Re TB Email received from Dr Ruth Watkins (virologist) January 28 2010
First of all a little note on Neospora caninum. This protozoan parasite is so similar to Toxoplasma gondii that it has only been realised recently that it is to dogs what Toxoplasma gondii is to cats.
The parasite has its sexual cycle in the gut of dogs as toxoplasma gondii does in cats, the definitive hosts. Dogs acquire the organism from eating raw meat as do cats, meat that contains the bradyzoites in cysts that reside in tissue (muscle or brain) for the rest of the life of a host who consumes the oocysts inadvertently, that have been released onto the pasture or soil in faeces from the infected definitive host. These secondary hosts can also be infected by eating the bradyzoites as in the case of humans consuming raw meat with T gondii bradyzoite cysts in the muscle cells.
Moredun are working on a vaccine for Neospora caninum that I presume will be rather similar to that for T gondii; a live vaccine given once in the heifer's life before she becomes pregnant for the first time - this is how the T gondii vaccine is used in sheep.
Thus this will prevent the primary infection during the pregnancy. N caninum does not infect humans whereas T gondii does. At least there is hope for cattle breeders for whom N caninum is an increasing problem.
I also believe that to tackle M bovis infection in cattle, the infection in other species in which it is endemic will also have to be addressed. Badger experts are implacable in their opposition but none are microbiologists and there their arguments fall down.
I used to believe that there was insufficient evidence - about 5 years ago - to justify the killing of badgers, the killing of which seemed like part of the inane response of DEFRA, Kill Kill Kill as they so horribly responded to the FMD epidemic , when of course there was a highly effective vaccine ready for use.
I have changed my mind about badgers now.
I have purchased 2 textbooks, vols one and two Handbook of Tuberculosis the main editor being Stefan Kauffman published by Wiley: Molecular biology and Biochemistry and Immunology and Cell Biology. There are 2 others on TB and AIDS and the clinical aspects of TB in humans.
They are very largely on M tuberculosis but much of the information will apply to M bovis and there is nothing like as much information on M bovis yet, and all there is will be driven by the understanding of M tuberculosis.
I think the subject of mycobacteria is fascinating and far more complex and interesting than virology! Mycobacteria are the most difficult bacteria to work on and understand. At least 2000 proteins are encoded and the bacteria can fine tune the expression of these to respond to their environment.
Our immune systems are not only manipulated by the organisms that infect us but also by dead mycobacteria in the environment that we consume in drinking water for instance.
If you look on Wikipedia there are 100s of species (very few are pathogenic for humans or cattle) and more I am sure to be found, probably largely by molecular methods I expect (a bit like papilloma viruses of warts for instance, these cannot be grown in culture).
With the sequencing of the genomes of a number of mycobacteria and a drive in understanding the gene expression and the function of protein families the subject is at an interesting juncture as has happened in the last 2 decades in virology driven by our search for understanding and control of the AIDS epidemic.
Mycobacteria are also a unique bacterial species in the way they cause disease, usually by a slow increase in the number of organisms present in an active infection, perhaps after years or decades of latency in the infected host. They maintain infection in an endemically infected population by trans- generation infection, parent to offspring or grandparent to offspring, again like virus infections such as many of the herpes viruses.
The only way to control the M bovis epidemic is to make sure that each infected animal infects less than one other on average.
This applies to cattle and badgers, the main endemic infected populations in the UK (what role other wildlife such as deer play, or for that matter cats inc. feral, sheep and other domestic animals not to forget humans in the continuation of the chain of infection is unquantifed). As this must cover generations due to latency and reactivation of M bovis it will not be quickly achieved.
In the book M bovis infection in Animals and Humans edited by Thoen Steele and Gilsdorf published by Blackwell, it is clear that skin testing cattle to eradicate M bovis has not been successful anywhere in the world where infection is endemic in another species of animal that overlaps environmentally with cattle.
Control of TB infection is approached very differently for humans and animals.
In the case of the great reduction in infection with M tuberculosis and M bovis that has been achieved in the 20th century in humans in developed countries no one approach was used to the exclusion of any other.
Many approaches were used as they came along and were recognised to offer a benefit. Prevention of infection in the first place by pasteurisation of milk and vaccination of babies and children with BCG (it has recently been shown this can prevent infection though its main effect was reducing serious mortal disease with little effect on chronic pulmonary infection. It has recently been decided that the BCG vaccine is not effective if given to people over the age of 35).
Later the screening of the population for active infection by various means (heaf tests and chest X rays for example) and the treatment of that active infection with multiple drug therapy, following up contacts of cases shown to be shedding the infection in the sputum to detect and treat any active infection in contacts, and perhaps above all the improvement in living conditions and nutrition that meant that families no longer all slept together in one bed or in the same room.
