Newcastle disease

Newcastle disease is a contagious bird disease affecting many domestic and wild avian species. First found in Newcastle, United Kingdom in 1926, then by Burnet in 1943 in Australia in connection with laboratory infection where the virus was isolated from a ocular discharge of a patient to show the specific antibody titre in the patient's blood. Newcastle has a negative sense single stranded genome which codes for a RNA directed RNA polymerase, hemagglutinin- neuraminidase protein, fusion protein, matrix protein, phosphoprotein and nucleoprotein in the 5' to 3' direction. Its effects are most notable in domestic poultry due to their high susceptibility and the potential for severe impacts of an epizootic on the poultry industries. It is endemic to many countries.

Newcastle disease was discovered in Newcastle upon Tyne, England in 1926 (Doyle), but also at this time slightly different strains were found in other parts of the world.

Exposure of humans to infected birds (for example in poultry processing plants) can cause mild conjunctivitis and influenza-like symptoms, but the Newcastle disease virus (NDV) otherwise poses no hazard to human health. Interest in the use of NDV as an anticancer agent has arisen from the ability of NDV to selectively kill human tumour cells with limited toxicity to normal cells.

No treatment for NDV exists, but the use of prophylactic vaccines and sanitary measures reduces the likelihood of outbreaks.

Causal agent

Description

The causal agent, Newcastle disease virus, is a negative-sense single-stranded RNA virus. Transmission occurs by exposure to faecal and other excretions from infected birds, and through contact with contaminated feed, water, equipment and clothing.

Strains

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.

Use as an anticancer agent

In 1999, promising results were reported using an attenuated strain of the Newcastle virus, codenamed MTH-68, in cancer patients^[1] by researchers who had isolated the strain in 1968.^[2][3] 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, codenamed NDV-HUJ, which showed promising results in 14 glioblastoma multiforme patients.^[4]

History of NDV in cancer therapy

Even if the oncolytic effect of the Newcastle Disease Virus (NDV) was documented already in the 1950s, the main advances of viruses in cancer therapy came with the advent of reverse genetics technologies (Flanagan et al 1955 in Mullen & Tanabe 2002^[5], Vigil et al 2007^[6]). With these new possibilities, studies of modified NDV strains with enhanced cancer treatment properties have been put on the agenda. This was demonstrated by Vigil et al (2007)^[6] where the engineered Hitcher B1 NDV/F3aa strain was 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 was 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 (Zamarin et al 2009b)^[7].

NDV, pros and cons in cancer therapy

NDV possesses many unique anti-cancer properties and thereby provides an excellent base in virotherapy research. NDV has selectivity on oncogenic cells, were it replicate without, or in a less pronounced way, harming normal cells (Elankumaran et al 2006^[8], Fábián et al 2007^[9]). It binds, fuse into and replicate within the infected cells’ cytoplasm independent of cell proliferation (Elankumaran et al 2006)^[8]. One of the main issues using NDV in 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 (Mullen & Tanabe 2002^[5], Kuruppu & Tanabe 2005)^[10].

NDV-induced mechanisms leading to tumor cell death

The precise way in which the presence of NDV induce tumor cell death remains to be clarified and may show variation both regards strains of NDV and to which type of cancer is targeted. Elankumaran et al (2006)^[8] showed that NDV triggers apoptosis 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 of Elankumaran et al (2006)^[8] also indicate that the extrinsic pathway is activated by TNF-related apoptosis-inducing ligand (TRIAL)-induced NDV-mediated apoptosis in a late stage. Altomonte et al (2009)^[11] studied a hyperfusogenic NDV/F3aa(L289A) with refined abilities to fusing into somatic cells. NDV has aggregating properties causing syncytia formations of tumor cell which, apart from amplifying immune based cell killing, also result 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, Vigil et al (2008)^[12] demonstrated an increase of CD4+ and CD8+ T-cells within the tumor cells when inducing NDV/F3aa recombined with the cytokine interleukin-2 (IL-2). Also Zamarin et al (2009a)^[13] show that a NDV/F3aa-IL-2 strain induced the immune system, giving a cytotoxic effect on the tumor cells. A 15-year study on patient with malign melanoma showed increased numbers of oligoclonal CD8+ T-cells in the blood, suggesting that the vaccination with NDV oncolysates was associated with prolonged survival among the patients and that CD8+ T-cells played an important role (Batliwalla et al 1998)^[14].

Use as a biological weapon

Newcastle disease was one of more than a dozen agents the United States researched as potential biological weapons before the nation suspended its biological weapons program^{[citation needed]}.

Transmission

NDV is spread primarily through direct contact between healthy birds and the bodily discharges of infected birds. The disease is transmitted through infected birds' droppings and secretions from the nose, mouth, and eyes. NDV spreads rapidly among birds kept in confinement, such as commercially raised chickens.

High concentrations of the NDV are found in birds' bodily discharges; therefore, the disease can be spread easily by mechanical means. Virus-bearing material can be picked up on shoes and clothing and carried from an infected flock to a healthy one.

NDV can survive for several weeks in a warm and humid environment on birds' feathers, manure, and other materials. It can survive indefinitely in frozen material. However, the virus is destroyed rapidly by dehydration and by the ultraviolet rays in sunlight. Smuggled pet birds, especially Amazon parrots from Latin America, pose a great risk of introducing NDV into the US. Amazon parrots that are carriers of the disease but do not show symptoms are capable of shedding NDV for more than 400 days.

Clinical findings

Symptoms

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 two to 15 days. An infected bird may exhibit the following signs:

They can include 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 seven 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

Postmortem lesions

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

Diagnosis

Immunological tests

Enzyme linked immunosorbent assay (ELISA), PCR, and sequence technology tests have been developed.

Virus isolation

Samples

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.

Handling

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.^[15]

Prevention

Any animals that are showing symptoms of Newcastle disease should be quarantined immediately. New birds should also be vaccinated before being introduced to your flock. There is an inactivated viral vaccine available, as well as various combination vaccines.

References

• Nelson CB, Pomeroy BS, Schrall K, Park WE, Lindeman RJ. (1952). An outbreak of conjunctivitis due to Newcastle disease virus (NDV) occurring in poultry workers. Am J Public Health 42(6):672–8.

Footnotes

External links

• World Organisation for Animal Health (OIE)
• Department of Environment, Food and Rural Affairs, UK
• United States Animal Health Association VELOGENIC NEWCASTLE DISEASE [2]
• Iowa State University Department of Veterinary Pathology, Center for Food Security and Public Health, "Newcastle Disease" [3]
• Full description of the disease
• Erich Traub
• Plum Island Animal Disease Center
• Species Profile- Exotic Newcastle Disease (Paramyxovirus -1), National Invasive Species Information Center, United States National Agricultural Library. Lists general information and resources for Exotic Newcastle Disease.

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