The Applicability of the Hypothesis of Independent Action to Fatal Infections in Mice given Salmonella typhimurium by Mouth

Abstract

SUMMARY:Mice were challenged by mouth with a suspension containing equal numbers of streptomycin-sensitive (Str-) and streptomycin-resistant (Str+) variants of Salmonella typhimurium. These variants were of equal virulence but the Str+ variant grew more slowly in Vivo than the Str-variant. The LD50 dose contained c. 5 x lo6 bacteria. Heart blood obtained from mice dying from many LD50 doses nearly always contained a great excess of the S t r variant, but blood from mice dying from less than one LD 50 dose contained either Str-, Str+, or a mixture of Strand Str+ variants. The appearance of the Str+ variant alone in the latter mice strongly suggests that these fatal infections were initiated by a very small number of organisms or possibly by a single organism. It is therefore concluded that these organisms were acting independently. In this system, it is likely that any bacterium which enters the tissues from the gut can initiate a fatal infection and that the probability of effecting such an entrance almost entirely determines the probability of an inoculated bacterium causing a fatal infection.The inoculation of a partially resistant host with many bacteria will often cause a fatal infection when the inoculation of one bacterium is very unlikely to do so. Of several hypotheses advanced to account for this phenomenon, the most satisfactory appears to be that described elsewhere (Meynell & Stocker, 1957) as the 'hypothesis of independent action' which postulates ( a ) that bacteria act independently after inoculation, and (b) a mean probability (1 > p > 0) per inoculated bacterium of initiating a fatal infection which is constant and unaffected by the number of bacteria inoculated. On this hypothesis therefore, there will always be a chance that the death of a host inoculated with many bacteria will be caused by the progeny of only one of the inoculated bacteria. Although many of the inoculated bacteria may multiply to some extent, the total toxic effect of their clones will never be fatal and will be negligible compared to the toxic effect of the clone descended from only one of the inoculated bacteria. The progenitor of this clone may thus be said to have initiated the fatal infection.A well-known alternative hypothesis is that of the minimal lethal dose which postulates that if the dose exceeds a critical minimum size, death is inevitable; while if it is smaller than the minimum, the host is certain to survive. Thus, a lethal dose might be supposed to saturate the host defences so that death follows the multiplication either of all the inoculated bacteria or of those bacteria not needed for saturation. I n the latter case, a fatal infection could * Present address.

Quantal and graded dose-responses of bluetongue virus: a comparison of their sensitivity as assay methods for neutralizing antibody

“…The finding in the present study that the character of the quantal responses to MBTV was the same at three successive readings even though the infectivity end-point gradually increased did not support the assumption that the response curves only reflected the distribution of virus particles in inocula. The data are, however, consistent with the more general version of the independent active theory (Meynell, 1957) which assumes that each particle has a probability P of initiating an infection. The different curves in Fig.…”

“…Therefore, the response lines could be considered parallel and differences in virus titres directly given by the displacements of the lines at the probit value 5. The probit slope values of all four responses were higher than those expected according to the independent active theory (Meynell, 1957) as under this theory the slopes should be equal to or less than 2.…”

“…Deviation of observed quantal dose-response curves from the theoretical oneor-more particle Poisson curve have, however, been observed in some virus-host systems (Bryan & Beard, 1940;Meynell, 1957;Fazekas de St Groth & Cairns, 1952;Armitage & Spicer, 1956). In particular, the slopes have been significantly less than that of the Poisson curve.…”

FliC-Specific CD4+ T Cell Responses Are Restricted by Bacterial Regulation of Antigen Expression

“…Therefore, it is not surprising that most Salmonella do not progress farther than the intestinal lumen but are contained by host defenses in the small intestine or are eliminated. Although high doses of Salmonella (many times the oral LD 50 ) have been used in experimental models of oral infection, near the oral LD 50 only a few bacteria successfully escape to systemic circulation and colonization (80,81). Based on the fact that FliC-specific CD4 ϩ T cell activation occurs only at intestinal sites after oral infection (40), together with our observations that Salmonella express FliC only during extracellular phase growth (Fig.…”

Identification of Helicobacter pylori Genes That Contribute to Stomach Colonization

“…While screening of very-high-complexity libraries in single animals has been possible for systemic infection models such as interperitoneal mouse inoculation with Salmonella enterica and Mycobacterium tuberculosis (13,55), colonization of mucosal surfaces often results in survival bottlenecks such that clones no longer show independent action (37,40). These bottlenecks presumably result from innate defenses of mucosal barriers.…”