TB Research at UT-Houston – A review of cord factor: new approaches to drugs, vaccines and the pathogenesis of tuberculosis

Abstract

SUMMARY Tuberculosis remains a major threat as drug resistance continues to increase. Pulmonary tuberculosis in adults is responsible for 80% of clinical cases and nearly 100% of transmission of infection. Unfortunately, since we have no animal models of adult type pulmonary tuberculosis, the most important type of disease remains largely out of reach of modern science and many fundamental questions remain unanswered. This paper reviews research dating back to the 1950’s providing compelling evidence that cord factor (trehalose 6,6′ dimycolate [TDM]) is essential for understanding tuberculosis. However, the original papers by Bloch and Noll were too far ahead of their time to have immediate impact. We can now recognize that the physical and biologic properties of cord factor are unprecedented in science, especially its ability to switch between two sets of biologic activities with changes in conformation. While TDM remains on organisms, it protects them from killing within macrophages, reduces antibiotic effectiveness and inhibits the stimulation of protective immune responses. If it comes off organisms and associates with lipid, TDM becomes a driver of tissue damage and necrosis. Studies emanating from cord factor research have produced (1) a rationale for improving vaccines, (2) an approach to new drugs that overcome natural resistance to antibiotics, (3) models of caseating granulomas that reproduce multiple manifestations of human tuberculosis. (4) evidence that TDM is a key T cell antigen in destructive lesions of tuberculosis, and (5) a new understanding of the pathology and pathogenesis of postprimary tuberculosis that can guide more informative studies of long standing mysteries of tuberculosis.

Cord factors from atypical mycobacteria (Mycobacterium alvei, Mycobacterium brumae) stimulate the secretion of some pro-inflammatory cytokines of relevance in tuberculosis

“…Interest in cord factor remains open, mainly due to its adjuvanticity (Khader et al, 2007;Lima et al, 2001;Werninghaus et al, 2009) and its relation to the pathogenesis of tuberculosis (Hunter et al, 2009). Moreover, some aspects of the interaction of cord factor with antigen-presenting cells are being resolved, and recent findings have indicated that the scavenger receptors MARCO (macrophage receptor with collagenous structure) (Bowdish et al, 2009) and Mincle (a C-type lectin receptor) (Ishikawa et al, 2009;Schoenen et al, 2010) are involved in the recognition of this glycolipid.…”

“…Cord factor takes part in some specific pathological events of tuberculosis, such as formation of granulomas (the hallmark of primary tuberculosis) and caseation (Hunter et al, 2009), participating in the upregulation of the host lipid metabolism (Kim et al, 2010). It has been demonstrated that cord factor is secreted, together with other lipids, by macrophages infected with Mycobacterium bovis BCG (Rhoades et al, 2003) and that it is the most active lipid from a biological point of view (Geisel et al, 2005).…”

“…In M. tuberculosis, the immuno-modulatory activity of this glycolipid has been shown to rely on the presence of cyclopropane rings and keto and methoxy groups in its mycoloyl substituents (Dao et al, 2008;Rao et al, 2005Rao et al, , 2006. Most aspects of its activity have been attributed to an insoluble crystalline conformation consisting of linear arrays of trehalose head groups alternating with exposed hydrophobic mycolic acid domains (Hunter et al, 2009). Such conformation is acquired at water-hydrophobic interfaces, including oil, polystyrene and air, and would be adopted in physiological conditions at the granuloma (Hunter et al, 2009).…”

“…Most aspects of its activity have been attributed to an insoluble crystalline conformation consisting of linear arrays of trehalose head groups alternating with exposed hydrophobic mycolic acid domains (Hunter et al, 2009). Such conformation is acquired at water-hydrophobic interfaces, including oil, polystyrene and air, and would be adopted in physiological conditions at the granuloma (Hunter et al, 2009). It is understood that the biological properties of cord factor are independent of the dose but are related to the surface area of the molecule (Hunter et al, 2009).…”

“…Such conformation is acquired at water-hydrophobic interfaces, including oil, polystyrene and air, and would be adopted in physiological conditions at the granuloma (Hunter et al, 2009). It is understood that the biological properties of cord factor are independent of the dose but are related to the surface area of the molecule (Hunter et al, 2009).…”