv2020

Development of a novel hybrid alphavirus-SARS-CoV-2 particle for rapid in vitro screening and quantification of neutralization antibodies, antiviral drugs, and viral mutations

Timely development of vaccines and antiviral drugs is critical to control the COVID-19 pandemic 1-6. Current methods for quantifying vaccine-induced neutralizing antibodies involve the use of pseudoviruses, such as the SARS-CoV-2 spike protein (S) pseudotyped lentivirus7-14. However, these pseudoviruses contain structural proteins foreign to SARS-CoV-2, and require days to infect and express reporter genes15. Here we describe the development of a new hybrid alphavirus-SARS-CoV-2 (Ha-CoV-2) particle for rapid and accurate quantification of neutralization antibodies and viral variants. Ha-CoV-2 is a non-replicating SARS-CoV-2 virus-like particle, composed of SARS-CoV-2 structural proteins (S, M, N, and E) and a RNA genome derived from a fast expressing alphavirus vector 16. We demonstrated that Ha-CoV-2 can rapidly and robustly express reporter genes in target cells within 3-6 hours. We further validated Ha-CoV-2 for rapid quantification of neutralization antibodies, viral variants, and antiviral drugs. In addition, as a proof-of-concept, we assembled and compared the relative infectivity of a panel of 10 Ha-CoV-2 variant isolates (D614G, P.1, B.1.1.207, B.1.351, B.1.1.7, B.1.429, B.1.258, B.1.494, B.1.2, B.1.1298), and demonstrated that these variants in general are 2-10 fold more infectious. Furthermore, we quantified the anti-serum from an infected and vaccinated individual; the one dose vaccination with Moderna mRNA-1273 has greatly increased the anti-serum titer for approximately 6 fold. The post-vaccination serum has also demonstrated various neutralizing activities against all 9 variants tested. These results demonstrated that Ha-CoV-2 can be used as a robust platform for rapid quantification of neutralizing antibodies against SARS-CoV-2 and its variants.

microbiology↗

bioRxiv2020

PSGL-1 blocks SARS-CoV-2 S protein-mediated virus attachment and infection of target cells

P-selectin glycoprotein ligand-1 (PSGL-1) is a cell surface glycoprotein that binds to P-, E-, and L-selectins to mediate the tethering and rolling of immune cells on the surface of the endothelium for cell migration into inflamed tissues. PSGL-1 has been identified as an interferon-γ (INF-γ)-regulated factor that restricts HIV-1 infectivity, and has recently been found to possess broad-spectrum antiviral activities. Here we report that the expression of PSGL-1 in virus-producing cells impairs the incorporation of SARS-CoV and SARS-CoV-2 spike (S) glycoproteins into pseudovirions and blocks virus attachment and infection of target cells. These findings suggest that PSGL-1 may potentially inhibit coronavirus replication in PSGL-1+ cells.Competing Interest StatementThe authors have declared no competing interest.View Full Text

microbiology↗