Biochemical Challenge of Microbial Pathogenicity

BACTERIOLOGICAL REVIEWS, Sept., 1968, p. 164-184 Vol. 32, No. 3 Copyright c 1968 American Society for Microbiology Priiited in U.S.A. Biochemical Challenge of Microbial Pathogenicity H. SMITH Depcartmenit of Microbiology, The Uuiiversity, of Birminiglhamii, Bir-iniglhami1, Eniglantd INTRODUCTION.. ..... 164 STUDIES OF BACTERIAL PATHOGENICITY ..... .... 165 Difficulty of'Inivestigati,ig Biochenmicail Mechanlisms of PathogenlicitY. 165 Studies of Bacterial Behavior In Vivo.... 165 ASPECTS OF BACTERIAL PATHOGENICITY REQUIRING ATTENTION- 166 Intitiationl of Inlfectioni 166 Growth and Multiplication In Vivo. 166 Aggressive Activity........... 167 Inhihitors of blood atnd tissie hbactericidins............ 167 Inihibitors of' the actioni of plipagocvtes............................ 168 (i) Iihibitors of conltact. ..... 168 (ii) l liihi tor-s of intgestionl . 168 (iii) Inihibitors of initralcellutlair hactericidins: prom2otioni of intracellular growvth. 169 (iv) Repercussionu of ietertogeiueity of pliagocytic finIuctiOni Oni microbial requiire- ments for caggressitis. 170 Toxic Activity....................... 171 Toxi,is of overridling importalnce in disease 171 Toxi,Is which aire siglnificanlt bhlt niot the o;uly factors respoursible.for dlisecase. 171 Toxilns produced ini vitro hblt of ioiknown importance ill disea.se. 171 Toxic effe(cts in vivo ofhacteria which aippear to produice lo rolevait to-viii ifi vitro 171 (i) Toxilns revealedbl vsticlyinig hbacteria in more iiactuiral enviro.iciltsWi 172 (ii) Rolev of hypersensitiviity ili toxic maniJe*stations of disesn.A. 173 Relcatioli o' Protective Anitigens to Virule,ice Factors... 174 Biochenicall Bases of Host anid Tissuce Specificity,.... 174 Role ofucireaise ili kidney, localizations ofCoryniehacteriuon rena(ile and(i Proteuis mirabilis. 175 Role of ervthritol in the tissute specificity of the brlucellae 175 UNANSWERED QUESTIONS RELATING TO THE PATHOGENICITN' OF VIRUSES, FUNGI, PROTOZOA, AND MALIGNANT CELLS. 176 Viriuses. 176 Fui.igi. .. 178 Protozoa.. .... .. ...................... ................ 178 Ca,icer Cells . .... ..... .. 179 WHY STUDY BIOCHEMICAL MECHANISMS OF MICROBIAL PATHOGENICIT'I......... 179 LITERATURE CITED .. ... .. .. ..... 180 INTRODUCTION diphtheria, gas gangrene, and botulism) and the During this century, man's success in control- endotoxins of gram-negative bacteria have been ling infectious disease has been dramatic. Al- studied in detail (49. 93), and the chemistry of though diseases such as cholera, trachoma, ma- bacterial substances which inhibit the action of laria, and influenza are still major problems in phagocytes is known (17, 33), many of the mech- some areas, many infectious diseases can now be anisms of bacterial pathogenicity are still not controlled-by vaccination, by drugs, and, most clear. Thus, the bacterial products responsible effectively, by strict public health measures. This for many disease syndromes remain obscure, and success in controlling infectious disease has been little if anything is known about the biochemical paralleled and promoted by the equally successful bases for communicability, for survival and recognition and description of the causative growth of certain bacteria within phagocytes, for microorganisms-bacteria, protozoa, fungi, or host and tissue specificities, and for long-term viruses. In contrast, the biochemical mechanisms microbial survival in chronic diseases. These whereby these microorganisms produce disease phenomena are not confined to bacterial diseases; are still obscure. What is known is confined they occur in even less understood infections almost entirely to bacterial diseases, and even caused by other microbes. here information is scanty. Although the toxins In this review, it is not intended to describe the responsible for the classical toxemias (tetanus, most recent investigations of well-known bacterial 164 VOL. 32, 1968 MICROBIAL PATHOGENICITY 165 toxins and substances which prevent ingestion by tions, those of host tissues under microbial phagocytes, nor to catalogue further differences attack, are not physiological but pathological exhibited in vitro between virulent and avirulent and continually changing (110, 116); at present, strains of the same pathogenic species. There is they are not reproducible in vitro. Changes in recent literature on these subjects (17, 33, 49, 93). metabolism would therefore be expected when The intention here is to point out gaps in our bacteria from infected animals are cultured in present knowledge of the biochemistry of micro- vitro (116), and such changes have been demon- bial pathogenicity and to suggest possible meth- strated (see below). In turn, these changes in ods for filling them. Particular attention will be metabolism could affect