339

Microbial Pathogenicity and Host Defense MechanismsCrucial Parameters of Posttraumatic Infections B. Schlii ter an d Iv. Konig* Special-project Group 'Infection-rejection Mechanisms'. Department of Medical Microbiologyand Immunology. Huhr University. Boch um. File;

Posttraumatic a nd post oper ative infections which may be either localized or turn into se ps is arc a major cause of morbidity and mortality in surgical patient s. They derive from the imbalance be tween microbial pat hog-enicity facto rs a nd the host defense system . Th e virulence mec hanisms include ad hesion, che motaxis. invasion. resis tan ce, a nd productio n of toxins. In addition. local a nd/or systemic immune functio ns in these patients a re a ltered. Unspecific as well as specific cellular and humoral defe nse mec ha nisms are alTected. The inte raction of de fined microbial pathogen icity factors with immune effector cells results in the ac tivat ion of a variety of Inflammatory me diators; they a re a prerequisite for protective immu nity but also induce loca l or systemic damage in the host when they occur in excessive amounts or whe n thei r metabolis m is inadequa tely controlled . The a na lysis of the pa thophysiological eve nts during infection in surgical patien ts by ta king adva ntage of modern molecu lar a nd cell biological met ho ds may contribute to the develop men t of novel therapeutic strategies . Key words Trau ma - Infection - Path ogen icity facto rs - Host defe nse Inflammato ry me diators

Introd uctio n Locali zed and syste mic infections following trauma or majo r ope rations continue to be frequ ent a nd seve re cornplicati ons in surgica l patien ts although consider able progress in both the prophyla xis an d the a ntib iotic trea tment of infe ctions has been ac hieved du ring the last decades. Epidemiological studies pro vide evide nce that 60 to 88 % of all late posttrau matic death s are due to the occur re nce of generalized se pticem ia with consec ut ive mu ltiple orga n failur e (5. 20). However . the success of surgical the ra py is also uncertain if localized infections (e.g. of wounds, prosthetic devices , th e urogeni tal or the lower res pirato ry tr actl occur. Micro bial colonizat ion ca n proceed eithe r endogenously via the sprea d of the patients ' ow n flora (e.g. skin. upp er respir ator y a nd digestive tract) in the course of the med ical tre atment or exogeno us ly via the tra nsmission of the

Mikrobielle Pathogenlta t u nd kor pcrelgen e lnfcktnbwchr entscheide nde Faktoren der post traumntlschen Infektln n

Posttraumatische und postoperative lokale und septisc he lnfektlo nen. die die Hauptursachcn de r Mor bid ltat und Mortalitat im chlrurgtschcn l'aucntcngut darstellen , beruhen aus pathophysiologisehe r Sicht auf Storungen des Gleichgewic hts zw isc hen mikro bielle n Path ogcrutatsfa ktoren und dor korpereigcnen lnfektabwehr. Den verschiedenen Virule nzmechanismen der Mikroorganis me n wie Adharenz. Chemotaxis. lnvasivltat. Heslstenz und Toxinp rod uktion steht ein lokal und/oder systcmisch beeintrachtlgtes Immunsyste m diese r Patientun gegentiber. Sowohl die unspcztflsche als auc h die spczfflsche zellulare und humorale lnfektabwchr si nd betrolTen. Die lnterakuon deflnlerter mtk robleller Pathogenitatsfaktoren mit immunologischen Effektorzcllc n fllhrt zur Aktivieru ng zahlrcicher Mcdiatorcnsvsterno , die einerseits eine prote ktlve Funku on besitzen . andererseits bei fohlender Kontrolle ihrer Produktio n und /oder Metabolisieru ng lokale oder systemlsch e Schadc nsreaktioncn induzieren. Die Aufklarung der path ophystologischen Prozesse bei Infektionen ch irurgischer Patie nten durch moderne molekular- und zellb tologlsche Methodcn kan n zur Entwicklung neuer therapeutischer Ansatze bcit ragcn .

environ ment al flor a {e.g. medica l staff and equipment). In a ddition. micr oorga nisms may di rect ly ente r the circula tion via the tr a nslocati on fro m the digestive tract which ha s been con clus ively dem onstrated in expe rimen ta l an ima ls (1 5) . Th us. a new th erapeutic ap proa ch to the prevention of se pticemi a by enteric microorgan ism s is the se lective deconta mination of the digestive t ract by the ora l admi nistrati on of a ntibiotics which a re on ly poorly abso rbed Ie.g. a minoglycosides ) (49 ). Basically. the various clinical feat ures of posttraumatic infections reflect the individual ba lance of micro bia l pathogen icity factors as we ll as the local an d syste mic host defense mec ha nisms in these pati ents. During the last yea rs the un der standi ng of th ese path oph ysiologic pa rameters ha s been rapi dly exten de d du e to the inte ns ive coope ration between basic and clinical resea rch.

