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Discussion |
Department of Nutritional Sciences, University of Missouri, Columbia, Missouri
Dr. Kevin L. Fritsche.
Dr. Beck’s research on antioxidants and viral infections has important public health significance and emphasizes once again the necessity of keeping people as healthy and nutritionally fit as possible. Dr. Connelly’s research on lactoferrin and infectious diseases is of great interest considering current concerns about antibiotics. The widespread use of antibiotics in domestic animal agriculture in the United States is increasingly scrutinized and criticized as a potential source for creating antibiotic-resistant organisms that eventually get into the human system, mostly through the food chain. There is considerable interest in potentially adding lactoferrin or other kinds of bacteriostatic peptides to the diet to reduce or totally eliminate the use of antibiotics.
Dr. Kenneth D.R. Setchell.
I was intrigued by Dr. Conneely’s comment regarding the inconsistent findings from her inflammatory bowel disease (IBD) models. In our work with IBD, we have observed fairly good antiinflammatory effects of soy isoflavones. The mechanism appears to be inhibition of the activity of insulin expression in colonic cells and is probably more upstream through NF-kappa transcription factor. Some of the inconsistencies in reproducing the effects in animal models could be due to the background or control diet fed to the animals.
Dr. Orla M. Conneely.
I agree, but there are two problems associated with controlling the diet. The first is variability. As the animals get sick, they begin to eat less, and it becomes difficult to control their food intake. This problem can be overcome by the use of transgenic expression. We have made transgenics in which lactoferrin is overexpressed throughout the intestine with the use of the intestinal fatty acid binding protein. The second problem is that the response is species specific. Using human lactoferrin in the mouse is not optimal because the affinity for the receptor is 10-fold lower; thus, much more lactoferrin is required for different species. In our intradermal studies, we used mouse lactoferrin because we could produce limited amounts of it. Also, one of the key reasons we focused on the skin was that we needed only a small amount of material. Our studies have shown that lactoferrin is species specific and independent of iron. For this reason, we used the transgenic model because we can produce mouse lactoferrin.
Dr. Setchell.
In terms of transgenic expression, in some circumstances diet can markedly override the phenotypic expression of the transfected gene. There are a number of examples to support this observation. Many investigators have not sufficiently considered the role of diet because they have no control over the dietary exposure in animals they buy.
Dr. Melinda A. Beck.
Dr. Conneely, what is the mechanism for the ability of lactoferrin with the interleukin-1-ß to prevent TNF-
expression?
Dr. Conneely.
We don’t know except to say that an interaction is involved. Now that we have observed that lactoferrin is upstream of TNF- and that it’s interacting with the receptors of those cells, we are using in vitro cultures to identify the signaling pathway. Some studies suggest that, at least in lymphocyte cells, lactoferrin activates kinase pathways that may, in fact, repress TNF expression.
Dr. Kedar N. Prasad.
Do other cellular genes, such as oncogenes, become mutated under the deficient condition, or is the mutation unique for glutathione peroxidase?
Dr. Beck.
Our glutathione peroxidase work was done to mimic selenium deficiency and to look at mutations in the virus, not in any host cellular functions.
Dr. Carl L. Keen.
Some metabolite reactive oxygen species may be causing a change. Why must one assume that the changes will always be from benign viruses to deleterious viruses? Couldn’t the change be in either direction?
Dr. Beck.
It depends on how one looks at the mechanism involved—as direct oxidative damage to the RNA or as a selection process. We know that RNA viruses will mutate; whenever an RNA virus is involved, there is a quality species, which is a mixture of sequences. What you are actually sequencing is a consensus sequence. We may be selecting out a more virulent genotype because it is a more fit virus that is able to replicate to higher titers and it works better in the animal. As a result, the outcome is more pathogenic. In our experiments, we are actually selecting out a more virulent gene type that is already there, rather than one that is mutating.
Dr. Fritsche.
Is there any potential adverse effect of adding lactoferrin, for example, to infant formula? Is it going to affect iron absorption or availability, or have any other adverse effect?
Dr. Conneely.
Lactoferrin has been tested in safety toxicity studiesand is currently approved for oral administration. Our studies in mice show that lactoferrin has no impact on iron status, serum iron levels, intestinal iron absorption, etc.
Dr. David M. Klurfeld.
Is lactoferrin, which is most concentrated in milk, found in whey protein? Whey proteins have been recently shown to markedly affect immune modulation and inhibit colon cancer in fetus-stage animals.
Dr. Conneley.
Yes, lactoferrin is in the whey protein. It is downregulated in virtually all cancers. Some studies have shown that administration of lactoferrin in vivo inhibits the growth of head and neck cancers. This effect could be due simply to iron sequestration and inhibition of cellular proliferation. At present, there is no evidence that lactoferrin is involved with immune modulation. Nevertheless, it is one of many proteins in milk that is thought to protect against cancer and microbial infections.
Dr. Setchell.
How do you explain the gender bias in terms of the role of selenium and the effects on coxsackievirus and the development of cardiomyopathy? I believe estrogen plays a role in cardiomyopathy.
Dr. Beck.
There have been mouse models for coxsackievirus-induced myocarditis for a long time. Both strain and gender differences in mice are evident in these studies. Some mice are more susceptible to coxsackievirus-induced myocarditis than are others. The overall trend is for male mice to be more susceptible to this virus than female mice. Huber has suggested that estrogen is protective. We have used male mice in our studies because of their increased susceptibility to this virus.
Dr. Fritsche.
What is the underlying biochemistry of the mutations that are occurring in these RNA viruses?
Dr. Beck.
We are trying to do some in vitro studies independent of the immune system to determine if the effect is direct or due to a selective process.
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