OOZl-9681/78/0201-0067$02.00/O

J Chron Dis Vol. 31, pp. 67-72 0 Pergamon Press Ltd. 1978. Printed in Great Britain

Editorial

BACTERIAL ADHERENCE: FIRST STEP IN PATHOGENESIS OF CERTAIN INFECTIONS WILLIAM

P. REED* and RALPH

C. WILLIAMS,

JR.

Medical Service, Veterans Administration Hospital and The University of New Mexico School of Medicine, Albuquerque, New Mexico, U.S.A. (Received 21 April 1977) Abstract-Many bacterial infections such as streptococcal pharyngitis, shigellosis and gonococcal urethritis are caused by organisms which are located at a mucosal surface or which must penetrate into mucosa to cause disease. Recently accumulating evidence suggests that an initial step in this process is attachment of the organism to the mucosa. Such attachment initially results in colonization with or without subsequent invasion and inflammation. Certain bacterial species adhere more readily to epithelial cells from some locations than to cells from other locations, and it is the areas to which they adhere most tightly that seem the most likely to become infected. This phenomenon may help explain the selective tendencies of streptococci to cause pharyngitis and of coliform organisms to cause urinary tract infection. Also, the observation that enteroccocci and other streptococci adhere to cardiac valves appears to correlate with their high frequency as a cause of tndocarditis. The immune response to these organisms may be crucial in determining the range of microorganisms that can colonize and infect. Secretory IgA appears to prevent adherence of some bacterial species to epithelial cells, at least under in vitro experimental conditions. An improved understanding of the spectrum of such bacterial adherence as well‘as of its mechanism and the host’s immune response may lead to improved means for preventing infections that begin with attachment of bacteria to cells.

INTRODUCTION

The study of immunity to infection has clarified’ several ways by which the body recognizes and destroys infecting agents. The emphasis on killing or inactivation of invading microorganisms has tended tq overshadow our awareness of other aspects of immunity. However, one aspect that has been examined with increasing interest in recent years is the host’s influence over the organisms that colonize its external surfaces. We live surrounded by a sea of bacteria, and our health depends in no small measure on an ability to keep them from invading our tissues. Growth and spread of bacteria are promoted by numerous offensive devices which we counter with a variety of host defences including the ability of skin and mucus membranes to resist penetration by microorganisms. One feature that may aid bacteria in tissue invasion is an ability to adhere to epithelial surfaces. This ability enables microorganisms to colonize skin and mucus membranes, and in case of cutaneous injury large numbers may be available to penetrate directly into deeper tissues. A few organisms such as gonococci, shigellae and salmonellae may be capable of breaching even normal ‘mucosa, but logically as well as experimentally the first step in pathogenesis of these diseases appears to be attachment of the bacteria to epithelial cells [l-3]. There is some evidence available to support the concept that bacterial adherence may also be the first step in the pathogenesis of numerous other infections including pharyngitis [4], urinary tract infection [S, 61, bacterial endocarditis [7], infection of prothetic devices [S] and perhaps even dental caries [9]. The phenomenon of bacteria adhering to various surfaces as well as to themselves may be observed throughout our environment. For instance, oceans contain innumerable microorganisms, many of which are found adhering to organic and inorganic surfaces. * Request reprints from: William P. Reed, M.D., Veterans Administration Hospital, 2100 Ridgecrest Drive, SE. Albuquerque, NM 87108, U.S.A. 61 C.D.31/2--n

William

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P. Reed and Ralph

C. Williams,

Jr.

The rate of multiplication of organisms free in sea water is considerably lower than for organisms which are attached to a surface [lo]. The reason for this preferential growth on surface is not fully known, but it has been postulated that nutrients or growth factors may accumulate in such regions leading to a more hospitable microenvironment. The advantages gained by bacteria in attaching to epithelial surfaces of higher animals may be quite different, but the phenomenon is not unique or restricted to such hosts. Bacteria may attach through several different mechanisms as shown in Table 1. These mechanisms and other features of bacterial attachment will be discussed for several types of colonization and infection, DISEASES