* suppo rted by the Deutsche Forschungsgemeinschaft (Ko 427/ 7-2) and the Bundes minister des lnneren

Thorac. cardtcvasc . Surgeon 38 {1990J :t N - 347 © Georg Thieme Verlag Stuttgart NewYor k

c-

Itecetved for Publi cation: xtarch 18. 1990

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Summar)'

8. S chluter. It' Konig

Thome. eardiovase. S urgeon 38 (1990J

Microbial pathogenicity factors

Table2

Microbial pathogenicity can be collectively defined as the biochemical mechanisms by which microorgan isms cause disease. Microorganisms vary in their path ogen ic potency. Thus. there are obligate pathogens which induce clinical infections even when the patients ' host defense is unaltered (e.g. Bord eteUa pertussis, Corynebacterium diphtheri ae). However. such microorganisms only play a marginal role in intensive care medicine. In contrast, the facultatively pathogenic microorganisms are of great importance. They lead to severe infections in immun ocompromised pat ients but as a rule not in healthy subjects (e. g. Pseudomonas ssp.. Acinetobacter ssp., Enterobacter ssp.. Stre ptococcus pneumoniae . Staphylococcus aureus, Candida albtca ns). Under specia l conditions (e.g. intravascular catheterization, thro mbosis of mesenteric vessels, perforations in the digestive tract) microorgani sms of the patients' own nora (e. g. Streptococcus viridans. Staphylococcus epidermidis, anae robes) which show only low pathogenicity on their own give rise to septic complications . The path ogens most frequen tly isolated duri ng thoracic infections are summa rized in Tab le 1 (6. 17. 23. 55).

pmciple

responsible microbial pathogenicity factors(examples)

adherence

adhesins,fimbriae. lipoteichoicacid, fibronectin-binding protein flagella. chemotacticreceptors

Table 1

Microbial spectrum 01thoracic infections

classification

prevalentmicroorganisms

aerobes: grern-positivecocci:

Staphylococcusaureus.coagulase-negative staphylococci (e.g. S.epidermidis). Streotccoccuspneumoniae

grem-negative rods:

Haemophitus influenzae. Enterobacteriaceae (e.g.Klebsiella pneumonae. E. coli, Enlerob· acter, Serratia). Legionella ssp, Pseudornonas eerugmosa

chemotaxis

gremoositive cocci:

Peptococcus ssp. (e.g.P.magnus. P.saccharolyticus. P.prevotii). Peptostreptococcus ssp. (e.g. P.aoaeroblus. P. intermedius. P. micros). microaerophilic cocciandstreptococci

gram-positivesporulating

rods

Oostridiumssp. (e.g. C. perfringens. C. seencum, C.novyi. C. ramosum. C. hiStolyticum, C. sccrogenes. C. sordelliiJ

gram-positive nonsporulating microorganisms

Actinomyces, Atachnia. Eubacterium ssp. (e.&- L lentum E. limosum, E. alaetolyticuml, Bilidobacterium eriksonii

gram-negative rods:

Bacteroides ssp. (e.g.B. fragilis, B.melenoogenicus),Fusobacteriumssp. (e.g.F.nucleetum, F. necrophorum, F. venum, F. momferum)

fungi:

Candidassp.

parasites:

Pneumocystis cannu

modifiedaccording to (17)

Studies perfor med during the last years provide evidence that microbial path ogenicity is due to multiple factors such as adherence. chemotaxis. invasion. resistan ce aga inst host defense mechan isms. and production of toxins (Tab le 2) (18. 26. 47.50). Bacterial adhe rence to epithelial su rfaces (e.g. skin . mucosa) is a prerequisite for the colontzation of tissu es and proceeds via the interact ion ormolecu-

intracellularlypersisting microorganisms:invasins, lst erotysin, and other membrane-disintegrating factors

fMlSKlll

exlracel1ularlypersistingmicroorganisms: proteases,Iipases, DNAses.hyaluronidase,ccaagenases. fibrinolysin, neuraminidase resistance

capsule.slime, M-protein (streptococci gr. A), Oent'gen (salmonellae), IgA-proteases, antigenic variation

production of toxins

endotoxins,exotoxins te.g. hemolysns,neurotoxins,cholera toxin, pertussis toxin)

