Submitted to: Infection and Immunity
Publication Type: Peer reviewed journal
Publication Acceptance Date: 1/2/2004
Publication Date: 4/1/2004
Citation: Khalifeh, M.S., Stabel, J.R. 2004. Effects of interferon-g, interlukin-10, and transforming growth factor-b on the survival of mycobacterium paratuberculosis in monocyte-derived macrophages from naturally infected cattle. Infection and Immunity. 72:1974-1982. Interpretive Summary: Johne's disease is a chronic, debilitating intestinal disorder in cattle characterized by diarrhea, reduced feed intake, weight loss and death. Cattle usually become infected as young calves by ingesting feces containing the causative bacteria. However, symptoms of disease do not usually present themselves until the animals reach 3 to 5 years of age or even older. During this time the animal is infected and may be shedding the organism in its feces without showing any clinical signs of disease. In addition to reduced milk production by these animals, they also present a potential infective threat to the rest of the herd. Johne's disease is difficult to diagnose and therefore to control. Development of accurate and sensitive diagnostic tests is dependent upon understanding the immune responses of the host animal during infection. This study demonstrated that animals in different stages of infection with the same microorganism have very different immune responses. This information is helpful in understanding the difference between an animal being able to control the infection and an animal that succumbs to clinical disease. It is possible that this information will lead to better understanding of the pathogenesis of disease and aid in new preventative and therapeutic regimes.
Technical Abstract: Interferon-g plays a significant role in the control of mycobacterial infections, including Mycobacterium paratuberculosis. However, the contribution of other immunoregulatory cytokines such as IL-10 and TGF-b in Johne's disease has not been investigated as yet. In the present study, we examined the effects of in vivo and in vitro infection with M. paratuberculosis on the production of IFN-g, IL-10 and TGF-b by peripheral blood mononuclear cells (PBMC). We also examined the effects of exogenous IFN-g, IL-10 and TGF-b on M. paratuberculosis survival in the cell cultures. PBMC obtained from naturally infected cows, regardless of their disease status, specifically upregulated IL-10 and TGF-b in culture supernatants in response to stimulation with live M. paratuberculosis. Non-stimulated PBMC recovered from subclinically infected animals secreted the lowest levels of TGF-b but after stimulation with live M. paratuberculosis TGF-b levels in the culture supernatants increased to levels similar to that produced by PBMC from healthy animals. Compared to healthy cows, naturally infected animals had higher numbers of viable M. paratuberculosis recovered from their cultures after in vitro infection with M. paratuberculosis. The addition of exogenous IL-10 and TGF-b to PBMC isolated from healthy cows inhibited the bactericidal activity of these cells as evidenced by the increased number of viable M. paratuberculosis recovered from those cultures compared to cell cultures containing medium alone. These data suggest an important immune regulatory role of IL-10 and TGF-b during infection with M. paratuberculosis that may be directly related to their effects on macrophage activation and killing of M. paratuberculosis.