RELATED

TO

ADHERENCE

Dental caries. A large share of the knowledge regarding the role of bacterial adherence in infections was gained through investigations into the role of bacteria in dental disorders, and of the host’s immunological interactions with these bacteria. Many investigators have contributed to our knowledge in this area, but much of the pioneering work was done by Gibbons and co-workers. Certain types of bacteria adhere to smooth enameled surfaces and may accumulate on teeth in microcolonies referred to as plaque. Acidic metabolic by-products of these organisms are largely responsible for dental caries. Although a number of organisms participate in plaque formation, the one most readily implicated as carriogenic is Streptococcus mutans which adheres to teeth through polysaccharides manufactured by both the organism and the host. S. mutans uses only sucrose to manufacture its adherent polysaccharide, dextran, and this may account for the well-known propensity of this particular sugar to promote cavities [Ill]. A diet low in sucrose may reduce cavity formation by limiting the attachment of these organisms to teeth, but many other carbohydrates may serve as substrates for the metabolic products that destroy enamel. These observations suggest that dental caries may be an infectious disease, and in fact Koch’s postulates have been fulfilled with dental caries in both conventional and germ-free animals [9, 121. Streptococci in the mouth. Studies by Gibbons and co-workers have shown that a number of streptococcal species may adhere to epithelial cells in the mouth, but that some of these species have a tendency to adhere selectively to epithelial cells from certain areas [13]. The organisms also have a tendency to colonize the areas of the mouth corresponding to their epithelial adhering capacities, with S. salivarius found predominantly on the dorsum of the tongue, S. mitus on buccal mucosa, and when the diet contains sucrose S. mutans is found on teeth. Differences also exist in the TABLE

Organisms

Type of infection

Streptococcus mutans

Dental

Staphylococcus epidermidis

Ventriculo-atria1 infections

A Streptococcus pyogenes

1.

Currently recognized of adherence

caries

Dextran containing polysaccharide manufactured from sucrose shunt

Mucoid substance organism

Pharyngitis

Lipoteichoic

Cystitis

and pyelonephritis

Pili

Intestinal organisms (E. coli, Shigella, Salmonella, Vibrio, other bacteria)

Diarrhea

or no disease

Neisseria gonorrhea

Urethritis

Pili

Enterococcus and Streptococcus viridans

Endocarditis

Unknown

Group Enteric

organisms

mechanism

Fimbriae,

.

eleborated

acid in fimbriae

flagellae

by

Bacterial adherence

69

ability of various organisms to adhere to cells from several animal species and appear to account for the different flora carried by these. species [14]. Group A beta hemolytic Streptococcus pyrogenes are well known for their tendency to cause pharyngitis, and have been shown to adhere to pharyngeal epithelial cells through small structures called fimbriae which project from the surface [4]. Fimbriae contain an antiphagocytic virulence’ factor known as M protein which was initially thought to participate in the binding to epithelial cells [4,15], but it now appears that binding is through lipoteichoic acid which is also present in fimbria [16,17]. The epithelial cell sites to which the bacteria bind may be glycoproteins including some that contain blood group substances. This assumption is based on the observation that salivary glycoproteins may inhibit the binding of streptococci, with various species of organisms being inhibited differently by individual glycoproteins [18]. The selective nature of binding protein may help to account for regional and species variations in colonization, with the bacteria that attach more avidly reducing colonization by those that are less tightly bound. Binding appears to be essential for colonization of areas such as the mouth where organisms would otherwise be washed away by the flow of fluid. Urinary tract infections. A correlation exists between the relative abilities of S. pyogenes and Escherichia coli to attach to pharyngeal or bladder epithelial cells and their ability to cause disease. S. pyogenes adheres better to pharyngeal epithelial cells, and is a frequent cause of pharyngeal inflammation, while E. coli adhere better to bladder epithelial cells, and are a common cause of cystitis [15]. This correlation supports the concept that bacterial-epithelial cell adherence must precede some infections, and that it also determines the range of microorganisms that may invade different organs. It appears that one of the bladder’s primary mechanisms for preventing infection is an ability to inhibit bacteria from attaching to the mucosa, thus allowing the bladder to eliminate organisms [S]. Pyelonephritis is commonly caused by organisms ascending through the ureters to the kidney, and once in the renal pelvis the bacteria must traverse epithelium to enter the medulla. Electron microscopic studies by Silverblatt have shown that the step preceding penetration by Proteus mirabilis into the renal medulla is the attachment of organisms to the epithelial surface through long slender projecting organelles called pili [6]. Pili are present on many Gram negative bacteria, and are to be distinguished from the fimbriae previously mentioned, and from motile flagellae. They have long been known to attach one bacterium to another for the transfer of genetic-like information, but little is known about the mechanisms by which they attach to other surfaces such as epithelial cells. Enteric infections. An early indication that attachment of bacteria to epithelial surfaces was important in the pathogenesis of disease came from the observation by LaBrec, Formal and co-workers that shigella must penetrate into the mucosa before they cause disease [3]. Subsequent studies on immunity to Vibrio cholera by Fubara and Freter gave additional early clues that the association of bacteria with epithelium is important in the pathogenesis of toxin induced disease, even in the absence of penetration [19]. In the case of cholera it may be that the association with the mucosa prevents the rapid flow of intestinal fluids from washing the organisms away, or it may be that toxin production near the epithelial surface leads to more effective absorption. Some organisms such as enteropathogenic E. coli cause diarrhea especially when they proliferate in the small intestine, a region which is normally relatively free from bacteria [20]. The ability to adhere to small bowel mucosa may be one of the features that is necessary for such organisms to cause disease, and one of our ‘immune mechanisms may be an ability to prevent this attachment [21]. Fimbriae, flagellae, and perhaps pili may each serve as the organelle for attaching different bacteria to the intestine [22,23]. Gonococcal urethritis. Neisseria gonorrhea is highly pathogenic when it comes in contact with mucosal surfaces, especially those of the urethra. Like Gram negative rods, Gram negative cocci can produce pili through which the bacteria attach to a variety

