scholarly journals STUDIES ON NATURAL IMMUNITY TO PNEUMOCOCCUS TYPE III

1936 ◽  
Vol 64 (2) ◽  
pp. 281-305 ◽  
Author(s):  
Morris F. Shaffer ◽  
John F. Enders ◽  
Chao-Jen Wu
Keyword(s):  
Bacterial Species ◽  
Early Period ◽  
Avirulent Strain ◽  
Polymorphonuclear Leucocytes ◽  
Natural Immunity ◽  
Experimental Conditions ◽  
Animal Body ◽  
Type Iii ◽  
Antigenic Properties ◽  
Pneumococcus Type

The results which have been presented show that under the conditions of artificial cultivation at 37°C. definite differences exist between two smooth strains of Pneumococcus Type III both of which are highly virulent for mice by the intraperitoneal route, but which may be sharply distinguished in their virulence for rabbits. These differences consist in the size of the fully developed intact capsule and the interval of time required for its loss. The somewhat smaller capsule of the avirulent strain, well formed and easily demonstrable during the early period of growth, diminishes quickly, while the large capsule of the strain virulent for rabbits is retained for a considerably longer period. Closely correlated with the time at which this reduction of capsule occurs is the appearance of changes in the surface properties of the bacteria which are revealed by a shifting of the range of acid agglutination, susceptibility to clumping in anti-R serum and ingestion by normal adult human polymorphonuclear leucocytes and serum. Since it has been shown that these alterations as growth continues, result in a loss of characteristics which distinguish the strictly type specific, fully capsulated pneumococcus and ultimately lead to a state temporarily approximating that of the completely avirulent R form, and since under the experimental conditions they are inaugurated sooner, advance more rapidly and are more complete in the rabbit avirulent organism, we believe that they may partly account for difference in rabbit virulence of the two strains. In the following paper an attempt has therefore been made to correlate this behavior in vitro with the events attendant upon inoculation into the animal body. The studies of Clark and Ruehl (16), Henrici (17), Bayne-Jones and Adolph (18) and others have demonstrated a marked increase in the size of the bacterial cell associated with the early phases of growth. These authors have dealt chiefly with noncapsulated rod forms and even Clark and Ruehl who included cultures of various cocci do not make reference to variations in capsule size. Recently Seastone (19) has called attention to the large volume occupied by young capsulated streptococci. Similarly we have found that increase and decrease of Pneumococcus Type III volume appears to be due largely to the formation of capsule in young cultures and its subsequent loss as the organisms age. Because of the relatively great proportion of capsule in comparison with soma, a greater disparity exists between the volume of young and old pneumococci than that found by those who have studied bacteria lacking this structure. Of interest in connection with our observations are those of Preisz (20) on the nature of the capsules of virulent anthrax bacilli and strains attenuated by cultivation at 42.5°C. The latter produced soft, rapidly dissolving capsules while such structures in the former were characteristically firm and were retained by the bacilli for longer periods. This worker also noted in confirmation of the earlier work of others, that the capsules of B. anthracis are lost during the course of growth in serum media and in the subcutaneous tissues of the susceptible mouse. We have demonstrated that the R variants derived under the same conditions from the two smooth strains of Pneumococcus Type III reveal certain characteristics by which they may be distinguished from each other in respect to cell and colony morphology, growth in broth, as well as growth at 41°C. (cf. Paper I). By employing the method of Griffith, these two R variants have been induced to revert to the S form. Following the injection into mice of the various possible combinations of living R variant and the killed S organisms of either rabbit virulent or avirulent strain, as well as very large numbers of the R variant alone, S forms emerged which in their various attributes, notably that of virulence for rabbits, resembled the original smooth strain from which the particular R variant involved was dissociated. The function of the smooth killed organisms in the process of transformation appeared to be only that of a stimulus toward reversion to the S. They apparently play no rôle in determining the virulence or the growth properties of the resulting S form. These observations indicate that the factors involved in virulence are conditioned by stable physiological properties peculiar to the individual strain and that although temporarily inactive during the R state, they are again resumed unaltered upon the transition to the S form. They serve also to reemphasize the fact, apparent from several studies but perhaps not sufficiently realized, that the R variants of the pneumococcus, even though obtained under the same conditions from the same type but from different strains, may vary definitely in their various attributes. Finally, they strongly suggest that the degree of virulence of a given strain of a bacterial species may be determined not only by its ability to multiply in the environment of the host and to synthesize certain substances of definite chemical and antigenic properties, but also by the capacity to elaborate these in greater or lesser degree and under the conditions of parasitism within the animal body to maintain them in contact with the soma of the cell in such state that they afford an efficient barrier to the defensive mechanisms of the host.

