Mycobacterial cell wall contains various
lipids (
glycolipids and
phospholipids) to contribute to its hydrophobic property or
acid-fastness and these surface molecules contact with host cells in the early step of
infection. Among them,
cord factor (
trehalose 6,6'-dimycolate, TDM or CF) is the most ubiquitous component, which may be a key molecule for pathogenesis and immunity. Initially,
cord factor was isolated from a highly virulent strain of M.
tuberculosis which grows in the form of
serpentine cords, and showed a marked toxicity for mice when it was administrated intravenously. These observations led to the early hypothesis that cell wall components are related to virulence. However, later studies revealed that
cord factors were also found in other non-cord-forming mycobacterial species and other
mycolic acid-containing bacteria. Structural studies demonstrated that there were various mycoloyl
glycolipids differing in
carbohydrate moiety such as
glucose mycolate,
mannose mycolate,
arabinose mycolate and
fructose mycolate besides
trehalose mycolate in
acid-fast bacteria. Therefore, the interest has been focused to the structure-activity relationships of mycoloyl
glycolipid and to the mechanism of virulence for host animals. So far, it has been demonstrated that
cord factor showed lethal toxicity,
granuloma forming activity, adjuvant activity,
tumor regressing activity and non-specific
infection prevention activity in experimental animals. We have extended investigations further on the structure analysis and immunomodifying activities of
cord factor and related mycoloyl
glycolipids from various species of mycobacteria, nocardia, rhodococci and gordona, and demonstrated that the most activities were shown in
trehalose or
glucose esters, but not in
mannose,
arabinose or
fructose esters. Furthermore, it was shown that the longer chain-mycoloyl
glycolipids showed the higher toxicity and immunomodifying activities. In mice, in vivo,
cytokine inducing activities such as
IL-1, IFN-gamma,
TNF-alpha,
GM-CSF and
chemotactic factor were observed and in vitro,
TNF-alpha,
GM-CSF,
chemotactic factor,
complement, NO,
PGE2 inductions and
protein kinase C activation were demonstrated. Furthermore, recently, we have demonstrated that
cord factor induced a marked thymic
atrophy due to the cortical lymphocyte apoptosis before
granuloma formation in mice. It was also established that
cord factor showed antigenicity in mice and rabbits and human tuberculous patient sera contained specific
antibody (IgG) reactive against
cord factor. From above results,
cord factor seems to be one of the most potent
immunomodulators in the mycobacterial cell wall components pathologically and beneficially.