Multiplication and Survival of Tubercle Bacilli in the Organs of Mice

Pierce, Cynthia H.; Dubos, René; Schaefer, Werner B.

doi:10.1084/jem.97.2.189

Cited by 115 publications

(68 citation statements)

References 12 publications

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“…boris (Vall~e strain) was used in all experiments. In general, the maintenance of the culture of tubercle bacilli and the infection of mice were carried out by techniques previously described (10). The culture, transferred weekly in tween albumin liquid medium, was replaced every 4 months by a new isolate of Vall~e obtained from the lungs of experimentally infected mice, in order to insure maximum virulence.…”

Section: Methodsmentioning

confidence: 99%

A Genetic Study of Susceptibility to Experimental Tuberculosis in Mice Infected With Mammalian Tubercle Bacilli

Lynch

Pierce-Chase

Dubos

1965

The Journal of Experimental Medicine

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A study has been made of the genetic aspects of the difference between two inbred strains of mice (C57B1/6 and Swiss) in response to experimental infection with mammalian tubercle bacilli. Males and females, 4 to 6 weeks of age were inoculated intravenously with 0.2 ml of a 1/50 culture dilution of Mycobacterium tuberculosis var. bovis (Vallée strain) grown in tween albumin medium. Mean survival time for C57B1 animals was 28.1 ± 0.6 days and for Swiss, 55.3 ± 0.6 days postinfection. The characteristic survival time of the two strains was reversed in mice receiving a smaller infective dose. The age of mice at the time of inoculation also affected the results of infection: both C57B1 and Swiss, inoculated at 12 months of age, died at the same rate, but when inoculated at older ages, C57B1 survived slightly longer. Bacteriologic studies demonstrated that there was no significant difference between the two mouse strains with regard to the numbers of viable units of tubercle bacilli recovered from various organs during the 2 week period following infection with a 10–3 culture dilution of Vallée. Moreover, the standard infective inoculum (1/50 culture dilution) did not activate corynebacterial pseudotuberculosis in C57B1 mice, a strain known to be latently infected with Corynebacterium kutscheri, rapid multiplication of tubercle bacilli occurred, but no corynebacteria were recovered. When C57B1 and Swiss strains were crossed, survival tests after infection with the standard inoculum demonstrated that mice of the F1 generation were more resistant than either parent. Whether the overdominance was due to a new combination of parental genes for resistance or to heterosis was not determined. The increased litter size of the F1 mice, an evidence of increased vigor, supports the view that heterosis was involved. In backcrosses to the resistant strain (Swiss), survival time gradually became stabilized at approximately the parental level. In the 1st backcross to the susceptible strain (C57B1), survival times fell into two classes indicating segregation of genes, with perhaps dominance of genes from the Swiss. After repeated backcrosses to C57B1, mice of the 4th backcross generation had a survival time essentially the same as that of the original parental strain. On the basis of having obtained progeny characterized by the original parental susceptibilities after genetic tendencies had been intermingled by crossbreeding, it was concluded that hereditary factors influenced the response of mice to experimental infection with M. tuberculosis. The number of genes was not determined.

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Section: Methodsmentioning

confidence: 99%

A Genetic Study of Susceptibility to Experimental Tuberculosis in Mice Infected With Mammalian Tubercle Bacilli

Lynch

Pierce-Chase

Dubos

1965

The Journal of Experimental Medicine

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“…with quarter-strength Ringer's solution. The organs were then disintegrated by insertion of a Teflon grinder (Pierce, Dubos & Schaefer, 1953) revolving at 5300 r.p.m., this stage being carried out in a safety cabinet fitted with an extraction fan and an ultra-violet sterilizing lamp. No intact host cells could be seen in films of suspensions treated in this way.…”

Section: Methodsmentioning

confidence: 99%

The growth of micro-organismsin vivowith particular reference to the relation between dose and latent period