William

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P. Reed and Ralph

C. Williams,

Jr.

of cells including epithelial cells and spermatozoa [l, 24,251. Colonial variants that fail to produce pili also fail to attach and are nonpathogenic. Lack of pathogenicity, however, may be more complex than this and may involve other factors such as resistance to phagocytic killing. Bacterial e&car&is. Transient bacteremias appear to be relatively common, but usually no significant disease results. However, some bacterial species such as enterococci produce endocarditis with a frequency that seems disproportionately high in respect to their relative infrequency in bacteremia. It seems reasonable to assume that before circulating organisms can cause endocarditis they must first either attach to the endocardium or be caught in a fibrin meshwork on the valve. Measurements of the avidity of a number of bacterial species for attaching to excised valve leaflets have shown a rough correlation between the avidity of attachment and the frequency with which the species cause endocarditis [7]. The rarity of endocarditis in relation to the higher frequency of bacteremia may be due to the fact that few of even the most avid organisms seem to attach. For instance less than 2% of the available enterococci actually attached to valve leaflets under in vitro experimental conditions [7]. It seems possible, therefore, that after bacteremia has occurred the next step in pathogenesis of endocarditis is the association of organisms with the endocardium, perhaps by direct attachment or by entanglement in fibrin which is then followed by bacterial growth and valve destruction. Prosthetic infections. Certain prostheses are highly prone to become infected, with rates of over 25% being reported for ventriculo-atria1 shunts [26]. There is also a peculiar tendency for shunts to become infected by S. epidermidis (S. albus), an organism of normally low pathogenicity. The sero group of S. epidermidis most frequently responsible for ventriculo-atria1 shunt infections has been shown to produce a mucoid substance which adheres to the plastic of the shunt and enmeshes the organisms [S]. This permits the organisms to survive for long periods in a protected environment, but some of them escape into the blood stream, so bacteremia is common. With their low pathogenicity these organisms seldom produce secondary infectious foci, but fever may occur and the intense immunological response may cause immue complex deposition nephritis. Therefore, in some instances these infections may be regarded as involving only the prosthetic devices, and the disease they produce is largely the result of the release of antigenic materials into the bloodstream, and of the hosts’ reaction to these antigens. In other cases adjacent tissue is also invaded by the infectious process. HOST

Non-speci$c.

RESPONSE

TO

COLONIZATION

A number of mechanical, biochemical, nutritional, and microbiologic factors influence the colonization of body surfaces. It is not the purpose to discuss these here, but some of the more important ones will be listed. The flow of fluids (saliva, urine, small intestinal contents), ciliary action, coughing, and sneezing all tend to expel organisms. Anti-bacterial substances found on surfaces include lipids on the skin, and lysozyme as well as a peroxide-thiocyanate system in saliva. Some types of microorganisms may interfere with other species by consuming nutrients, by producing toxic substances analogous to antibiotics, and by proliferating more rapidly or occupying the most favorable sites. Zmmunity to bacterial adherence. Local immunity at mucosal surfaceS is characterized by the production of a unique immunoglobulin, secretory immunoglobulin A (sIgA), by mucosal surfaces [27]. This immunoglobulin appears in external fluids and is resistant to breakdown by digestive enzymes, so it is well suited to function at the intestinal mucosa. Secretory IgA may inactivate viruses but in studies with Shigella it does not appear to be bactericidal either by itself, or in combination with complement or polymorphonuclear leukocytes [28,29]. Rather, it appears capable of preventing the attachment of at least certain bacterial species to epithelial cells. This has been shown for streptococci adhering to oral epithelial cells [30], for VI cholerue and intestinal epithelium [19], and for Shigella and intestinal epithelial cells (unpublished observations).

