Immunogenicity and Protection Induced by a Mycobacterium tuberculosis sigE Mutant in a BALB/c Mouse Model of Progressive Pulmonary Tuberculosis

• Published in: Infection and Immunity Vol. 78; no. 7; pp. 3168 - 3176
• Main Authors: Pando, Rogelio Hernandez, Aguilar, Leon Diana, Smith, Issar, Manganelli, Riccardo
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society for Microbiology 01.07.2010; American Society for Microbiology (ASM)
• Subjects: Animals; Bacterial diseases; Bacterial diseases of the respiratory system; Bacterial Proteins - genetics; Bacteriology; beta-Defensins - analysis; Biological and medical sciences; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Fundamental and applied biological sciences. Psychology; Human bacterial diseases; Infectious diseases; Interferon-gamma - analysis; Lung - chemistry; Lung - immunology; Male; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Nude; Microbial Immunity and Vaccines; Microbiology; Miscellaneous; Mycobacterium bovis; Mycobacterium tuberculosis; Mycobacterium tuberculosis - genetics; Mycobacterium tuberculosis - immunology; Mycobacterium tuberculosis - pathogenicity; Nitric Oxide Synthase - analysis; Polymerase Chain Reaction; Sigma Factor - genetics; Tuberculosis, Pulmonary - immunology; Tuberculosis, Pulmonary - microbiology; Tumor Necrosis Factor-alpha - analysis; Lung disease; Animal model; Respiratory disease; Pulmonary tuberculosis; Mycobacterial infection; Immunity; Infection; Immunogenicity; Mycobacterium tuberculosis; Mycobacteriales; Bacteriosis; Mycobacteriaceae; Bacteria; Actinomycetes; Mutation
• ISSN: 0019-9567; 1098-5522
• DOI: 10.1128/IAI.00023-10

Tuberculosis is still one of the main challenges to human global health, leading to about two million deaths every year. One of the reasons for its success is the lack of efficacy of the widely used vaccine Mycobacterium bovis BCG. In this article, we analyze the potential use of an attenuated mutant of Mycobacterium tuberculosis H37Rv lacking the sigma factor σE as a live vaccine. We have demonstrated that BALB/c mice infected by the intratracheal route with this mutant strain showed significantly higher survival rates and less tissue damage than animals infected with the parental or complemented mutant strain. Although animals infected with the sigE mutant had low bacillary loads, their lungs showed significantly higher production of the protective factors gamma interferon (IFN-γ), tumor necrosis factor alpha (TNF-α), inducible nitric oxide synthase (iNOS), and β-defensins than those of animals infected with the parental or complemented mutant strain. Moreover, we demonstrate that the sigE mutant, when inoculated subcutaneously, was more attenuated than BCG in immunodeficient nude mice, thus representing a good candidate for a novel attenuated live vaccine strain. Finally, when we used the sigE mutant as a subcutaneous vaccine, it was able to induce a higher level of protection than did BCG with both H37Rv and a highly virulent strain of M. tuberculosis (Beijing code 9501000). Taken together, our findings suggest that the sigE mutant is a very promising strain for the development of a new vaccine against tuberculosis.