Cord factor (alpha,alpha-trehalose 6,6'-dimycolate) inhibits fusion between phospholipid vesicles.

Abstract

The persistence of numerous pathogenic bacteria important in disease states, such as tuberculosis, in humans and domestic animals has been ascribed to an inhibition of fusion between the phagosomal vesicles containing the bacteria and lysosomes in the host cells [Elsbach, P. & Weiss, J. (1988) Biochim. Biophys. Adia 974, 29-52; Thoen, C. 0.(1988)J. Am. Vet. Med. Assoc. 193, 1045Assoc. 193, -1048. In tuberculosis this effect has been indirectly attributed to the production of cord factor (a,a-trehalose 6,6'-dimycolate). We show here that cord factor is extraordinarily effective at inhibiting Ca2+-induced fusion between phospholipid vesicles and suggest a mechanism by which cord factor confers this effect. These findings are likely to be important in our understanding of the pathogenesis and treatment of many diseases of bacterial etiology.

Arrest of Mycobacterial Phagosome Maturation Is Caused by a Block in Vesicle Fusion between Stages Controlled by rab5 and rab7

“…Furthermore, bacterial toxins affecting small GTP-binding proteins via ADPribosylation or transfer of glucose from UDP-glucose have been identified in C. botulinum (57,58) and Clostridium difficile (59). Based on the local effects within MPC and the more generalized effects of M. bovis BCG preinfection on subsequently formed LBC, it is possible that some mycobacterial (51,52,60,61) or other putative activities directly or indirectly interfere with the regulation of membrane sorting processes.…”

Single dose of a vaccine based on DNA encoding mycobacterial hsp65 protein plus TDM-loaded PLGA microspheres protects mice against a virulent strain of Mycobacterium tuberculosis

“…Owing to the prominence of the trehalose hydrophilic portion, there is an increase in hydration around the vesicle, providing a steric blockage to cellular fusion phenomena. 29 In the same fashion, TDM entrapped into microspheres could be released into the phagosome, blocking or delaying the fusion of lysosome, avoiding DNA degradation. Since there is no clear evidence about how DNA crosses over barriers such as nuclear membranes, phagosomes, and endosomes, TDM could allow more time for DNA to do this.…”

CD3+ cells transfer the hypersensitive granulomatous response to mycobacterial glycolipid trehalose 6,6′-dimycolate in mice

“…However, recent findings suggest that the pathophysiological response to TDM manifests itself in multiple ways. TDM involvement in toxicity, inhibition of phagosomal maturation, and primary and hypersensitive granulomatous responses is only now being fully appreciated (Bloch, 1950;Guidry et al, 2004;Hunter et al, 2006;Indrigo et al, 2002;Lima et al, 2001;Seggev et al, 1984;Spargo et al, 1991;Yamagami et al, 2001;Yarkoni & Rapp, 1978). The lipid-rich cell walls of mycobacteria have proven to be an important defence mechanism aiding their survival within the host.…”