Respiratory Disease in Rats and Mice

Infectious respiratory disease of rats and mice is the bane of their owners, be they scientist, fancier or pet keeper. It is the most common form of ill health in these animals and has many names. Traditionally fanciers have called it snuffles or asthma.

There are several infections that can cause it, both bacterial and viral but the commonest cause in adult rats and mice is Mycoplasma pulmonis.

There has been a mountain of research done on Mycoplasma infections in rats and mice because it is an economically important disease. Whatever you may think about the use of these animals in research, the fact remains that it is a multimillion pound industry and the modern quality assurance schemes have made research into anything that might interfere with results necessary. As far as possible I have sifted through the relevant research to present this overview on the current state of play. For those who are not interested in the science I suggest you skip to the conclusions. The understanding of this infection contains much immunology. I have included as little as possible so as not to confuse anyone. For those who can handle it I suggest you refer to the references for more detailed information.

Both rats and mice have probably evolved alongside their Mycoplasma and it is probable that, with the exception of barrier raised stock, all the rats and mice in the world are infected. The scientific community call the condition Murine Respiratory Mycoplasmosis or MRM and the symptoms have been recognised in laboratory rats since the turn of the Century. It was one of the major reasons for the development of Caesarian raised barrier stock, although this has not always been successful. Even with the most modern techniques, laboratory stock can sometimes still become infected.

The bacteria itself has no cell wall and is very sensitive to drying, heat, disinfectants etc and cannot survive for long outside the body. It is passed, one rat to another by aerosols exhaled from other rat or mouse lungs. An aerosol is a small droplet of liquid. Some aerosols are small enough to be inhaled directly into the lungs while other larger ones will remain in the upper respiratory tract. Aerosols are formed whenever liquid surfaces are broken and they are also exhaled from the respiratory tract.

With M. pulmonis only rats and mice carry it and they are the only species affected. They cannot catch it from rabbits, humans or other rodents. However, rats and mice can transmit it to each other. Other species have their own species of Mycoplasma but each one behaves a bit differently. Rats and mice become infected with respiratory Mycoplasma either at birth if the doe has vaginal infection or by inhaling infected aerosols later. After inhalation the organism will attempt to colonise the respiratory skin by attaching itself to the cell membrane. If it does not succeed then it will not be able to colonise. The lower the number of infecting organisms the longer it takes for the host to develop symptoms. (Razin and Barile 1985)

The organisms that do succeed in growing produce hydrogen peroxide which causes local tissue damage and a mitogen which stimulates lymphoid tissue in the lungs into growth. A mitogen is a chemical substance that stimulates cells into multiplying (that is undergoing mitosis). In this case the mitogen works on immune tissue in the lungs (called BALT or bronchus associated lymphoid tissue) that is responsible for producing lymphocytes- both the white cells responsible for producing antibodies (B lymphocytes) and T lymphocytes which have a range of functions, including cell mediated immunity and control of B lymphocytes. In addition the organism causes a chronic inflammatory response in the lungs (Razin and Barile 1985).

It does not cause symptoms in animals under three months old, if younger animals get a respiratory infection then it is not Mycoplasma but is more likely to be a virus such as Sendai or SDAV. Mycoplasma disease does not show symptoms until the infection has been well established for some time and considerable tissue changes have occurred. Therefore the idea that treating the rat as soon as the symptoms occur is somehow 'getting in early' is entirely false.

It is important to differentiate whether or not a rat has an upper or lower respiratory tract infection. In rats the disease tends to be chronic and even without treatment often the only symptom is rattling or noisy breathing or sneezing. Pneumonia is rare and most affected rats have upper respiratory tract disease only. Upper respiratory tract disease includes rhinitis (cold symptoms), sinusitis, labyrinthitis (middle ear disease). Lower respiratory disease includes conditions ranging from mild bronchitis to pneumonia and sometimes emphysema. A rat with noisy or snuffling breathing is unlikely to have lower respiratory tract disease if it is otherwise healthy, eating and in good condition. It is far more likely to have sinusitis. Although the infection does not usually kill rats by itself they are rarely successful in getting rid of it from their system. The reason for this is not known. In mice ,the disease tends to cause more severe disease including acute alveolar pneumonia, although if they survive this they will develop a chronic bronchopneumonia . The ones I have seen always look ill with laboured breathing and a rough, staring coat. Even if they are not culled they usually die anyway. Treatment in mice is even less successful than it is in rats due to the massive amount of lung damage that occurs. The reason that rats do not usually become as ill as mice is that in rats the bugs are rapidly cleared from the air sacs (alveoli) in the lungs by a type of white cell called a alveolar macrophage but in mice this does not happen, which is why they end up with severe pneumonia. In both rats and mice the condition is made worse by high levels of ammonia and a concurrent infection with Sendai virus or SDAV. It does not appear to matter in which order the infections are contracted. the reasons are not clear, although it had been thought that this was due to either infection preventing the hairs in the lungs (cilia) from beating and thus removing the particles from the lungs or interfering with the killing mechanism. This is now considered not to be very likely however, as rats with Sendai seem to be able to clear Mycoplasma from their lungs just as fast as those without (Nicholls et al 1992, Shanks and Percy 1995).

