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

Abstract

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.