Meynell

1958

J. Hyg.

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The growth of Salmonella typhimurium in mice was studied by performing viable counts on pooled viscera and, in the case of fatally infected mice, by determining the relation between size of dose and mean death time. The results suggested that this system conformed to a general model which postulates (a) that the organisms causing the response (death in the present experiments) increase in vivo at a rate which is constant for all doses, and (b) that the response is certain to occur when their number reaches a constant figure. It follows that logarithm of dose (for doses > 1 ED50) should be linearly related to mean latent period (the interval between inoculation and response). A search of the literature showed that this relation was observed in many reported infective systems.The interpretation of the observations on partially resistant mice (LD50 = 102.5−106 organisms) was not straightforward for the hypothesis of independent action (Meynell & Stocker, 1957) states that only a random fraction of the inoculum usually initiates each response. Multiplication of this fraction is considered to cause a reduction in host resistance so that other organisms surviving in vivo began to increase in numbers and to contribute to the fatal infection. The observations showed that this could well occur as (i) the counts on all mice, whether fatally infected or not, increased exponentially for 2–3 days after inoculation; (ii) the growth curves of fatally infected mice showed exponential increase of the whole inoculum as postulated; and (iii) the length of the death time was found to be determined by the growth of the whole inoculum and not by the predicted random fraction. The viable count per fatally infected mouse at the time of death was approximately constant at 108.75 organisms. There was no evidence that the course of the infection was influenced by organisms which may have been killed in vivo as the requirements of the model were satisfied by the observed behaviour of the viable organisms alone. The rate of increase of organisms in a fatally infected animal was found to be less, the greater the LD50 of the host; which suggested that the degree of host resistance was determined by successive random events occurring after inoculation.The latent period/log dose curve provides a new test of the hypothesis of independent action, since this predicts that most responses to doses equal to or less than 1 ED50 are each initiated by only one inoculated organism. Hence, the latent period should become approximately constant at such doses. This was found to be so in the present experiments.The authors are grateful to the Medical Research Council for meeting part of the expenses of this work by a grant to G. G. M. They also wish to acknowledge the help of Dr W. R. Bryan, Dr B. Mandel, Dr D. B. W. Reid and Dr G. T. Stewart who provided unpublished data.

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“…An important new piece of information revealed by the present study is that the superior anti-BCG resistance of Bcg r mice during the first 20 days of infection is also expressed in their lungs, the organs most susceptible to infection with virulent Myco. tuberculosis [12]. On the other hand, Bcg r mice showed no preimmunity resistance advantage over Bcg s mice in their livers and kidneys.…”

Section: Discussionmentioning

confidence: 91%

Mice that carry the resistance allele of the Bcg gene (Bcgr) develop a superior capacity to stabilize bacille Calmette–Guérin (BCG) infection in their lungs and spleen over a protracted period in the absence of specific immunity

Medina

North

1996

Clinical and Experimental Immunology

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SUMMARYIn mice, natural resistance to infection with BCG is under the influence of an autosomal gene designated Bcg. It is shown here in agreement with others that mice that possess the dominant resistant allele of the gene (Bcg r ) are more capable than mice that possess the susceptible recessive allele (Bcg s ) at restricting the growth of BCG in their lungs, as well as in their spleens, during the first 20 days of infection. It is shown, in addition, that in the absence of specific immunity the resistance difference between Bcg r and Bcg s mice became much more pronounced as infection progressed beyond day 20. Whereas T celldepleted Bcg r mice developed a capacity after day 20 to cause infection in their lungs and spleens to stabilize and plateau for a least 40 days, T cell-depleted Bcg s mice were unable to prevent infection from progressing in these organs. On the other hand, both types of T cell-depleted mice were capable of causing infection to plateau in their livers and kidneys. Moreover, this T cell-independent mechanism of resistance was essentially abolished in all organs in which it was expressed by treating the mice with hydrocortisone. In the lungs of immunocompetent Bcg s mice, failure to stabilize infection was associated with heavily infected macrophages and failure to contain BCG at original sites of infection.

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Multiplication and Survival of Tubercle Bacilli in the Organs of Mice

Cited by 115 publications

References 12 publications

A Genetic Study of Susceptibility to Experimental Tuberculosis in Mice Infected With Mammalian Tubercle Bacilli

A Genetic Study of Susceptibility to Experimental Tuberculosis in Mice Infected With Mammalian Tubercle Bacilli

The growth of micro-organismsin vivowith particular reference to the relation between dose and latent period

Mice that carry the resistance allele of the Bcg gene (Bcgr) develop a superior capacity to stabilize bacille Calmette–Guérin (BCG) infection in their lungs and spleen over a protracted period in the absence of specific immunity

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