virulence. Bacterial directed to areas where there are now some in- virulence is usually reduced by subculture in dications of the direction future research should vitro, because bacteria lose the capacity to form take. The review is restricted to microorganisms one or more of the full complement of virulence pathogenic for animals. Because bacteria have attributes manifested in infected animals (110, received more attention in virulence studies than 116). Also, apparent virulence factors might be other microorganisms, they are dealt with more produced in vitro which are not formed, and extensively than the other pathogenic microbes. therefore not relevant, in vivo (116). Thus, However, if only to emphasize the dearth of bacteria grown in vitro can be incomplete or mis- knowledge in this field, the mechanisms of patho- leading with regard to the possession of virulence genicity of viruses, fungi, protozoa, and cancer attributes; this, coupled with the fact that bac- cells are discussed briefly in the context of con- terial behavior in vivo is not easily examined (see cepts applied to bacterial pathogenicity. The near below), forms the essence of the difficulties en- synonymous terms pathogenic and virulent will countered in studies of pathogenicity. be used as suggested by Miles (55), i.e., the former in respect to species and the latter in respect to Studies of Bacterial Behavior In Vivo degrees of pathogenicity of strains within species. Obviously, virulence factors can be produced in laboratory cultures if the requisite nutritional STUDIES OF BACTERIAL PATHOGENICrrY conditions are known. This has already been Pathogenic bacteria are peculiarities. The accomplished in studies of classical bacterial great majority of bacteria are harmless and often toxins and some antiphagocytic substances. How- beneficial. Obviously, pathogenic bacteria have a ever, for problems of pathogenicity which have chemical armory which enables them to invade a so far defied solution by conventional procedures host and produce disease. The problem is to with in vitro cultures, the above discussion sug- identify the weapons in this armory, their relative gests the study ofbacterial behavior in vivo. There importance, their chemical nature, and their mode are no vitalistic leanings behind this suggestion, of action on the host. This task is relatively simple merely a realistic assessment of an approach that when pathogenicity is determined by a single might reveal aspects of pathogenicity which later bacterial product easily produced in vitro, as in could be reproduced in vitro by appropriate diphtheria and tetanus. In the majority of infec- changes in cultural conditions. tious diseases, however, pathogenicity cannot be Information on bacterial behavior in vivo can related to a single microbial product and its bio- be gained in several ways. First, bacteria and their chemical bases are difficult to identify for the products can be separated directly from the dis- reasons given below. eased host for biological examination and for Difficulty of Investigating Biochemical chemical and serological study in vitro. Second, Mechanisms the behavior of organisms growing in vivo and of Pathogenicity their repercussion on the host can be examined, The main factor contributing to difficulty in either in the whole animal or in restricted tissues. this field is that virulence-the disease-producing The largest gaps in our knowledge of pathogenic- capacity of a population of microbes-is detect- ity occur here; detailed experimental pathology able only in vivo and is markedly influenced by and precise biochemical determinations are not changes in growth conditions due to selection of easily accomplished during infection, and only in types and to phenotypic change (84). a few cases have such studies supplemented the Most pathogenic species contain attenuated clinical pictures. Yet this information is vital, if strains which are often indistinguishable from mechanisms of pathogenicity are to be understood virulent strains in the available tests in vitro. Thus, and if relevant biological tests for potential viru- virulence is determined by small genetic differ- lence factors are to be designed. Not the least ences which may be fully expressed only under among the difficulties is the lack of suitable lab- the conditions ofthe test for virulence; i.e., during oratory animals in which human infections, e.g., growth in vivo. The decisive nutritional condi- bacillary dysentery and typhoid or meningo- 166 SMITH BACTERIOL. REV. coccal and gonococcal infections, can be truly surfaces are mixed, and only small numbers of simulated. Third, light can be shed on particular the pathogenic component may be present at the phases of microbial behavior in vivo by making start of

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