lar ligan ds on the bacterial surface (adhestns) with specific epithelial receptors. The adhesins are frequently expressed on defined bacte rial organelles (fimbriae) which facilitate the close conta ct of ad hesins and cellular receptors . In fact, the expression of adhesins and fimbriae depends on environmental conditions which thus influence the site and the route of microbial colonization and infection. For instance. E. coli strain s with Scfimbriae (specificity for surface receptors conta ining sialic acid) are predominantly isolated during septicemia and neonatal menin gitis whereas E. coli stra ins with Pvfimbriae (specificity for galactose-containing surface receptors) are frequently observed in uropath ogenic isolates (44. 56). Fibronectin which is an extra cellular matrix- and plasma glycoprotein and binds in lar ge amounts to mucosa l surfaces is involved in bacter ial adhere nce (591. Microorganisms vary in their affinity to fibronectin (Table 3). It has been shown that Streptococcus Table 3

anaerobes:

Microbial pathogenicity factors

Fibronectin·bindingbymicroorganisms

affinity

microorganisms

high

streptococci gr. A,C, G staphylococci (S. eureus. S.haemolyticus)

variable

Streptococcus pneumoniae,alpha-hemolyticstreptococci (e.g S. sanv acus. S. sanguis, S. mutans), coagulase-negativestaphylococci (e.g.S.saprophyticus.S. wamen, S. hyicus. S. simulans. S. hominis) streptococcigr. B. D. M. N. P. U coagulase-negativestaphylococci (e.g.S.eoioermdls.S. capitis, S. xyIosus, S. cohniij gram-negative microorganisms: Pseudomonasaetugmosa.Klebsiellapneumoniae, Eschenct ua coli, Neisseria ssp, Haemophilusinfluenzae

modified according to (50)

pyogenes and Staphylococcus aureus inter act via defined str uctures (Ii poteichoic acid , fibronectin-bindi ng protein) with fibronectin and thus adhere to epithelial surfaces (7. 46). After heart transplantations or othe r major opera tions fibron ectin is released in large amount s from the mucosal surfaces of th e upper respira tory tract (67). Staphylococci and strept ococci present in the bronchial lumen bind to th e fibronectin released and thus fail to adhe re to the resp ira tory epithelium. Consequently, the coloniza tion and infection by gram-negative enteric microorgan isms such as E. coli or P. aeruginosa which show only a low fibronectin affi nity is favoured in these clinical setti ngs.

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340

Thom e. eardiovasc. Su rgeon 38 (19 90)

Microbial Pathogenicity and Host Def ense Mechanisms

disr uption ofthe cell membran e and cell death . Other toxins such as the toxin of C. diphtheriae or the exotoxin A of P. ae ruginosa inhibi t the cellular protein biosynth esis. However. the function of microbial toxins is by no means restricted to the cytotoxic effects men tioned a bove. In fact . the toxins exert a complex modulator y role on immu ne effector cells (37) (comp are section on pat hogeni city factors a nd inflammation). lIost defen se mech a nism s It has been well esta blished that un specific as well as specific host defense mecha nisms a re impaired in pat ien ts after major trauma or surgery (Table 4). The local and systemic immune dysfunctions are a prerequi site for the occurren ce of localized or systemic infect ious complications. In most cas es the extent of the immunological alterations correla tes with the severity of the tra uma . The immun e com petence is restored when the patients recover from their injur ies .

Table 4 Tratme-assocteted alt erationsof the host defense unspecifichost defense neutrophil granulocytes: chemotaxis 1, phagocytosis microbicidal potency 1, chemiluminescence

specific hostdefense f-lymphocytes: T·cell proliferation 1. cylokine production IL·2, IL·3.I L·5.IFN I. CD25 expression CD8 + T-cells l-CD4+ f-ceus 1

1.

t.

Itme-oependent il l

generationof IJB4 1, IJB4·receptorexpression 1 monocytes/ macroohages: altered antigen presentation, phagocytosis 1, oxidative metabolism 1, production of IL·} (time-dependent generationof PGE2 and TNFu l

B·lymphocyles: B·cell proliferation

Inme-depencent ill,

lll,

activity of serum complement (time·dependent ill

inducedimmunoglobulin synthesis 1 CD23 expression 1, sCD23 release 1 serum immunoglobulins 1_