scholarly journals STUDIES ON NATURAL IMMUNITY TO PNEUMOCOCCUS TYPE III

1936 ◽  
Vol 64 (2) ◽  
pp. 307-330 ◽  
Author(s):  
John F. Enders ◽  
Morris F. Shaffer ◽  
Chao-Jen Wu
Keyword(s):  
Virulent Strain ◽  
Blood Stream ◽  
The State ◽  
The Body ◽  
Polymorphonuclear Leucocytes ◽  
Natural Immunity ◽  
Phagocytic Cells ◽  
Fixed Tissue ◽  
Type Iii ◽  
Pneumococcus Type

Among the experimental findings reported in this paper to which we wish to give particular emphasis are the following: 1. The results which follow the intravenous injection into rabbits of two strains of Pneumococcus Type III of different degrees of virulence vary with the state of the capsule. Thus when this structure is completely developed both remain in the blood. A culture of either strain begins to become susceptible to the blood-clearing mechanism contemporaneously with the onset of capsular degeneration and the initiation of other concomitant changes at the surface of the organism (cf Paper II), which occur much earlier with the less virulent strain. 2. When, in either case, removal from the blood stream occurs, this is effected by the phagocytic cells of the body. There is no suggestion that a new or unknown mechanism is involved. The greatest share of the burden is borne by the fixed phagocytic cells of the liver and spleen, and to a less extent by those of the lung and bone marrow. Nevertheless, it has been demonstrated that the polymorphonuclear leucocytes may also participate. 3. Phagocytosis by the leucocytes of the normal animal either in intro or in vivo has been observed only at such a time as the capsule has become impaired. Ingestion of the organisms by the fixed tissue cells appears also to be effective only under the same condition and is accordingly observed with much younger cultures of the less virulent strain. 4. Following their removal from the blood and their accumulation within the fixed phagocytes of the organs, destruction of most of the cocci proceeds within 2 to 4 hours. Both strains are destroyed provided they are in the state favorable to phagocytic attack. 5. Evidence has been presented which indicates that just as in vitro, so in a local area of inflammation within the body, aging with attendant capsular loss and increasing susceptibility to phagocytosis may take place. 6. With organisms from either strain a variable period of lag follows their injection into the blood stream, even when they are introduced in a state of active multiplication and complete encapsulation. 7. Differences in virulence for rabbits of two strains of Pneumococcus Type III do not imply that this animal possesses a defensive mechanism which is absent in other species, since it has been possible to demonstrate similar differences when the organisms are injected intravenously into mice. This fact indicates that the factors determining the degree of virulence of these strains are to be sought in the organisms themselves, rather than in the kind of host.

scholarly journals STUDIES ON NATURAL IMMUNITY TO PNEUMOCOCCUS TYPE III

1936 ◽  
Vol 64 (3) ◽  
pp. 425-438 ◽  
Author(s):  
John F. Enders ◽  
Chao-Jen Wu ◽  
Morris F. Shaffer
Keyword(s):  
Elevated Temperatures ◽  
Blood Stream ◽  
The Body ◽  
Intravenous Route ◽  
Natural Immunity ◽  
Phagocytic Cells ◽  
Adjuvant Effect ◽  
Type Iii ◽  
Essential Components ◽  
Pneumococcus Type

