Human Wharton's Jelly Mesenchymal Stem Cells Secretome Inhibits Human SARS-CoV-2 and Avian Infectious Bronchitis Coronaviruses.

Human SARS-CoV-2 and avian infectious bronchitis virus (IBV) are highly contagious and deadly coronaviruses, causing devastating respiratory diseases in humans and chickens. The lack of effective therapeutics exacerbates the impact of outbreaks associated with SARS-CoV-2 and IBV infections. Thus, novel drugs or therapeutic agents are highly in demand for controlling viral transmission and disease progression. Mesenchymal stem cells (MSC) secreted factors (secretome) are safe and efficient alternatives to stem cells in MSC-based therapies. This study aimed to investigate the antiviral potentials of human Wharton's jelly MSC secretome (hWJ-MSC-S) against SARS-CoV-2 and IBV infections in vitro and in ovo. The half-maximal inhibitory concentrations (IC50), cytotoxic concentration (CC50), and selective index (SI) values of hWJ-MSC-S were determined using Vero-E6 cells. The virucidal, anti-adsorption, and anti-replication antiviral mechanisms of hWJ-MSC-S were evaluated. The hWJ-MSC-S significantly inhibited infection of SARS-CoV-2 and IBV, without affecting the viability of cells and embryos. Interestingly, hWJ-MSC-S reduced viral infection by >90%, in vitro. The IC50 and SI of hWJ-MSC secretome against SARS-CoV-2 were 166.6 and 235.29 µg/mL, respectively, while for IBV, IC50 and SI were 439.9 and 89.11 µg/mL, respectively. The virucidal and anti-replication antiviral effects of hWJ-MSC-S were very prominent compared to the anti-adsorption effect. In the in ovo model, hWJ-MSC-S reduced IBV titer by >99%. Liquid chromatography-tandem mass spectrometry (LC/MS-MS) analysis of hWJ-MSC-S revealed a significant enrichment of immunomodulatory and antiviral proteins. Collectively, our results not only uncovered the antiviral potency of hWJ-MSC-S against SARS-CoV-2 and IBV, but also described the mechanism by which hWJ-MSC-S inhibits viral infection. These findings indicate that hWJ-MSC-S could be utilized in future pre-clinical and clinical studies to develop effective therapeutic approaches against human COVID-19 and avian IB respiratory diseases.

Cellular and viral oncogenes: the key to unlocking unknowns of Kaposi's sarcoma-associated herpesvirus pathogenesis.

Oncogenic viruses carry an extensive arsenal of oncogenes for hijacking cellular pathways. Notably, variations in oncogenes among tumor-producing viruses give rise to different mechanisms for cellular transformation. Specifically, Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic virus able to infect and transform a variety of cell types. The oncogenicity of KSHV disseminates from the virus' ability to induce and encode a wide variety of both cellular and viral oncogenes. Such an array of cellular and viral oncogenes enables KSHV to induce the malignant phenotype of a KSHV-associated cancer. Evolutionarily, KSHV has acquired many oncogenic homologues capable of inducing cell proliferation, cell differentiation, cell survival, and immune evasion. Integration between inducing and encoding oncogenes plays a vital role in KSHV pathogenicity. KSHV is alleged to harbor the highest number of potential oncogenes by which a virus promotes cellular transformation and malignancy. Many KSHV inducing/encoding oncogenes are mainly expressed during the latent phase of KSHV infection, a period required for virus establishment of malignant cellular transformation. Elucidation of the exact mechanism(s) by which oncogenes promote KSHV pathogenicity would not only give rise to potential novel therapeutic targets/drugs but would also add to our understanding of cancer biology. The scope of this review is to examine the roles of the most important cellular and viral oncogenes involved in KSHV pathogenicity.

Membrane-Associated Kaposi Sarcoma-Associated Herpesvirus Glycoprotein B Promotes Cell Adhesion and Inhibits Migration of Cells via Upregulating IL-1ß and TNF-α.

OBJECTIVES: Kaposi sarcoma-associated herpesvirus (KSHV) glycoprotein B (gB) is expressed on the viral envelope as well as on the cytoplasmic membrane of infected cells. In the current study, we aimed to decipher the impact of membrane-associated gB on adhesion and migration of cells via modulating the expression of cytokines. METHODS: A combination of polymerase chain reaction array, cell adhesion assay, and wound-healing migration assay was conducted to study the influence of the gB-induced cytokines on cell adhesion and migration. RESULTS: Membrane-associated gB was demonstrated to significantly upregulate the expression of IL-1ß and TNF-α. Elevated levels of these cytokines were observed in conditioned medium (CM) collected from gB-expressing cells (gB-CM) compared to CM collected from untransfected cells or cells transfected with empty vector. KSHV gB-induced IL-1ß and TNF-α play a role in the ability of gB-CM to mediate cell adhesion while inhibiting migration. CONCLUSION: Our results provide novel evidence that demonstrates full-length gB expressed on cell membrane to mediate adhesion and inhibit migration of cells not only by autocrine mechanism mediated by RGD-based interactions [Hussein et al.: BMC Cancer 2016; 16: 148], but also by paracrine mechanism mediated by gB-induced IL-1ß and TNF-α.

Beyond RGD: virus interactions with integrins.

Viruses successfully infect host cells by initially binding to the surfaces of the cells, followed by an intricate entry process. As multifunctional heterodimeric cell-surface receptor molecules, integrins have been shown to usefully serve as entry receptors for a plethora of viruses. However, the exact role(s) of integrins in viral pathogen internalization has yet to be elaborately described. Notably, several viruses harbor integrin-recognition motifs displayed on viral envelope/capsid-associated proteins. The most common of these motifs is the minimal peptide sequence for binding integrins, RGD (Arg-Gly-Asp), which is known for its role in virus infection via its ability to interact with over half of the more than 20 known integrins. Not all virus-integrin interactions are RGD-dependent, however. Non-RGD-binding integrins have also been shown to effectively promote virus entry and infection as well. Such virus-integrin binding is shown to facilitate adhesion, cytoskeleton rearrangement, integrin activation, and increased intracellular signaling. Also, we have attempted to discuss the role of carbohydrate moieties in virus interactions with receptor-like host cell surface integrins that drive the process of internalization. As much as possible, this article examines the published literature regarding the role of integrins in terms of virus infection and virus-encoded glycosylated proteins that mediate interactions with integrins, and it explores the idea of targeting these receptors as a therapeutic treatment option.