Thiamin bypass: an unusual phenomenon in the Lyme disease pathogen Borrelia burgdorferi
The story behind "Lyme disease spirochete Borrelia burgdorferi does not require thiamin"
Thiamin (also known as vitamin B1) was first discovered by Christiaan Eijkman who received the 1929 Nobel Prize in Medicine. Since then, thiamin biosynthesis and utilization have been studied extensively in different organisms across three kingdoms. Due to its vital role in central carbohydrate metabolism and amino acid biosynthesis, thiamin is believed to be essential for all living organisms.
A new work from our group, out last week in Nature Microbiology (doi: 10.1038/ nmicrobiol.2016.213), challenge this dogma by providing unequivocal evidence that Lyme disease pathogen Borrelia burgdorferi (Bb) dispenses with the use of thiamin, which has not been previously reported in any organisms. Bioinformatics studies reveal that Bb lacks thiamin biosynthetic pathway, thiamin uptake system and thiamin salvage pathway, and, most importantly, has no thiamin pyrophosphate-dependent enzymes (image on the left). Along with the bioinformatics analysis, thiamin and its derivatives could not be detected in Bb cells. In addition, depletion of thiamin and its derivatives with BcmE, an enzyme that degrades thiamin, has no impact on Bb in vitro growth and in vivo survival during its enzootic infectious cycle. Follow up studies reveal that the level of thiamin and its derivatives in Ixodes scapularis ticks, the enzootic vector of Bb, is extremely low, suggesting that by dispensing with use of thiamin Borrelia species and perhaps other tick-transmitted bacterial pathogens, are uniquely adapted to survive in tick vectors before transmitting to mammalian hosts.
Lyme disease is the most common vector-borne disease in North America and Europe, and has become a great threat to public health. The CDC estimates that more than 300,000 people are diagnosed annually with Lyme disease. Currently, no vaccine is available for Lyme disease prevention. Compelling evidence suggests that Bb is a very unusual pathogen in terms of its biology and pathogenicity, and our studies further underscore this notion. Given the vital role of thiamin in microbial metabolism, dispensing with thiamin presents a seemingly insurmountable evolutionary challenge for an organism. To overcome this challenge, Bb must have acquired alternate metabolic pathways. Bb lacks a TCA cycle, oxidative phosphorylation, or any pathways for de novo biosynthesis of carbohydrates, amino acids, or lipid and it has evolved a unique mechanism to bypass lack of thiamin-dependent enzymes. For instance, Bb lacks pyruvate dehydrogenase (PDH) and pyruvate oxidase (POX), two thiamin pyrophosphate-dependent enzymes. Thus, it cannot generate acetyl-CoA through pyruvate oxidation. Instead, it converts pyruvate to lactate using a lactate dehydrogenase (LDH) and produces acetyl-CoA from metabolism of acetate that is mediated by acetate kinase (ACK) and phosphate acetyltransferase (PAT) (image on the right). This unique carbon metabolic pathway may well be the key adaptation that allows Bb to survive in the tick vector in response to thiamin deficiency.
The paper is published in Nature Microbiology here: http://www.nature.com/articles/nmicrobiol2016213