Since there is no evidence for the occurrence of type specific antibody in the normal rabbit and since, as we have shown, the Pneumococcus Type III whether avirulent or virulent is not removed from the blood stream or destroyed when the capsule is intact, the following factors which have been revealed in the course of our work appear to represent certain essential components, if not the complete mechanism, upon which the natural immunity of the rabbit against this organism depends. (a) The elevation of the body temperature after intravenous infection to 41°C. or thereabouts and its maintenance for varying periods. (b) The ability of the phagocytic cells, both fixed and mobile, to attack any cocci which have become vulnerable through the deterioration of capsular integrity. (c) The adjuvant effect of an antibody, reacting with the somatic C carbohydrate, which enhances the phagocytosis of such organisms as no longer possess a completely intact envelope. Conversely, the varying degrees of virulence for rabbits observed among Pneumococcus Type III strains are based upon: (a) differences in the ability of the organisms to multiply at the elevated temperatures encountered in the infected host. Strains markedly susceptible to the harmful influence of this factor fail to induce a generalized fatal infection. Not all "thermo-resistant" strains are highly virulent, however, and these may contrast sharply with regard to (b) size of the capsule and the ease with which it is impaired or completely lost. The capsules must be maintained intact for a sufficient time until multiplication of the organisms can proceed to such a degree that death of the host results. Avirulent strains even when capable of growth at 41°C. appear to be unable to satisfy this requirement. The differences in virulence of various strains apparently conditioned by these factors are not limited solely to the case of the rabbit, since for at least two strains similar differences in virulence have been shown to exist when the intravenous route of infection is employed in mice.

scholarly journals Stimulants to Bacterial Variation

1924 ◽  
Vol 23 (3) ◽  
pp. 317-346 ◽  
Author(s):  
Arthur Eastwood
Keyword(s):  
Bacterial Cell ◽  
Bacterial Species ◽  
Special Kind ◽  
Animal Origin ◽  
Natural Immunity ◽  
Susceptible Animal ◽  
Animal Body ◽  
Daughter Cells ◽  
Wide Range

1. Immunity cannot be completely explained by antigen-antibody reactions, even if the term ‘antibodies’ be made sufficiently elastic to include various obscure properties which are exhibited, in vivo, in the actively immune animal. Various other factors have to be considered. One of these is the influence of stimuli upon the vital capacities of bacteria.2. Transmissible bacterial autolysis appears to be due to a stimulus acting upon the growing bacterial cell and leading to the splitting off of a certain number of daughter-cells which are non-viable, and consequently undergo autolysis.3. Transmissible autolysis is not due to a stimulus sui generis but is no more than a particular incident in the general phenomena of bacterial variation.4. The secretions of bacteria in pure culture may stimulate, control, or retard their growth and may lead to the production of variants.5. When introduced into the animal body, bacteria encounter stimulants of animal origin which may be either favourable or unfavourable to their growth and are to be distinguished from the stimulants attributable to the bacteria themselves.6. One aspect of the differences between natural immunity and natural susceptibility may be interpreted as due to differences in the stimuli inherent in the particular animal species and to consequent differences in their effects upon the particular bacterial species.7. Similarly, when no better explanation is available, the acquired immunity (active or passive) of a susceptible animal may be interpreted as a change of the animal's stimulant action from one which was favourable (or indifferent) to the growth of a bacterium to one which is adverse, i.e., a stimulant to the reproduction of daughter-cells which are non-viable in the animal body.8. Leucocytes are one of the sources of material possessing two kinds of properties, viz., (a) stimulant action on the growth capacities of cells (both bacterial and animal) and (b) enzyme action on the constituents which living and dead cells possess in common. The older researches on the characters of leucocytic extracts were occupied with (b), though they may occasionally be linked up with (a), since there are some indications that their leucocytic material was also acting as „lytic substance.”9. In some cases it must remain, for the present, an open question whether demonstrable antibacterial action is attributable to some more or less obscure enzymes or to what I have termed „stimuli.”10. A stimulus may be a substance which is also an antibody, and its stimulative properties may be highly specific. But it would be absurd to assume that for each special kind of stimulative effect there is a special and chemically distinctive kind of stimulus. Both stimuli and antibodies usually possess a wide range of different combining affinities which cannot be explained on the „mosaic” theory that each different combination is due to the presence (in the stimulus or antibody) of a different chemical group.11. A stimulus, as distinct from a food, causes the bacterial cell to function in a particular way but is not incorporated as part of the structure of the cell. This convenient distinction, however, does not imply that there is necessarily a sharp line of demarcation between a stimulus and a food.

scholarly journals STUDIES ON NATURAL IMMUNITY TO PNEUMOCOCCUS TYPE III

1936 ◽  
Vol 64 (1) ◽  
pp. 7-18 ◽  
Author(s):  
John F. Enders ◽  
Morris F. Shaffer
Keyword(s):  
Natural Immunity ◽  
Type Iii ◽  
Pneumococcus Type

1. A correlation appears to exist between the failure of certain strains of Pneumococcus Type III to grow at 41°C. and their lack of virulence for rabbits. 2. It is likely that the capacity to grow at 41°C.—an attribute constantly but not exclusively associated with strains of Pneumococcus Type III virulent for rabbits—is a prerequisite, but not the sole factor, in determining their virulence for these animals.