Most fanciers have been aware for a long time that some strains of rats and mice are more susceptible than others and the conventional wisdom is never to breed with stock that is showing symptoms. Any snuffling animals on the show bench are quickly disqualified and because of this selection it appears that in fanciers' rats at least; while they sometimes get mild sneezes or snuffles, rarely become ill with it. However pet shop rats, which are often intensively bred with little quality control due to the very poor money offered to the breeders are far more likely to become seriously ill. This is well known in laboratories as well, with some strains being extensively used by researchers because of their susceptibility. However, even among inbred strains the symptoms are very variable between individuals as are the amount of tissue changes. It has been shown that the animals which develop lower respiratory tract symptoms are those with the most pronounced growth of tissue. In resistant rats increases in lymphoid tissue reached maximum growth after 28 days, however in sensitive rats the tissue was still increasing in size after 120 days. Sensitive strains of mice and rats can even develop the disease when treated with extracts of the organism, without any live cells being present (Razin and Barile 1985). That this response is down to genetic control has been considered likely for many decades. In mice there has been some discussion about what gene is responsible but there is a reasonable amount of evidence that a single dominant gene is responsible. The same work does not seem to have been done in rats but it would seem logical that the disease in rats is also under genetic control (Cole 1983, Lai et al 1993).

Some strains of Mycoplasma are also more virulent than others. Virulence seems to be linked to their ability to stick on to the cell membranes in the lung, their ability to resist being eaten by the macrophages and the amount of damage they can do to the cilia (Howard and Taylor 1979).

In protection against Mycoplasma it is not clear how important production of antibodies is. While antibodies are produced against the Mycoplasma they do not appear to control the infection in the respiratory tract. However, they do appear effective in stopping the spread of the organism to other organs. In immunocompromised animals, widespread infection can occur but not in normal animals ( Denny and Taylor-Robinson 1972) . It has been shown in mice that mice with respiratory infection do not develop infections of the reproductive tract unless they are unable to produce T lymphocytes (Taylor-Robinson and Furr 1994). I have noticed in rats that those which develop uterine infections (due possibly to Mycoplasma) have not had snuffles and vice versa. The control of the infection in the lungs appears to be down to activation of the macrophages. If these are not activated then the disease is not controlled.

There has been some success with vaccines in laboratories, both ones made of formalin killed M. pulmonis and more modern recombinant ones. However, these were produced for research purposes only and there is no chance that they will ever be commercially available (Lai et al 1994).

The traditional antibiotic used to treat Mycoplasma with varying degrees of success is oxytetracycline, although chloramphenicol is better for labyrinthitis. These have been largely superseded by Baytril (enrofloxacin). A number of common antibiotics such as the penicillins, cephalosporins and newer Imipenems are of no use against this bug because unlike other bacteria the Mycoplasmas do not have a cell wall and this is what these antibiotics work on. However, no antibiotic can achieve a lasting cure and in many cases no improvement is seen. The reason for this seems to be that no antibiotic can be expected to kill or inhibit all the organisms, they rely on the host being able to mop up the remainder. In M. pulmonis infections this does not appear to happen, the reasons for this are not known as, unlike some other organisms which cause chronic disease this organism remains outside the cells. (It is likely however that the reason is that the macrophages which are the primary infection control cell in the lungs have not been activated and do not recognise the Mycoplasma as being a target). Also, the overgrowth of lymphoid tissue in the lungs contributes to the symptoms. Long term use of antibiotics, even where two or more are used, can still lead to resistance. This is not only in the Mycoplasma but also in other bacteria. Where treatment is not having much effect it should be discontinued to stop the spread of resistant organisms in the environment.

Conclusions:

There is no magic bullet for respiratory Mycoplasma in rats and mice, where animals develop symptoms it is best to consider that they have got it for life. In susceptible animals, especially mice , this means that they may develop pneumonia and probably die. In rats, most develop snuffles only and this does not appear to affect their quality of life, irrespective of whether or not they receive any antibiotics. Where chest infection occurs and the rat is a pet, long term treatment with antibiotics can be attempted, although resistance can be a problem. For the breeder, rats with symptoms are not an infection hazard to the rest of the stock - they have almost certainly got it anyway. However, you should never breed with a snuffling rat as, chances are you may breed this tendency in. All owners should be more careful to clean out regularly, rats produce lots of urine which soon turns to ammonia in dirty rat cages and high ammonia levels will make this condition worse. Using newspaper or tissues as a sole source of bedding is also to be discouraged.

References:

COLE, B. (1983) H2 gene control and biological activities of a T-cell mitogen derived from Mycoplasma arthritidis; a review. Yale Journal of Biology and Medicine 56, 605-612.

Denny F and Taylor-Robinson D. (1972) The role of thymus dependent immunity in M. pulmonis infections of mice. Journal of Medical Microbiology 5, 327-337.

GYLES and THOEN eds. (1986) Pathogenesis of bacterial infections in animals. Chap 25. Ames Iowa State University Press.

FURR PM, and TAYLOR-ROBINSON D, (1993) M. pulmonis infection of the murine oropharynx protects against subsequent vaginal colonisation. Epidemiology and Infection 111, 307-313.

HOWARD C and TAYLOR G (1979) Variations in the virulence of strains of M. pulmonis related to susceptibility to killing by macrophages. Journal of General Microbiology 114, 284-294.

LAI WC, BENNETT M et al (1994) Protection of mice against experimental infection. Vaccine 12, 291-298.

LAI WC, LINTON G et al (1993) Genetic control of resistance to M. pulmonis infection in mice. Infection and Immunity 4615-4621.

NICHOLLS P SHOEB T et al (1992) Pulmonary clearance of M. pulmonis in rats. Laboratory Animal Science 42, 454-457.

RAZIN and BARILE eds. (1985) The Mycoplasmas. Vol. 4, New York, Academic Press.

SHANK M and PERCY D (1995) Effect of time of exposure to rat coronavirus and M. pulmonis on respiratory tract lesions. Canadian Journal of veterinary research. 59, 60-66

TAYLOR-ROBINSON D and FURR DM (1994) Protection of mice against Vaginal colonisation by M. pulmonis. Journal of Medical Microbiology. 40, 197-201.