Bacterial

adherence

71

Shigella infections of the conjunctiva of experimental animals are relatively easy to study, and in many respects they mimic intestinal infections. Secretory IgA protects the conjunctiva from these organisms, but IgG and IgM fail to protect [21]. Thus, sIgA has a protective role which may operate through its prevention of bacterialepithelial attachment, but the possible protective role of IgG and IgM remain questionable in this regard. It seems possible that IgG and IgM may function in secretions as antitoxins, and together with complement and leukocytes they are undoubtedly bactericidal after the mucosa has been penetrated. At the present time it is unclear whether sIgA prevents epithelial attachment of all or only some bacterial species. Certainly this immunologic mechanism is not .sufficiently potent to prevent all attachment and colonization, and any explanation of its antibacterial role must take this into account. It may be that tolerance develops to non-pathogenic bacteria, or perhaps sIgA is inactive when bacteria are previously attached and proliferating. Or, this immunoglobulin may be effective only against small numbers of freshly encountered bacteria, and then only when similar or cross-reacting species have previously induced antibodies. This view of the immune response to bacterial attachment is shown schematically in Fig. 1. A better understanding of the host’s mechanisms for inhibiting bacterial attachment to mucosal surfaces may aid efforts to protect against many diseases such as those discussed as well as many other diseases including, for instance, diphtheria and trachoma. Even lower respiratory infections such as pneumococcal pneumonia may be preceded by bacterial-epithelial attachment in the pharynx. Topical immunizations appear to have some role in protections against diseases that begin on mucosa. They have been very effective in some viral diseases such as polio, but although they have been shown to have an effect in some bacterial diseases they are not routinely available for control of bacterial diseases. Different mechanisms may well protect against attachment within body tissues, and a better understanding of these could possibly lead to immunological techniques for protection of high risk patients against bacterial endocarditis. Such an approach may be of value since the effectiveness of antibacterial prophylaxis has not been proven, and commonly used antibiotic schedules have been shown to be of little value in an animal model [31]. It does not appear that such protection will occur as the result of currently used forms of immunization since hyperimmune animals used for the production of pneumococcal vaccines appear to be highly susceptible to pneumococcal endocarditis [32,33]. Routine immunization procedures induce high levels of IgM and subsequently of IgG. Little is known about techniques for inducing high serum levels of IgA antibodies but perhaps they could protect against endocarditis if the immunization procedures could be developed. BACTERIAL ADEEBXNCE Inhibition

by non-wecific

DUE TO TOXINS

DEBASE

Inactivation

Fig. 1. Schematic

by antibodies

factors

and SIRA

DISEA6DUE TO PENFPRATION Bacterial killing by I@4 or IQ + complement and leukocytes

representation of bacterial adherence and its consequences letters. The host response is shown in “lower case”.

