Virulent Newcastle disease

NDV strains can be categorised as velogenic (highly virulent), mesogenic (intermediate virulence), or lentogenic (nonvirulent). Velogenic strains produce severe nervous and respiratory signs, spread rapidly, and cause up to 90% mortality. Mesogenic strains cause coughing, affect egg quality and production, and result in up to 10% mortality. Lentogenic strains produce mild signs with negligible mortality.

In 1999, promising results were reported using an attenuated strain of the Newcastle virus, code named MTH-68, in cancer patients[9] by researchers who had isolated the strain in 1968.[10][11] It appears the virus preferentially targets and replicates in certain types of tumor cells, leaving normal cells almost unaffected. In 2006, researchers from the Hebrew University also succeeded in isolating a variant of the NDV, code named NDV-HUJ, which showed promising results in 14 glioblastoma multiforme patients.[12] In 2011, researchers at the Memorial Sloan–Kettering Cancer Center and the Icahn School of Medicine at Mount Sinai found that NDV modified with the viral protein NS1 had enhanced replication in cancer cell lines overexpressing the antiapoptotic factor Bcl-xL. The researchers suggested in cells that resist the normal inducement of apoptosis when infected will give NDV more time to incubate in cell and spread. Many cancer cells will overexpress antiapoptotic factors as part of tumor development. This mechanism of delaying apoptosis in abnormal cells gives NDV the specificity it needs to be an efficient cancer-fighting oncolytic virus.[13]

Though the oncolytic effect of NDV was documented already in the 1950s, the main advances of viruses in cancer therapy came with the advent of reverse genetics technologies [14][15] With these new possibilities, studies of modified NDV strains with enhanced cancer-treatment properties have been put on the agenda. A study[15] demonstrated the engineered Hitcher B1 NDV/F3aa strain could be modified to express a highly fusogenic F-protein in combination with immunostimulatory molecules such as IFN-gamma, interleukin 2, or tumor necrosis factor alpha. Promising results were discovered with proteins associated to the adaptive immune system, which paved the way for possibilities to use NDV to create a tumor-associated antigen. Another study showed how NDV/F3aa could be modified to express NS1, an influenza virus protein with capability to modulate with the innate immune response, for example, by suppressing the induction of the cellular interferons.[16]

NDV possesses many unique anticancer properties and thereby provides an excellent base in virotherapy research. NDV has selectivity on oncogenic cells, where it replicates without, or in a less pronounced way, harming normal cells.[17][18] It binds, fuses into and replicates within the infected cells’ cytoplasm independent of cell proliferation.[17] One of the main issues using NDV treatment is the host/patient immune response against the virus itself, which prior to the time of the reverse genetics technology, decreased the applicability of NDV as a cancer treatment.[14][19]

The precise way in which the presence of NDV induces tumor cell death remains to be clarified and may show variation regarding the strains of NDV used and which type of cancer is targeted. NDV triggers apoptosis[17] in a wide range of cancer cell types via the mitochondrial/intrinsic pathway, through loss of membrane potential and thereby inducing release of cytochrome c in the tumor cell. The results[17] also indicate the extrinsic pathway is activated by TNF-related, apoptosis-inducing ligand-induced, NDV-mediated apoptosis in a late stage. Another study[20] found a hyperfusogenic NDV/F3aa(L289A) with refined abilities to fuse into somatic cells. NDV has aggregating properties causing syncytia formations of tumor cells, which, apart from amplifying immune-based cell killing, also results in necrosis of cells. This pathway was believed to lead to a considerable boost of immune activation and potentially an antitumor response, which was supported by observations of a significant accumulation of NK-cells and neutrophils following the infusion of NDV/F3aa(L289A) in hepatocellular carcinoma cells. In addition, an increase of CD4+ and CD8+ T-cells occurs within the tumor cells when inducing NDV/F3aa recombined with the cytokine interleukin-2 (IL-2).[21] An NDV/F3aa-IL-2 strain induced the immune system, giving a cytotoxic effect on the tumor cells.[22] A 15-year study on patients with malignant melanoma showed increased numbers of oligoclonal CD8+ T-cells in the blood, suggesting vaccination with NDV oncolysates was associated with prolonged survival among the patients, and CD8+ T-cells played an important role.![23]

Egg drop after a (otherwise asymptomatic) Newcastle disease infection in a duly vaccinated broiler parent flock

Signs of infection with NDV vary greatly depending on factors such as the strain of virus and the health, age and species of the host.

The incubation period for the disease ranges from 4 to 6 days. An infected bird may exhibit several signs, including respiratory signs (gasping, coughing), nervous signs (depression, inappetence, muscular tremors, drooping wings, twisting of head and neck, circling, complete paralysis), swelling of the tissues around the eyes and neck, greenish, watery diarrhea, misshapen, rough- or thin-shelled eggs and reduced egg production.

In acute cases, the death is very sudden, and, in the beginning of the outbreak, the remaining birds do not seem to be sick. In flocks with good immunity, however, the signs (respiratory and digestive) are mild and progressive, and are followed after 7 days by nervous symptoms, especially twisted heads.

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  Torticollis in a mallard
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  Same symptom in a broiler
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  PM lesions on proventriculus, gizzard, and duodenum

Petechiae in the proventriculus and on the submucosae of the gizzard are typical; also, severe enteritis of the duodenum occurs. The lesions are scarce in hyperacute cases (first day of outbreak).

Enzyme-linked immunosorbent assay, polymerase chain reaction, and sequence technology tests have been developed.

For routine isolation of NDV from chickens, turkeys, and other birds, samples are obtained by swabbing the trachea and the cloaca. Cotton swabs can be used. The virus can also be isolated from the lungs, brain, spleen, liver, and kidneys.

Prior to shipping, samples should be stored at 4 °C (refrigerator). Samples must be shipped in a padded envelope or box. Samples may be sent by regular mail, but overnight is recommended.[24]