Modulation of the immune response to mycobacteria: implications on protection and pathology
Year: 2009
Type: dissertation
Abstract: Effective control of Mycobacterium tuberculosis infection requires the induction of inflammatory T helper (Th) 1 responses and avoidance of tissue damage. However, little is known about the mechanisms that rule the fine balance between protection and pathology in this infection. The anti-inflammatory cytokine IL-10 is important for the regulation of the immune response to several pathogens. However, despite the fact that elevated levels of IL-10 have been detected in tuberculosis patients, the role of IL-10 during M. tuberculosis infection is not clearly understood. In this study, we evaluated the impact of a transient over-expression of IL-10, during either the innate or the adaptive phases of the immune response, in the outcome of infection. For this, we used a novel animal model, the PMT-10 mice, which over-express IL-10 under the control of a zinc-inducible promoter. These transgenic animals were infected with M. tuberculosis, either via the intranasal or intravenous route and the expression of IL-10 was induced at different stages of the infection. Over-expression of IL-10 early after infection did not influence the capacity of PMT-10 mice to control bacterial growth, regardless the route of inoculation. In contrast, over-expression of IL- 10 during the chronic phase of infection caused significant effects in the progression of M. tuberculosis infection. Interestingly, whereas in intravenous infection, late IL-10 induction resulted in a transient increase in susceptibility of PMT-10 mice to M. tuberculosis, in intranasal infection, induction of IL-10 led to an increased resistance of PMT-10 mice that was maintained until the end of the experiment. However, no major differences were observed between induced and noninduced PMT-10 mice concerning the dynamic of cells or cytokine expression during infection that could explain the different outcomes observed. Although the cellular and molecular mechanisms underlying the differences observed remain unknown, altogether our data suggest that the impact of IL-10 expression during an infection with M. tuberculosis is variable. Indeed, we show for the first time that the timing of IL- 10 expression as well as the route of inoculation can determine the outcome of M. tuberculosis infection. Further understanding of our observations might be useful in the context of immunomodulatory strategies based on IL-10 expression or suppression.
Author: Daniela Maria Ramos Pereira
Institution: University of Minho
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2268412694