Protein finding could lead to inflammatory treatment
that undesirably shields a skin poxvirus from the immune system as
the key ingredient in a new topical treatment for inflammatory
diseases.
Furthermore, the scientists think that a drug could eventually be designed to override the activity of the protein as a cure for the molluscum contagiosum virus (MCV).
The incidence of MCV infections has increased with the rise of AIDS. MCV is an opportunistic infection in immunocompromised people, with MCV lesions growing very large and persisting for much longer periods, even years, in this population.
In the study, researchers from the University of Illinois, Shisler and Daniel Brian Nichols, a doctoral student in microbiology, treated human embryonic kidney cells with cytokines known to activate NF-kB.
NF-kB is a cellular transcription factor that activates the expression of genes involved in inflammation.
Cytokines are chemicals made by immune cells that boost the immune system by stimulating inflammation to fight infectious pathogens.
The researchers found that NF-kB levels were always lower in MC160-expressing cells.
This finding represents the first time a function for MC160 has been found and the scientists have theorised that protein's role is to inhibit NF-kB activation in MCV-infected skin cells, to prevent cytokines from boosting the immune system. MC160 is probably helping the virus persist.
Further studies revealed that MC160 shuts down the NF-kB-triggered inflammatory response by degrading a subunit of the immune system's I Kappa Kinase (IKK) complex.
The normal function of IKK is to trigger the degradation of a protein that inhibits NF-kB activity. MC160 subsequently causes the IKK complex to fall apart to prevent the phosphorylation process that turns on NF-kB.
"Our findings regarding MC160 provide yet another example of how viruses inhibit NF-kB activation," said Joanna Shisler, a professor of microbiology in the U. of I. College of Medicine at Urbana-Champaign who studies poxviruses.
"So we are starting to get a broader feeling that there is a common mechanism, that of inhibiting NF-kB activity, that all viruses are trying to utilise to survive in the host. What is interesting is that MC160 appears to be doing it in a completely novel way, than any identified before, by focusing on this IKK complex," she added.
MC160, which is only made in skin cells and stays within them, as a therapeutic tool, could be the potential cure for such painful inflammatory responses caused by cytokine production in rheumatoid arthritis, Crohn's disease and similar maladies.
Shisler said that the protein's large size (almost 60 kiloDaltons) could hopefully be reduced to smaller, activity-specific peptide regions, simplifying the preparation of a topical treatment that would inhibit painful inflammatory responses.
The molluscum contagiosum virus that produces MC160 is a distant relative of smallpox and causes a benign, short-lived skin infection in children and sexually active young adults.
It is a common disease, with antibodies detected in up to 50 per cent of populations tested in numerous studies.
The lesions resemble chickenpox (a disease actually caused by a herpes virus) and are often confused as such. There is no treatment.
The study, which reveals more of the function of the protein (MC160) and how it works on a molecular level to inhibit inflammatory responses, appears this month in the Journal of Virology.
