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LspA inactivation in Mycobacterium tuberculosis results in attenuation without affecting phagosome maturation arrest

¹ Institut für Medizinische Mikrobiologie, Universität Zürich, Gloriastrasse 32, CH-8006 Zurich, Switzerland
² Molecular Infection Biology, Research Center Borstel, D-23845 Borstel, Germany
³ Nationales Zentrum für Mykobakterien, Gloriastrasse 30, CH-8006 Zurich, Switzerland

Correspondence
Peter Sander
psander{at}immv.uzh.ch

The success of Mycobacterium tuberculosis depends on its ability to survive within host macrophages. Here, M. tuberculosis avoids the acidic, hydrolytically competent environment of the phagolysosome by arresting phagosome maturation. Having shown previously that a M. tuberculosis mutant deficient in lipoprotein signal peptidase (LspA) is strongly attenuated in vivo in a mouse model of infection, we now studied putative mechanisms involved in attenuation of the lspA : : aph mutant at a cellular level. In this work we investigated the ability of the mutant to interfere with two host defence mechanisms, i.e. Toll-like receptor (TLR)2-dependent immune response and phagosome maturation. While mycobacterial lipoproteins have been reported to trigger a TLR2 signalling pathway critical for innate immune responses, we found that growth control of the lspA : : aph mutant was independent of TLR2. In addition, the lspA : : aph mutant arrested phagosome maturation to an extent similar to that of the wild-type, as measured by lysosomal-associated membrane protein 1 (LAMP1) co-localization and intraphagosomal pH. These observations demonstrate severe attenuation even in the presence of arrested phagosome maturation, and point to a role for the early phagosome in growth restriction of the M. tuberculosis lspA mutant.

Four supplementary figures showing kinetics of in vivo growth of M. tuberculosis wild-type and mutants in spleen over a 108 day period, restoration of wild-type growth in IFN--activated BMDM by complementation of M. tuberculosis lspA, growth of wild-type, mutant and complemented strains in Middlebrook 7H9-ADC, and TNF- secretion by BMDM in response to infection with wild type and mutant strains, are available with the online version of this paper.