Influence of the mouse Bcg Tbc-1 and xid genes on resistance and immune responses to tuberculosis infection and efficacy of bacille Calmette–Guérin (BCG) vaccination

Abstract

SUMMARYWe have studied the role of three mouse distinct non-H-2 genes (Bcg, Tbc-1, xid ) in several phenomena of antituberculosis immunity and resistance. On the basis of median survival time (MST) of mice following infection with virulent Mycobacterium tuberculosis H37Rv, Bcg gene did not control resistance to the lethal dose of H37Rv infection in non-vaccinated and Myco. bovis (BCG)-vaccinated mice. However, Bcg r allele, in comparison with Bcg s allele, determined more effective suppression of an early multiplication in spleens of H37Rv mycobacteria after a low dose (5 2 10 4 colony-forming units (CFU)) injection. CBA/N mice, which are not protected efficiently against tuberculous challenge by BCG vaccination, were characterized by a decreased in vitro proliferation of immune lymph node cells, both spontaneous and stimulated with mycobacterial antigens. The decreased proliferation was due to immunosuppression caused by interactions between responding T cells and CBA/N antigen-presenting cells (APC). We have confirmed that the defective response to BCG-vaccination in CBA/N mice is linked with the X-chromosome and thus is presumably determined by the xid gene itself. I/St mice (Tbc-1 s ), supersusceptible to H37Rv infection, were not able to restrict the growth of H37Rv mycobacteria in spleens, even following infection with a low dose (5 2 10 4 ), but restricted the growth of Myco. bovis BCG more effectively than Bcg s mice.

Genetic control of resistance to experimental infection with virulentMycobacterium tuberculosis

“…There is ample experimental evidence for the role of host genetic factors in the outcome of infection with virulent M. tuberculosis in several species of laboratory animals (8)(9)(10)(11)(12)(13). The ability to control the establishment and progression of tuberculosis infection was shown to vary between, as well as within, species.…”

Relationship between NRAMP1 gene polymorphism and efficacy of BCG vaccine in helminth-infected populations

“…Koh et al (2005) stated that heterozygous intron 4 (469 + 14 G/C) of NRAMP1 is observed with significantly greater frequency in patients with non-TB mycobacterial lung infections than in control subjects. On the other hand, Nikonenko et al (1996) found that the efficiency of BCG vaccine is not dependent on the NRAMP1 gene polymorphism. They ascribed their negative result to the fact that TB susceptibility measured by mortality does not necessarily correspond to TB susceptibility measured by parasite growth in organs.…”

“…There may be a negative correlation between the dose of infectious helminth and the magnitude of the immune response (Steel and Nutman, 2003). The NRAMP1 gene polymorphism is another factor affecting BCG efficacy (Nikonenko et al, 1996).…”

“…Also, although the NRAMP1 gene is able to regulate bacterial growth in organs after a high level of infection, this finding has been documented only for intravenous injection of BCG vaccine. However, in the experiments by Nikonenko et al (1996) mice were vaccinated subcutaneously. Alm et al (2002) found no statistically significant interaction using logarithmic regression between BCG vaccination and the NRAMP1 gene polymorphism in relation to atopy.…”

Efficacy of Isoniazid Therapy in Mice with Different Genetic Susceptibility to Infection

“…Among forty inbred mouse strains studied by our lab during last decades, mice of the I/St Strain demonstrated the highest of susceptibility to infection with M. tuberculosis strain H37Rv [1][2][3][4][5][6]. Unlike the majority of conventional mouse strains, after M. tuberculosis infection I/St mice form necrotic and hypoxic lung granulomas [6,7], similar to those in humans [8], and in another hyper-susceptible mouse strain C3HeB/FeJ [9].…”