shown

in capital

12

William P. Reed and Ralph C. Williams, Jr. REFERENCES

1. Ward ME, Watt PJ: Adherence of Neisseria gonorrhoeae to urethral mucosal cells: an electronmicroscopic study of human gonorrhea. J Infect Dis 126: 601, 1972 with, and its 2. Tannock GW, Blumershine RVH, Savage DC: Association of Salmonella typhimurium invasion of, the ileal mucosa in mice. Infect Immun 11: 365, 1975 3. Labrec EH, Schneider H, Magnani TJ, Formal SB: Epithelial cell penetration as an essential step in the pathogenesis of bacillary dysentery. J. Bacterial 88: 1503, 1964 4. Ellen RP, Gibbons RJ: M protein-associated adherence of Streptococcus pyogenes to epithelial surfaces: prerequisite for virulence. Infect Immun 5: 826, 1972 5. Parson CL, Greenspan C, Mulholland SG: The primary antibacterial defense mechanism of the bladder. Invest Ural 13: 72, 1975 6. Silverblatt FJ: Host-parasite interaction in the rat renal pelvis. A possible role for pih in the pathogenesis of pyelonephritis. J Expl Med 140: 1696, 1974 7. Gould K, Ramirez-Ronda CH, Holmes RK, Sanford JP: Adherence of bacteria to heart valves in vitro. J Clin Invest 56: 1364, 1975 8. Bayson R, Penny SR: Excessive production of mucoid substance in Staphylococcus SIIA: a possible factor in colonization of Holter shunts. Dev Med Child Neurol 27: (suppl.) 25, 1972 9. Gibbons RJ: Bacteriology of dental caries. J Dent Res 43: 1021, 1964 10. Zobell CE: The effect of solid surfaces upon bacterial activity. J Bacterial 46: 39, 1943 mutans to dextran synthesized in the presence of extracellular Il. Kuramitsu HK: Adherence of Streptococcus dextransucrase. Infec Immun 9: 764, 1974 12. Bowen WH: Prospects for the prevention of dental caries. Hosp Practice 163, May 1974 13. Gibbons RJ, Van Houte J: Selective bacterial adherence to oral epithelial surfaces and its role as an ecological determinant. Infect Immun 3: 567, 1971 14. Gibbons RJ, Spine11 DM, Skobe Z: Selective adherence as a determinant of the host tropisms of certain indigenous and pathogenic bacteria. Infect Immun 13: 238, 1976 pyogenes. 15. Ellen RP, Gibbons RJ: Parameters affecting the adherence and tissue tropisms of Streptococcus Infect Immun 9: 85, 1974 16. Beachey EH: Binding of group A streptococci to human oral mucosal cells by lipoteichoic acid. Trans Assoc Am Phys 88: 285, 1975 17. Beachey EH, Ofek I: Epithelial cell binding of group A streptococci by lipoteichoic acid on fimbriae denuded of M protein. J Expl Med 143: 759, 1976 18. Williams RC, Gibbons RJ: Inhibition of streptococcal attachment to receptors on human buccal epithelial cells by antigenically similar salivary glycoproteins. Infect Immun 11: 711, 1975 19. Fubara ES, Freter R: Protection against enteric bacterial infection by secretory IgA antibodies. J. Immunol 111: 395, 1973 coli: ilial 20. Nagy B, Moon HW, Isaacson RE: Colonization of porcine small intestine by Escherichia colonization and adhesion by pig enteropathogens that lath K88 antigen and by some acapsular mutants, Infect Immun 13: 1214, 1976

21. Reed WP, Cushing AH: Role of immunoglobulins in protection against shigella-induced keratoconjunctivitis. Infect Immun 11: 1265, 1975 22. Duguid JP, Gillies RR: Fimbriae and adhesive properties in dysentery bacilli. J Path Bacterial 74: 397, 1957 23. Takeuchi A, Zeller JA: Ultrastructural indentification of spirochetes and flagellated microbes at the brush border of the large intestinal epithelium of the rhesus monkey. Infect Immun 6: 1008, 1972 24. Swanson J, Sparks E, Young D, King G: Studies on Gonococcus infection-X. Pili and leukocyte association factor as mediators of interactions between gonococci and eukaryotic cells in vitro. Infect Immun 11: 1352, 1975 25. James-Holmquest AN, Swanson J, Buchanan TM, Wende RD, Williams RP: Differential attachment by piliated and nonpiliated Neisseria gonorrhoeae to human sperm. Infect Immun 9: 897, 1974 26. Schoenbaum SC, Gardner P, Shilliot J: Infections of cerebrospinal fluid shunts: Epidemiology, clinical manifestations, and therapy. J Infect Dis 131: 543, 1975 27. Tomasi Jr TB, Tan EM,-Solomon A, Pendergast RA: Characteristics of an immune system common to certain external secretions. J Expl Med 121: 101, 1965 28. Reed WP, Albright EL: Serum factors responsible for killing of Shigeffa. Immunol 26: 205, 1974 29. Reed WP: Serum factors capable of opsonizing Shigella for phagocytosis by polymorphonuclear neutrophils. Immunol 28: 1051, 1975 30. Williams RC, Gibbons RJ: Inhibition of bacterial adherence by secretory immunoglobulin A: a mechanism of antigen disposal. Science 177: 697, 1972 31. Durack DT, Petersdorf RG: Chemotherapy of experimental streptococcal endocarditis-I. Comparison of commonly recommended prophylactic regimens. J Clin Invest 52: 592, 1973 32. Wadsworth AB: A study of the endocardial lesions developing during pneumococcus infection in horses. J Med Res 34: 279, 1919 33. Mair W: Pneumococcal endocarditis in rabbits. J Path Bacterial 26: 426, 1923

Bacterial adherence: first step in pathogenesis of certain infections.

OOZl-9681/78/0201-0067$02.00/O J Chron Dis Vol. 31, pp. 67-72 0 Pergamon Press Ltd. 1978. Printed in Great Britain Editorial BACTERIAL ADHERENCE: F...
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