The [Delta]fbpA mutant derived from Mycobacterium tuberculosis H37Rv has an enhanced susceptibility to intracellular antimicrobial oxidative mechanisms, undergoes limited phagosome maturation and activates macrophages and dendritic cells

• Published in: Cellular microbiology Vol. 10; no. 6; p. 1286
• Main Authors: Katti, Muralidhar K, Dai, Guixiang, Armitige, Lisa Y, Marrero, Carlos Rivera, Daniel, Sundarsingh, Singh, Christopher R, Lindsey, Devin R, Dhandayuthapani, Subramanian, Hunter, Robert L, Jagannath, Chinnaswamy
• Format: Journal Article
• Language: English
• Published: Oxford Hindawi Limited 01.06.2008
• ISSN: 1462-5814; 1462-5822
• DOI: 10.1111/j.1462-5822.2008.01126.x

Mycobacterium tuberculosis H37Rv (Mtb) excludes phagocyte oxidase (phox ) and inducible nitric oxide synthase (iNOS) while preventing lysosomal fusion in macrophages (MΦs). The antigen 85A deficient ([Delta]fbpA ) mutant of Mtb was vaccinogenic in mice and the mechanisms of attenuation were compared with MΦs infected with H37Rv and BCG. [Delta]fbpA contained reduced amounts of trehalose 6, 6, dimycolate and induced minimal levels of SOCS-1 in MΦs. Blockade of oxidants enhanced the growth of [Delta]fbpA in MΦs that correlated with increased colocalization with phox and iNOS. Green fluorescent protein-expressing strains within MΦs or purified phagosomes were analysed for endosomal traffick with immunofluorescence and Western blot. [Delta]fbpA phagosomes were enriched for rab 5, rab 11, LAMP-1 and Hck suggesting enhanced fusion with early, recycling and late endosomes in MΦs compared with BCG or H37Rv. [Delta]fbpA phagosomes were thus more mature than H37Rv or BCG although, they failed to acquire rab7 and CD63 preventing lysosomal fusion. Finally, [Delta]fbpA infected MΦs and dendritic cells (DCs) showed an enhanced MHC-II and CD1d expression and primed immune T cells to release more IFN-γ compared with those infected with BCG and H37Rv. [Delta]fbpA was thus more immunogenic in MΦs and DCs because of an enhanced susceptibility to oxidants and increased maturation.