PNEUMOCOCCUS TYPE III PNEUMONIA. AN ANALYSIS OF 500 CASES

1936 ◽  
Vol 191 (3) ◽  
pp. 305-318 ◽  
Author(s):  
RUSSELL L. CECIL ◽  
NORMAN PLUMMER ◽  
MARSH McCALL
Keyword(s):  
Type Iii ◽  
Pneumococcus Type

scholarly journals THE INACTIVATION OF BIOLOGICALLY ACTIVE PROTEINS, AND THE VIRUS OF WESTERN EQUINE ENCEPHALOMYELITIS BY PERIODIC ACID

1948 ◽  
Vol 87 (5) ◽  
pp. 445-455 ◽  
Author(s):  
Walther F. Goebel ◽  
Peter K. Olitsky ◽  
Arturo C. Saenz
Keyword(s):  
Biological Activity ◽  
Immune Globulin ◽  
Periodic Acid ◽  
Biologically Active ◽  
Chemical Alteration ◽  
Type Iii ◽  
Pathogenic Action ◽  
Pneumococcus Type

The action of periodic acid on two biologically active proteins, crystalline ribonuclease and pneumococcus Type III immune globulin, and on the virus of Western equine encephalomyelitis has been studied. The biological activity of the two proteins and the pathogenic action of the virus were destroyed by the reagent; the specific antigenicity of the immune globulin was retained, however, but that of the equine virus was lost. The bearing of these reactions on the chemical alteration of the respective substances has been discussed.

scholarly journals STUDIES ON PNEUMOCOCCUS IMMUNITY

1923 ◽  
Vol 38 (2) ◽  
pp. 149-161 ◽  
Author(s):  
Russell L. Cecil ◽  
Gustav I. Steffen
Keyword(s):  
Subcutaneous Injection ◽  
Type Ii ◽  
Subcutaneous Injections ◽  
Type Iii ◽  
Type Iv ◽  
Pneumococcus Type

1. Three subcutaneous injections of Pneumococcus Type II vaccine confer on monkeys a complete immunity against experimental Pneumococcus Type II pneumonia. A similar protection can be bestowed on monkeys against Pneumonococcus Type IV pneumonia by three subcutaneous injections of a vaccine prepared from the same strain of pneumococcus. 2. The subcutaneous injection of monkeys with three doses of Pneumococcus Type III vaccine confers a complete immunity against this type in only 50 per cent of cases (four out of eight monkeys vaccinated). 3. In spite of the immunity induced in monkeys by three subcutaneous injections of Pneumococcus Types II, III, and IV vaccine, specific protective bodies against the homologous types are not demonstrable in their serums when the vaccine is so administered.

scholarly journals THE INHIBITION OF SURFACE PHAGOCYTOSIS BY THE CAPSULAR "SLIME LAYER" OF PNEUMOCOCCUS TYPE III

1949 ◽  
Vol 90 (1) ◽  
pp. 85-96 ◽  
Author(s):  
W. Barry Wood ◽  
Mary Ruth Smith
Keyword(s):  
Methylene Blue ◽  
Electron Microscope ◽  
Large Volume ◽  
Logarithmic Phase ◽  
Type Iii ◽  
Slime Layer ◽  
Virulent Type ◽  
Specific Polysaccharide ◽  
Pneumococcus Type