There has been no attempt to eliminate all infections such as detect and treat all latent infections in humans in the UK if indeed latent infections could all be detected and treated successfully (latent organisms can be refractory to anti-microbials)
In cattle, the attempt to detect all infections, latent, early and active in early and late stages in cattle and kill all these animals is doomed to failure because the detection of all infections does not occur and there is a continual adding of new cattle cases by exposure and infection from other infected species in addition to other infected cattle.
The skin test has been used for at least 120 years and though surprisingly good as a test does not detect all cases, either because of early infection or lack of T4 helper cell immunity, called anergy.
This also affects the gamma interferon test. This latter test is less robust and many animals give strong positive results to the Bovigam test that uses purified protein derivative, (a misnomer as it contains at least 200 proteins), because of their non-specific immunity by natural killer cells especially under 6 months of age (Dr Vordermeier gave me this information).
Thus culling is heavy in cattle herds all tested by the bovigam test and will include many uninfected animals.
The design of the test is also not satisfactory as a diagnostic test that done once is kill or live!
There is no clear separation of infected from uninfected animals.
The more heavily infected animals will have a low or negative gamma interferon test as they will an inconclusive or negative skin test.
Antibody testing and confirmation of specificity is missing from the repertoire to test cattle to detect the late stage active infections. Highly infectious shedding of large amounts of organisms in sputum, faeces, urine or milk could be detected by culture or PCR; PCR offers a shorter test time but not greater sensitivity in diagnosis because until the stage of infection is reached when heavy shedding takes place (often in an apparently well animal though a human in that situation might visit the doctor and complain of night sweats and weight loss) so little mycobacterium is shed if at all that PCR does not offer advantage over culture.
A DEFRA study on 1000 cattle post mortems detected no sputum positive cases indicating that late stage infection and shedding in sputum is not commonly reached in cattle, but it will of course occur as will late stage infected cattle shedding by other routes.
But these animals are relatively rare and not the only source of infection for cattle as mentioned above. The majority of progressing active infections in cattle are removed by the present screening programme.
Apart from late stage infection and a high load of M bovis that switches the immune system response of T4 helper cells off, what is called anergy, leaving only the ineffectual antibody response which is stimulated greatly as a result, and is then an immune marker of active infection, it is possible that a virus infection with bovine viral diarrhoea virus (BVD) in cattle may also switch off the immune response of T4 helper cells for several months.
This virus causes significant immune suppression and a low white blood cell count for several months after infection though this does recover. False negative skin tests may occur when this virus is circulating in the herd, so active infection could be missed but would be expected to be picked up in such individuals by the skin test the next year during the annual testing as presently in Wales when convalescence from BVD virus is complete (measles can have the same effect in humans).
It will be very difficult to prove by molecular biology that the chain of M bovis infection has passed from this badger to that cow by sequencing. This has been recently demonstrated for Staphylococcus aureus, MRSA, from patient to patient via contaminated environment or direct infection as a nucleotide difference accumulates once avery 6 weeks in staphylococci. The MRSA organism multiplies fast and is easily sampled by swabbing. Such proof of a virus passing from one person to another has been shown for at least 2 decades, such as HIV from a blood donor to a recipient, or that the chicken pox virus causing shingles is identical to the one that caused chicken pox in that same individual 20 or more years ago. Bacteria are so much larger than viruses that the technology capable of sequencing such large DNA molecules is only just coming on line, but doubtless this will be achieved for M bovis one day too, demonstrating a chain of infection.
I agree with the Welsh Assembly Government that all means possible must be used to control the M bovis epidemic in cattle and that includes enormously reducing the badger population in the hot spot areas (notice George Monbiot not extermination which cannot be achieved by the culling methods proposed).
Reduction of the population may be enough to decrease the chance of overlap of badgers and cattle. We cannot wait while every different possible method is tested individually and scientifically and compared with others, this is not what has been done for human infection and in the end is ridiculous. No one method will control M bovis infection.
Also the badger groups so desperately cling to the idea that trans species infection does not take place because we do not understand how it can, therefore badgers are exempt. There are probably pieces of evidence that suggest mechanisms of transmission by the respiratory route from contamination on the ground. One is the occurrence of a disease in humans called Melioidosis and caused by Burkholderai pseudomallei that are bacteria found in the soil in certain parts of the world, such as the Northern Territory of Australia. Rain apparently brings this bacteria to the surface and aerosolizes it so that an outbreak of infection in humans can be expected after rain. Infection can also be by other routes than the respiratory route, such as contact and ingestion.
Even without fully understanding or explaining everything, progress can be made in controlling infection, but as many angles as possible will have to be used. A highly effective vaccine to prevent infection with M bovis is I believe some time away though there are probably benefits to be had from the BCG vaccine, for example vaccinating uninfected young cattle, similarly badgers, to prevent some cases of late stage infection and so break the chain of infection. However, I doubt this alone could reduce the number of new cases to less than one on average from each infected individual. A therapeutic vaccine would be useful as well to prevent reactivation of latent infection or send an active infection back to latency, but that too is distant at present.
Very interesting but sad.