Lipomannan (LM) and
lipoarabinomannan (
LAM) are mycobacterial
glycolipids containing a long
mannose polymer. While they are implicated in immune modulations, the significance of LM and
LAM as structural components of the mycobacterial cell wall remains unknown. We have previously reported that a branch-forming
mannosyltransferase plays a critical role in controlling the sizes of LM and
LAM and that deletion or overexpression of this
enzyme results in gross changes in LM/
LAM structures. Here, we show that such changes in LM/
LAM structures have a significant impact on the cell wall integrity of mycobacteria. In Mycobacterium smegmatis, structural defects in LM and
LAM resulted in loss of
acid-fast staining, increased sensitivity to β-
lactam antibiotics, and faster killing by THP-1 macrophages. Furthermore, equivalent Mycobacterium tuberculosis mutants became more sensitive to β-
lactams, and one mutant showed attenuated virulence in mice. Our results revealed previously unknown structural roles for LM and
LAM and further demonstrated that they are important for the pathogenesis of
tuberculosis. IMPORTANCE
Tuberculosis (TB) is a global burden, affecting millions of people worldwide. Mycobacterium tuberculosis is a causative agent of TB, and understanding the biology of M.
tuberculosis is essential for tackling this devastating disease. The cell wall of M.
tuberculosis is highly impermeable and plays a protective role in establishing
infection. Among the cell wall components, LM and
LAM are major
glycolipids found in all Mycobacterium species, show various immunomodulatory activities, and have been thought to play roles in TB pathogenesis. However, the roles of LM and
LAM as integral parts of the cell wall structure have not been elucidated. Here we show that LM and
LAM play critical roles in the integrity of mycobacterial cell wall and the pathogenesis of TB. These findings will now allow us to seek the possibility that the LM/
LAM biosynthetic pathway is a chemotherapeutic target.