Phenotypically distinct clinical isolates of Mycobacterium tuberculosis are capable of altering the balance that exists between the pathogen and human host and ultimately the outcome of infection. This study has identified two M. tuberculosis strains (i.e. HN885 and HN1554) among a bank of clinical isolates with a striking defect in phagocytosis by primary human macrophages when compared with strain Erdman, a commonly used laboratory strain for studies of pathogenesis. Mass spectrometry in conjunction with NMR studies unequivocally confirmed that both HN885 and HN1554 contain truncated and more branched forms of mannose-capped lipoarabinomannan (ManLAM) with a marked reduction of their linear arabinan (corresponding mainly to the inner Araf-␣(135)-Araf unit) and mannan (with fewer 6-Manp residues and more substitutions in the linear Manp-␣(136)-Manp unit) domains. The truncation in the ManLAM molecules produced by strains HN885 and HN1554 led to a significant reduction in their surface availability. In addition, there was a marked reduction of higher order phosphatidyl-myo-inositol mannosides and the presence of dimycocerosates, triglycerides, and phenolic glycolipid in their cell envelope. Less exposed ManLAM and reduced higher order phosphatidylmyo-inositol mannosides in strains HN885 and HN1554 resulted in their low association with the macrophage mannose receptor. Despite reduced phagocytosis, ingested bacilli replicated at a fast rate following serum opsonization. Our results provide evidence that the clinical spectrum of tuberculosis may be dictated not only by the host but also by the amounts and ratios of surface exposed mycobacterial adherence factors defined by strain genotype.Tuberculosis causes immense morbidity and mortality worldwide (1). The causative bacterium, Mycobacterium tuberculosis, is phagocytosed by and grows within host macrophages. Our recent studies (2, 3) have led to the conclusion that M. tuberculosis is adapting to the human host by cloaking its cell envelope molecules with terminal mannosylated (i.e. Man-␣(132)-Man) oligosaccharides that resemble the glycoforms of mammalian mannoproteins (4). These molecules include the abundant mannose-capped lipoarabinomannan (ManLAM), 2 lipomannan (LM), and phosphatidyl-myo-inositol mannosides (PIMs), which play a central role in M. tuberculosis immunopathogenesis (5). ManLAM and higher order PIMs (i.e. PIM 5 and PIM 6 ) have exposed Man-␣(132)-Man nonreducing termini that engage the mannose receptor (MR) on human macrophages during phagocytosis (3, 6, 7) and dictate the intracellular fate of M. tuberculosis by regulating formation of the unique vesicular compartment in which M. tuberculosis survives within the human host (2, 3).To date, studies of M. tuberculosis phagocytosis have focused largely on use of the common laboratory virulent strains Erdman and H 37 R v and the attenuated strain H 37 R a . Recently, banks of clinical isolates have been characterized in an attempt to link epidemiology and genetic analyses in order to better understand...

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