Molecular and supra-molecular structure related differences in toxicity and granulomatogenic activity of mycobacterial cord factor in mice.
To establish the structure biological activity relationship of cord factor (trehalose 6,6'-dimycolate, TDM), we compared the molecular or supra-molecular structure of TDM micelles with toxicity, thymic atrophy and granulomatogenicity in lungs and spleen of BALB/c mice. According to the difference in the mycolyl subclass composition, TDM was divided into two groups, one possessing alpha-, methoxy- and keto-mycolates in M. tuberculosis H37Rv, M. bovis BCG and M. kansasii (group A) and the other having alpha-, keto- and wax ester-mycolates in M. avium serotype 4, M. phlei and M. flavescens (group B), although mycolic acid molecular species composition differed in each group considerably. Supra-molecular structure of TDM micelle differed species to species substantially and the micelle size of TDM from M. bovis BCG Connaught was the largest. The highest toxicity was shown with TDM from M. tuberculosis H37Rv which possessed the highest amount of alpha- (47.3%) and methoxy-mycolates (40.8%), while TDM from M. phlei having the low amount of alpha-mycolate (11.6%) showed almost no toxicity with the given doses. The thymic atrophy was observed with TDM from group A, but not with TDM from group B. On the other hand, TDM from group B showed massive lung granulomatogenic activity based on the histological observations and organ indices. Taken together, group A TDM showed a wide variety of micelle sizes and specific surface areas, high to low toxicity and marked to moderate granulomatogenicity, while group B TDM showed smaller sizes of micelles and larger specific surface areas, lower toxicity but higher granulomatogenicity in lungs. Existence of higher amount of longer chain alpha-mycolates in TDM appeared to be essential for high toxicity and thymic apoptotic activity, whereas TDM possessing wax ester-mycolate with smaller sized micelles seemed to be less toxic, but more granulomatogenic in lungs in mice. Thus, the mycolic acid subclass and molecular species composition of TDM affect critically the micelle forms, toxicity and granulomatogenicity in mice, while the relative abundances and carbon chain length of alpha-mycolate affected the toxicity in mice.
Fujita
Yukiko
Y
Japan BCG Central Laboratory, 3-1-5 Matsuyama, Kiyose-shi, Tokyo 204-0022, Japan. y-fujita@bcg.gr.jp
Okamoto
Yuko
Y
Uenishi
Yuko
Y
Sunagawa
Makoto
M
Uchiyama
Takehiko
T
Yano
Ikuya
I
D000818:Animals; D017209:Apoptosis; D001284:Atrophy; D001835:Body Weight / Q000187:drug effects; D003311:Cord Factors / Q000737:chemistry* / Q000145:classification / Q000276:immunology / Q000633:toxicity*; D005260:Female; D006099:Granuloma / Q000139:chemically induced; D006651:Histocytochemistry; D008168:Lung / Q000473:pathology; D008214:Lymphocytes / Q000166:cytology; D051379:Mice; D008807:Mice, Inbred BALB C; D008823:Micelles; D023421:Models, Animal; D015394:Molecular Structure; D009161:Mycobacterium / Q000737:chemistry*; D013047:Specific Pathogen-Free Organisms; D013154:Spleen / Q000473:pathology; D013329:Structure-Activity Relationship; D013950:Thymus Gland / Q000473:pathology
D003311:Cord Factors; D008823:Micelles