What makes Mycobacterium bovis such a problem?

Part II: Mycobacterium bovis, the English bovine tuberculosis outbreak, badgers and the culling debate.

Mycobacteria represent a large group of incredibly tough environmental bacteria that have in many cases adapted to be successful pathogens, which are classically very slow in killing their victims. One such mycobacterial disease is tuberculosis, caused by Mycobacterium tuberculosis, which is probably one of the oldest described diseases known to man. The hardy organisms have been found to be responsible for the deaths of Egyptian Pharaohs and the disease was often described as “White plague” in the middle ages. This was because heavily infected victims cough up an off white frothy substance, packed with M. tuberculosis and blood, called sputum. M. tuberculosis is remarkable in another way; as one of the most significant diseases humans passed to animals (rather than vice versa), in this case to cattle some 6 to 10 thousand years ago. The product of that jump over the species barrier was Mycobacterium bovis, which is today one of the most prevalent and significant pathogens of domestic and wild animals.

Why mycobacteria are such good pathogens

Mycobacteria represent an ultimate trade off between factors that make them highly difficult to kill for the host immune system and yet heavily restrict their own growth. This means that mycobacterial diseases are classically slow taking months or years to cause disease, are usually very debilitating and go completely undetected until it’s too late. Arguably the most important factor for the success of mycobacteria such as M. bovis as a pathogen is their amazingly tough cell wall.

Unlike other bacteria, the cell walls of mycobacteria are heavily composed of lipids that make them extremely tough. This tough wall makes it very difficult for cells of the immune system, like macrophages to break down the organism and M. bovis will survive quite well in microphages. Despite the advantage of higher protection such an unusual cell wall does come with some key trade offs. Their cell wall is not very permeable to many substances, giving the microbe a tougher time acquiring nutrients and the organism spends large amounts of energy synthesizing fatty acids.

Another unusual characteristic of mycobacteria is that they have only one or two 16S ribosomal RNA cistrons (compared to 7 in Escherichia coli). This contributes to the immensely slow growth of mycobacteria as ribosomes are essential in the rapid production of new proteins, so the inability to rapidly produce more ribosomes means the microbes maximum growth speed is pretty much capped. Comparing E. coli to M. bovis is rather like comparing a Ferrari with a broken down jalopy with one wheel missing.

It can take (for example) up to two weeks to grow mycobacteria to useful numbers for an experiment in a lab, compared to one day for E. coli. Although seemingly a stupid idea for the organisms survival initially, it does have two key advantages. It’s very useful against antibiotics that target the ribosome, as only one mutation can instantly make the organism resistant and prevent any real damage. Additionally a slow growth rate makes it very easy to assess a changing situation and adapt to the new situation without committing to an ‘all or nothing’ style scenario.

Finally, mycobacteria are easily aerosolized (so they spread between individuals easily), are taken up by macrophages rapidly and are fairly drug resistant (largely due to their cell wall and their slow metabolism). Worst of all, the large presence of environmental reservoirs of mycobacteria makes an effective vaccination difficult. The current BCG vaccine (Bacillus of Calmette-Geurin) has often been found to be ineffective in providing immunological protection and part of the suspected reason for this is ‘confusion’ of the immune system by environmental mycobacteria.

M. bovis provides a particular threat to farm economies

Perhaps the most prominent reason for the problem with eliminating M. bovis from cattle is the large host range that M. bovis exhibits. As well as cattle and to a lesser extent humans the organism is known to infect badgers, possums, deer, sheep, ferrets, oxen, buffalo, lions and wildebeest. This immensely large host range makes control of the disease almost impossible in areas where there is a wild animal reservoir that can prevent elimination of M. bovis. The large host range of M. bovis is almost certainly a result of its wide metabolism and the fact most mammalian immune systems are pretty similar.

Elimination of this disease in some places of the world, such as New Zealand and the United Kingdom that has animal reservoirs is hence very difficult. Making things worse, the suspected animal reservoirs are also found in close association with cattle that are susceptible to infection. The important question that needs to be answered is what role do these vectors play in the transfer of M. bovis to cattle? Join us back this week for part III: What evidence suggests badgers infect cattle with M. bovis?

References

Primm P., C.A. Lucero and J.O. Falkinham III (2004). Health Impacts of Environmental Mycobacteria. Clinical Microbiology Reviews, 17:1,98–106.

Salyers A.A. and D.D. Whitt (2002). Bacterial Pathogenesis: A molecular approach 2nd edition. ASM press, Chapter 19:291-310.

Previous post by me about the origins of M. bovis. The quoted paper in particular.