CD4 T-Cell-Mediated Heterologous Immunity between Mycobacteria and Poxviruses

Abstract

The bacillus Calmette-Guerin (BCG) strain of Mycobacterium bovis is used in many parts of the world as a vaccine against Mycobacterium tuberculosis. Some epidemiological evidence has suggested that BCG immunization may have unpredicted effects on resistance to other pathogens. We show here in a mouse model that BCG immunization followed by antibiotic treatment to clear the host of the pathogen rendered three strains of mice partially resistant to infection with vaccinia virus (VV) but not to lymphocytic choriomeningitis virus (LCMV). VV-challenged BCG-immune mice developed a striking splenomegaly and elevated CD4 and CD8 T-cell responses by 6 days postinfection (p.i.). However, resistance to VV infection could be seen as early as 1 to 2 days p.i. and was lost after antibody depletion of CD4 T-cell populations. BCG-but not LCMV-immune memory phenotype CD4 T cells preferentially produced gamma interferon (IFN-␥) in vivo after VV challenge. In contrast, LCMV-immune CD8 T cells preferentially produced IFN-␥ in vivo in response to VV infection. In BCG-immune mice the resistance to VV infection and VV-induced CD4 T-cell IFN-␥ production were ablated by cyclosporine A, which inhibits signaling through the T-cell receptor. This study therefore demonstrates CD4 T-cell-mediated heterologous immunity between a bacterium and virus. Further, it poses the question of whether BCG immunization of humans alters resistance to unrelated pathogens.

The non-specific effects of vaccines

“…There is unequivocal evidence from studies in animals that infections and vaccines alter the subsequent response to unrelated (heterologous) infections 1–6 21 44. Randomised trials suggest that measles vaccine reduces mortality from infections other than measles by 47% (95% CI 23% to 63%) in girls (table 1) and that BCG reduces mortality from diseases other than tuberculosis by 25% (95% CI 6% to 41%) in girls and boys combined (table 3).…”

“…There have been many studies of the non-specific effects of BCG in animals,11 21 and some of the mechanisms are understood 44. In the 1940s and 1950s, several controlled trials were performed in children in the USA and the UK to evaluate the effect of BCG vaccination on mortality.…”

Simultaneous infection with gammaherpes and influenza viruses enhances the host immune defense

“…It can lead to enhanced or diminished protective immunity and can alter immunopathology. In previous studies it was found, that infections with Bacillus Calmette-Guérin (BCG), IAV, LCMV, mouse cytomegalovirus and Pichinde virus all confer a level of protective immunity against vaccinia virus (Selin et al, 1998;Mathurin et al, 2009;Chen et al, 2003).…”

Vaccination and heterologous immunity: educating the immune system

“…79,80 This is similar to results in adult mouse models of heterologous immunity where it was demonstrated that BCG-immune mice were more resistant to vaccinia virus infection and that this resistance was mediated by IFNg-producing CD4 T cells. 81 Interestingly, Steenhuis and others showed that in children, by 18 months of age, immunization with BCG resulted in lowered numbers of children with eczema, a Th2-immune mediated disease. 82 …”