ngin - Norfolk Genetic Information Network
Date:  1 March 2001


"In conclusion, genetic engineering is proving its ability to create novel devastating pathogens." from ABSTRACT
"Expression of Mouse Interleukin-4 by a Recombinant Ectromelia Virus Suppresses Cytolytic Lymphocyte Responses and Overcomes Genetic Resistance to Mousepox"

Ronald J. Jackson, Alistair J. Ramsay, Carina D. Christensen, Sandra Beaton, Diana F. Hall, and Ian A. Ramshaw - Journal of Virology - 75: 1205-1210 - February 2001

Commentary by Joe Cummins:
"Super viruses through genetic engineering"

The main worry about the newly developed science of genetic engineering during the early 1970s was genetic recombination to create super disease bearing viruses and bacteria. Even though the concerns are as valid now as they were thirty years ago those concerns have been suppressed as the economic benefits of genetic engineering have been promoted. The article below shows that recombinant mouse pox virus containing the gene for interleukin- 4 suppresses immune defense
against the virus and expression of immune memory.

Genetic resistance to clinical mousepox (ectromelia virus) varies among inbred laboratory mice and is characterized by an effective natural killer (NK) response and the early onset of a strong CD8+ cytotoxic T-lymphocyte (CTL) response in resistant mice. We have investigated the influence of virus-expressed mouse interleukin-4 (IL-4) on the cell-mediated response during infection. It was observed that expression of IL-4 by a thymidine kinase-positive ectromelia virus suppressed
cytolytic responses of NK and CTL and the expression of gamma interferon by the latter.

Genetically resistant mice infected with the IL-4-expressing virus developed symptoms of acute mousepox accompanied by high mortality, similar to the disease seen when genetically sensitive mice are infected with the virulent Moscow strain. Strikingly, infection of recently immunized genetically resistant mice with the virus expressing IL-4 also resulted in significant mortality due to
fulminant mousepox. These data therefore suggest that virus-encoded IL-4 not only suppresses primary antiviral cell-mediated immune responses but also can inhibit the expression of immune memory responses.

Fundamentals: In the experiments described above the gene added to the virus that caused the virus to turn off immune defense was interleukin-4. Interleukin-4 is a member of the cytokine regulators of the immune system.

Cytokines are proteins produced by the genes they include interleukins, tumor necrosis factor and interferons. There are presently 18 cytokines with the name interleukin (IL). Other cytokines have retained their original biological description, such as tumor necrosis factor (TNF). Another way to look at some cytokines is their role in infection and/or inflammation. Some cytokines clearly promote inflammation and are called proinflammatory cytokines, whereas other cytokines suppress the activity of proinflammatory cytokines and are called anti-inflammatory cytokines.

For example, IL-4, IL-10, and IL-13 are potent activators of B lymphocytes. However, IL-4, IL-10, and IL-13 are also potent anti-inflammatory agents. They are anti-inflammatory cytokines by virtue of their ability to suppress genes for proinflammatory cytokines such as IL-1, TNF, and the chemokines.

Interferon (IFN)-[Gamma] is another example of the pleiotropic nature of cytokines. Like IFN-[Alpha] and IFN-[Beta], IFN-[Gamma] possesses antiviral activity. IFN-[Gamma] is also an activator of the pathway that leads to cytotoxic T cells. However, IFN-[Gamma] is considered a
proinflammatory cytokine because it augments TNF activity and induces nitric oxide (NO). In summary, the cytokines both promote and prevent inflammation. Some fight pathogens while others shut down defense against pathogens. Cytokines modulate the numerous immune functions.

Our comments: The study described above clearly shows that genetic recombination is capable of creating virus (or other pathogens) with genes that allow the pathogen to overcome host defense and to spread with little or no control. There is growing evidence that viruses have used strategy of that type to overcome host defense during the course of their evolution. However, genetic modification will greatly hasten the mixing of regulatory cellular genes and virus genes. Gene therapy experiments may create dangerous pathogens , but can crop genetic engineering lead to creation of dangerous pathogens. Cytokine genes from human and animals have been extensively introduced intomcrop plants which have been tested in the open environment in field crops. Such experiments could easily lead to production of insect baculoviruses bearing human genes by recombination between the human genes in crops and the insect viruses. The insect baculoviruses readily infect human liver which normally produces non-pathogenic infection but with human genes
inserted infections could be devastating. Certainly, a wide range of new pathogensmmay be created by genetic recombination and experimenting with human gene constructions in the open environment invites such pathogens to produce themselves. The production of novel plant pathogens should also be considered because their production is highly likely. Here , the
analogy between animal viruses and mammalian regulators also extends to
plant viruses and the plant defense genes.

In conclusion, genetic engineering is proving its ability to create novel devastating pathogens.

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