Studying the protective efficacy of radiation-attenuated Plasmodium sporozoites as anti-infective malaria vaccine during concurrent infection with Mycobacterium tuberculosis
Immunology
Final Report Abstract
In summary, protection of mice from ECM by BCG was associated with reduced frequencies of CD8+ T cells in the brains and spleen. In contrast, and opposite to our original hypothesis that BCG-induced innate immune activation will protect mice from ECM by reducing parasitemia, BCG did not reduce parasite loads in blood, liver or brain. In line with this, proinflammatory cytokines were not elevated but lower in BCG-vaccinated animals, indicating immunosuppressive rather than immune activating functions of BCG. An immunosuppressive activity of BCG was already described 40 years ago. These early studies suggested that BCG modified the lymphocyte compartment and activates natural suppressor cells in the bone marrow. More recently, BCG was shown to have neuroprotective effects in experimental models of neurodegenerative diseases. In these studies, BCG prevented an increase in activation of microglia and induced anti-inflammatory and inflammation-resolving effects by the recruitment of regulatory T cells or inflammationresolving monocytes to the brain. This could explain why we observed reduced proinflammatory cytokines and chemokines and reduced recruitment of pathogenic T cells to the brain after PbA infection when mice had received BCG before. Another possible protective mechanism of BCG is that it diverts immune cells from entering the brain after PbA infection. Previous studies in the mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE) have shown that infection with BCG 6 weeks before the induction of EAE diverted activated myelin-reactive CD4+ T cells from the central nervous system to granulomas in the spleen and liver. Evidently, the peripheral inflammatory lesions nonspecifically attracted T cells and prevented the development of EAE. Intruigingly, there is also clinical evidence that BCG treatment can suppress neurodegenerative autoimmune responses since MS patients immunized with BCG had an almost 60% reduction of lesions as measured by MRI. Unfortunately, we were not able to identify the underlying mechanisms that are responsible for the partial protection mediated by BCG against PbA-induced ECM but importantly, the analysis of the extensive flow cytometric data we have acquired have not been completed. We expect to gather more information about important immune cell populations in spleen and liver (T cell subsets, DCs and monocytes/macrophages) which might give us an idea of the immune modulation induced by BCG in the context of PbA infection. Understanding these mechanisms can provide the rationale for developing effective adjunctive therapies to reduce the risk of death and brain damage in CM. Moreover, our findings corroborate the beneficial heterologous effects of BCG that have been described in mice and humans. Only very recently, a large, multinational study suggested that BCG vaccination is associated with a reduced risk of malaria in children under the age of 5 years in sub-Saharan Africa. This association was largest in regions with suboptmal BCG coverage. This study clearly implys that timely BCG vaccination could aid the global efforts to reduce malaria burden and emphasizes the need to improve BCG vaccination practice in regions with suboptimal coverage. Moreover, if BCG was able to prevent cerebral malaria as our data suggest, this established vaccine might serve a feasible, safe and cheap approach to prevent fatal malaria cases particularly in areas with reduced malaria transmission.