Five strains of type III pneumococcus have been shown to possess wide capsular slime layers during the logarithmic phase of growth in serum broth. The slime layer stains metachromatically with methylene blue and can be visualized under the electron microscope as a fuzzy halo which extends well beyond the surace of the capsule proper and causes centrifugates of the organism to be of extremely large volume. This outer capsular structure is most readily demonstrated in vivo and in nutrient broth containing glucose and serum. It disappears from the surface of the cell with aging of the culture, and is easily removed by dilute alkali, alcohol, and heat. Exposure of slime-covered type III pneumococci to homologous antibody and to type III polysaccharidase reveals that the slime layer contains the same type-specific polysaccharide that is present in the rest of the capsule. From a type III strain producing a prominent slime layer an intermediate mutant has been isolated which forms small non-mucoid colonies on blood agar and possesses a relatively small capsule with a barely discernible slime layer. The wide slime layer protects virulent type III pneumococci from surface phagocytosis. Whenever the type III cells lose their broad slime layer, whether from aging of the culture, from mutation, from exposure to injurious chemicals, or from the action of type III polysaccharidase, they become susceptible to phagocytosis by the surface mechanism. Once phagocyted the type III pneumococci are promptly destroyed, even in the absence of antibodies.

scholarly journals Further Comments on the Causation of Malignant Disease

1928 ◽  
Vol 28 (1) ◽  
pp. 9-32
Author(s):  
Arthur Eastwood
Keyword(s):  
Latent Period ◽  
Malignant Disease ◽  
De Novo ◽  
Animal Cell ◽  
Systemic Resistance ◽  
Natural Immunity ◽  
Active Growth ◽  
Animal Body ◽  
Chronic Irritation ◽  
Living Organisms

Invisible infective agents may be divided into: (1) true, ultramicroscopic, living viruses, which do not arise de novo and, so far as is known, are not ubiquitous; (2) transmissible infective agents which arise de novo and are propagated through living cells, but are not themselves living organisms; (3) stimulants to variation which arise de novo, are not transmissible, and are not living organisms.Class (1) is not represented in malignant disease. “Bacteriophage” is a representative of class (2); very probably the infective agent of fowl sarcoma comes under the same category, and possibly some important human diseases of doubtful aetiology. There is no satisfactory evidence that mammalian malignant disease is related to class (2); its causation, according to the “chronic irritation” theory, must be attributed to influences comprised within class (3).The stimulants to variation in class (3) depend for their effectiveness upon the unstable energy of living matter. The changes which they produce are “biological” in the sense that they are changes of chemical constitution which could not be obtained without the aid of vital processes.Regulation of normal growth in the animal body means regulation of the cell's facilities for obtaining energy. I think it is misleading to regard it as a forceful restraint (or stimulus) upon the cell's inherent capacity for unlimited growth.The assumption, borrowed from “natural immunity” towards bacteria, that there is in the animal body a natural principle which destroys frequently occurring foci of incipient malignancy is also unsubstantiated and misleading.During the latent period, certain cells, which subsequently grow into a neoplasm, lose their capacity to respond to inhibitory systemic influences. This change is brought about by local and not by systemic causes.As regards the special class of tumour derived from cells which have been displaced in foetal life, long residence in an abnormal situation does not appear to be equivalent to the ordinary latent period; but it may have had the effect of increasing their susceptibility, so that, if exposed to chronic irritation, the cells would more readily lapse into the latent period predisposing to malignancy.It is known that the various tissues of the animal body differ in their degree of susceptibility to the precancerous change. This is a cellular characteristic; so also is the difference in the susceptibility of one animal as compared with another. It is not a question of difference in a hypothetical humoral property of “systemic resistance.”On the termination of the latent period by a fresh stimulus to proliferation, certain cells commence active growth and are incapable of responding to systemic inhibitory influences. These conditions seem sufficient for the origin of an innocent neoplasm. But something more is required to explain malignancy, because the malignant cell is essentially different from the cells in a benign tumour.About the actual cause of the change to malignancy one can only offer conjectures. I have suggested a way in which the change may possibly be produced through the agency of the local endothelium and the autogenous formation of antibodies.On taking a broad view, the change into the malignant variant is not something unique; equally remarkable changes are to be found in the properties of bacteria. In both cases the facts have to be accepted, at present, without satisfactory explanation of the conditions which gave rise to them. One finds with bacteria that degradation or “roughness” may be a phase preparatory to the acquirement of new properties, just as the degradation of cells in the latent period seems to be a requisite preparation for acquiring the new property of malignancy. But the actual steps involved in the change from a bacterial saprophyte to an invasive parasite are as difficult to understand as are the processes involved in the conversion of a normal animal cell into its malignant variant.Throughout the study of cancer it is very desirable to maintain a clear distinction between cause and effect. For example, the enzymes peculiar to cancer are not the cause of cancer but the effect of the biological change which produced the cancerous cell.

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