Mycobacterium bovis BCG-Mediated Protection against W-Beijing Strains of Mycobacterium tuberculosis Is Diminished Concomitant with the Emergence of Regulatory T Cells

Abstract

Despite issues relating to variable efficacy in the past, the Mycobacterium bovis BCG vaccine remains the basis for new-generation recombinant vaccines currently in clinical trials. To date, vaccines have been tested mostly against laboratory strains and not against the newly emerging clinical strains. In this study, we evaluated the ability of BCG Pasteur to protect mice from aerosol infections with two highly virulent W-Beijing clinical strains, HN878 and SA161. In a conventional 30-day protection assay, BCG was highly protective against both strains, but by day 60 of the assay, this protection was diminished. Histological examination of the lungs of vaccinated animals showed reduced lung consolidation and smaller and more-organized granulomas in the vaccinated mice after 30 days, but in both cases, these tissues demonstrated worsening pathology over time. Effector T cell responses were increased in the vaccinated mice infected with HN878, but these diminished in number after day 30 of the infections concomitant with increased CD4 ؉ Foxp3 ؉ T cells in the lungs, draining lymph nodes, and the spleen. Given the concomitant decrease in effector immunity and continued expansion of regulatory Foxp3؉ cells observed here, it is reasonable to hypothesize that downregulation of effector immunity by these cells may be a serious impediment to the efficacy of BCG-based vaccines.The global epidemic of disease caused by Mycobacterium tuberculosis continues unabated, with recent figures indicating approximately 8 million new cases of tuberculosis (TB) each year, with about 2 million deaths (5,8,9,13,31,40). Among these infections, clinical isolates typed as belonging to the W-Beijing family of strains are becoming increasingly prevalent; in fact, it is believed that the Beijing genotype family is responsible for approximately 50% of TB cases in East Asia and now accounts for at least 13% of all isolates worldwide (4,17,29,31,33,37,38). The reason for the success of this family is unclear and is compounded by the suggestion that the current vaccine for tuberculosis, Mycobacterium bovis BCG, has actually selected for the emergence of this family (1).Despite recent recommendations (10), we know little about the actual basic biology of the newly emerging clinical strains of M. tuberculosis. Only one W-Beijing strain, HN878, has been extensively studied with animal models to date (19)(20)(21)(22)36); the data obtained shows that this isolate is extremely virulent, at least in comparison with the modestly virulent laboratory strains H37Rv and Erdman. A major difference, as recently demonstrated (22), is that while all the above strains potently induce effector immunity 20 to 30 days after low-dose aerosol infection of mice, this is soon replaced in HN878-infected mice by the emergence of CD4 cells expressing Foxp3, with many of these staining in addition for the immunosuppressive cytokine interleukin-10 (IL-10).Because vaccines for tuberculosis are usually tested against the laboratory strains, there is very limited information as...

Beijing Sublineages of Mycobacterium tuberculosis Differ in Pathogenicity in the Guinea Pig

“…This finding suggests that the RD142 strains are more immunogenic, and it is consistent with the ability of the guinea pigs to control and contain these particular strains more quickly. In addition, all strains induced some degree of regulatory host molecules (Foxp3, TGF-␤, and IL-17), which seems to be a general property of the Beijing strains analyzed in animal studies to date (32,44). Members of the RD207 sublineage gave the highest signals.…”

“…We also examined the induction of regulatory molecules, given our earlier observations (32,44) that this seems to be a common property of many of the Beijing strains. As the infections progressed, increases in message for Foxp3 were seen in all strains (Fig.…”

“…Of particular concern is the Beijing family of strains, a family that is thought to have enhanced pathogenicity, a predilection for drug resistance (15,47), and a less effective response to M. bovis BCG-based vaccines (32,35).…”

The History of Tuberculosis and Bacillus Calmette–Guérin Vaccine in Iran

“…Resultant IL-4 production and regulatory T-cell development may negatively regulate generation of Th1 type cells that could potentially contain TB infection, thereby leading to active disease and vaccine failure (12,18,(21)(22)(23). In recent mouse studies, CD4+ regulatory T-cells induced by BCG appeared to down-regulate effector T cell activity in mice infected with a virulent W-Beijing TB genotype; a finding with implications for BCG vaccination against highly virulent circulating TB strains (24).…”

Protective Vaccine Efficacy of the Complete Form of PPE39 Protein from Mycobacterium tuberculosis Beijing/K Strain in Mice

“…S2 in the supplemental material). Considering the high prevalence of the Beijing/K strain of M. tuberculosis and the relatively poor protection of BCG against the W-Beijing genotype of M. tuberculosis (8,47), it would be worthwhile to test MTBK_24820 derived from the strain as a vaccine candidate, particularly in an area where TB is endemic. The dominant epitope sites of the T cells observed in MTBK_24820 also exist in M. bovis BCG, but the subdominant epitope sites were not found in M. bovis BCG.…”