Introduction of Newcastle Disease Virus as Oncolytic Virus
Introduction of Newcastle Disease Virus
Newcastle disease virus (NDV) is an infectious avian paramyxovirus that affects many poultry and wild birds. Although this virus can spread to humans, in most cases it will not cause harm to human health, and only some cases have symptoms such as mild fever and / or conjunctivitis. Now, this virus has once again been widely concerned by medical workers because of its proven oncolytic activity against mammalian cancer. Animal model tests of NDV strains and NDV-based autologous tumor cell vaccines will expand our understanding of these new anti-cancer strategies and will eventually lead to the successful use of the virus in clinical settings.
Fig.1 Mechanisms of NDV-mediated anti-tumor effects. (Zamarin, 2012)
The Physicochemical Properties of NDV
NDV was first discovered on a farm near Newcastle upon Tyne in England in 1926. It is an important economic pathogen in a variety of poultry. Similar to other paramyxoviruses in its family, the NDV genome encodes 6 genes, including nucleocapsid protein (NP), phosphoprotein (P), matrix protein (M), fusion protein (F), hemagglutinin neuraminic acid Enzyme (HN) and RNA-dependent RNA polymerase (L). The genomic RNA is bound in a ribonucleotide protein complex (RNP) consisting of NP, P, and L, and is surrounded by a lipid envelope containing three viral glycoprotein spikes HN, M, and F.
NDV can be divided into three types according to the severity of the disease caused by poultry: late-onset, moderate-onset or immediate-onset. The cleavage site of the NDV fusion protein (F) is the main determinant of virulence. The F protein is initially synthesized as an inactive precursor (F0), which is proteolytically cleaved by the host cell protease into two disulfide-linked polypeptides and fused. The F0 of lentivirus has a univalent cleavage site that is cleaved by trypsin-like proteases only in the respiratory and digestive tracts. Besides, the highly fused F protein expressed on the surface of infected cells can effectively form syncytia, thereby promoting the spread of virus between cells.
NDV as Oncolytic Virus
The cytolytic activity of NDV in cancer cells can be divided into direct and indirect mechanisms. Direct mechanisms include the formation of multinuclear syncytia, the activation of extrinsic apoptotic pathways, the activation of intrinsic apoptotic pathways, the activation of the ER stress pathway, and the participation of the MAPK pathway. Indirect mechanisms allow the secretion of proinflammatory cytokines and chemokines, which recruit mediators for innate and adaptive immune responses, such as NK cells, lymphocytes, and macrophages. These protein factors can upregulate MHC and cell adhesion molecules by binding to viral glycoproteins expressed on the surface of infected cells (they can activate tumor-specific lymphocytes). Besides, it can further promote the anti-tumor immune response by activating macrophages and enhancing the adhesion of leukocytes.
Reference
- Zamarin, D.; Palese, P. Oncolytic Newcastle disease virus for cancer therapy: old challenges and new directions. Future microbiology. 2012, 7.3: 347-367.