Nonspecific immunostimulant activities of synthetic trehalose-6,6'-diesters (lower homologs of cord factor)

Abstract

Mycobacterial cord factors (6,6'-diesters of trehalose with mycolic acids ranging from C8o to Cso) have been shown to protect mice effectively against infection with Klebsiellapneumoniae or with Listeria monocytogenes. Our present findings indicate that the low-molecular-weight cord factor of Corynebacterium diphtheriae (with corynomycolic acids ranging from C28 to C36) is equally active. Moreover, its synthetic analog (with synthetic C32 mycolic acid) has the same activity. Two lower synthetic 6,6'-diesters of trehalose with C22 acids, which are described here for the first time, as well as dipalmitate and a dioleate of sucrose, were found inactive. The synthetic C76 trehalose diesters, which are capable of enhancing nonspecific resistance to infection, increase the immune response in mice, even when injected in metabolizable oil. They induce in the injected paws an inflammatory process weaker and more transient than the natural cord factor.

Comparison of immunomodulatory activities in mice and guinea pigs of a synthetic desmuramyl peptidolipid triglymyc

“…In contrast, in mice FIA has been repeatedly shown to have the same activity as FCA (12,15), except in certain experiments in which synthetic antigens were administered (30). Other agents such as trehalose dimycolate can be adjuvant active in mice, but are inactive in guinea pigs (2,28).…”

Mycolic acids: structure, biosynthesis and physiological functions

“…276 Another example of non-speci®c antibacterial immunity induced by cord factor was also reported against Klebsiella pneumoniae and Listeria monocytogenes, 277 and this same group also reported similar results with challenges with these same bacteria with lowmolecular-weight cord factor of C. diptheria with corynomycolic acids ranging from C 28 to C 36 . 278 Induction of non-speci®c immunity by cord factor has also been reported against parasites. A single dose of 200 mg of TDM in aqueous suspensions protected mice against a challenge with Schistosoma mansoni 10 days later.…”

Underestimated Manipulative Roles of Mycobacterium tuberculosis Cell Envelope Glycolipids During Infection

“…TDM also seems to interlock host fibrinogen, the latter then acting as a cofactor for TDM biological effects (53). M. tuberculosis TDM's biological properties have been described to rely on the whole molecule (54,55), and these include ( Table 1) 65; being antigenic and having antitumoral activity (63, 66); having adjuvant properties being able to generate optimal antibody responses (67); inducing host cachexia, a typical symptom in active TB disease (68); and being able to trigger non-specific host immune responses against both parasitic and bacterial infections (63,(69)(70)(71)(72). TDM is also shown to undergo cyclopropane modifications on its mycolates (73), driving a TDM-dependent reprogramming of the macrophage global gene expression during infection in vitro and in vivo (74).…”