The unsp ecific host def ense Polymorp honuclea r gra nulocytes form the first cellula r defens e line agains t invadi ng microorgani sm s. For this pur pose the y have multiple functional ca pacities includi ng adhe rence. deforma hility. or ien ta tion , movemen t, chemotaxis . recognition of nonself structures , phagocytosis . and intracellula r killing of microorga nism s. Th us, altera tions in the first defense line ma y be deleterious for the host. Nume rous studies reported that gran ulocyte functions (e.g. che motaxis . phagocytosis. microbicidal pote ncy) a re impaired following severe injuri es (4. 14). However. the un derlying biochemical mecha nisms a re only poorly un der stood. We have demon strated tha t neutrophil granulocytes from heavily bu rne d patients genera te lower a mounts of leukotriene 8 4 (LT84) up on cellular activation as compa red to cells from healthy donors (30 , 31). LTB4 is derived from a ra chidonic acid via the Iipoxygenase pat hway a nd represents the most potent chemotac tic stimulus for phagocytes. The reduc ed chemotactic potency of the patien ts' gra nulocytes is also due to a n en ha nced meta bolizat ion of LT8 4 into biologically inact ive compounds (12). In addition. the expression of fun ctional LTB4-r eceptors on the cell surface of gra nulocytes is diminish ed (13). In part, these altera -

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Anothe r path ogenicity factor is bacteri al chemotaxis. The capa bility of active movem en t towards chemical signa ls pr esent in the environ me nt allows the microorganism s to reach the sites where they a re optimally pr ovided with nutri ents. Furthermore. the chemotax is pr omotes the con tact of microorga nisms with mucosal surfaces as has been shown for the experime ntal int estinal infection by Salmon ella typhi (39). The invas ion into tissue is an additional crite rion of pathogen icity for seve ral microorganism s including intracellularl y (e.g . mycobacteria. Listeria and Yersinia ss p.) an d extracellula rly persisting bacteri a (e.g. streptococci, sta phylococci. Pseudomonas ssp.). The mechanisms of bacterial invasion have been exte ns ively investi gat ed in the experime ntal model of intestinal infection s ca use d by Yers inia (41). These microorgani sm s express invasins on their su rface which interact with specific receptors on the ta rget cells. After bindin g to the receptor the microorga nisms a re intern alized an d "stored" in vacuoles. Subseque ntly. an int racellula r replication can take place before the target cells a re lysed and/or left. Severa l receptors for invasin s have been shown to belong to a family of struc turally related rece ptor molecules (integrins). The integrin s are essential for the cellular adherence to extrace llular mat rix compone nts such as flbro nectin. Iaminin . collagen . and vitronec tin. for the for mat ion of cell-cell contact. and for phagocytosis (48). For instan ce. the recep tor for the com plement component C3b (CR31 whic h plays a major role during opsonophag ocytosis is involved in the intr acellular upta ke of mycoba cteria a nd legionellae. Extracellularly persisting microorganisms invade into the tissue by other me chan isms; th ey release enzymes a nd toxins (e.g. protea ses , lipases. hyalu ro nidase. fibrinolysin) which disintegrate the mecha nical barrier of th e skin or the mucosa. Microbial pathogenicity may also be due to the resistanc e a gainst host defense me chanisms (21). Basically. this is possible by pr eventing phagocytosis. In this regard. ba cteria produce slime or express capsules an d certa in sur face molecules (e.g. M-protein of stre ptococci group A, O-ant igen of sa lmonellae) which sterically inhib it the deposition of comp lemen t. Coag ulas e-negative sta phylococci frequent ly account for infections of pr osthetic de vices and intravascula r cat het ers a nd pr oduce slime factors which facilitate the bacterial adhe rence to the plastic sur faces and pr event phagocytosis (4 5). Other protective mechanisms of micr oor ganisms refer to a ntigen ic variations an d the relea se of exoenzy mes such as IgA-proteases. A class ical microb ial pat hogenicity factor is the pr odu ction of toxins (37. 40). Although bacteri al toxins belong to the best-cha racteri zed virulence factor s their act ual role during microbial colonization a nd infection is still poorly un derstood . Toxins a re classified in endotoxins from gra mnega tive micr oorganism s (lipopolysaceha ridesl a nd in exotoxins. A va riety of toxins a re ab le to lyse eu karyotic cells or to da mage them functiona lly. Especially. the hemo lysins play an importa nt ro le. Hemolysins act eithe r enzymatically (e.g. phosp holipase C of P. ae ruginosa, alphat oxin of C. perfringens . sphingomyelina se C of S. a ureus) or non -en zymatically (almo st all hem olysins from gra m-negative bacteria an d th e thi ol-activata ble cytolysins such as stre ptolysin a and listeriolysin} , These toxins are cytotoxic due to their inter action with defined cell mem brane structure s (e.g. cho lestero l). Conseq uently. the membran e permeability an d the cell volume increase which finally results in the

341

IJ. Schluter,

TllOrac. cardiol'a SC. Snrgeon38 (] 990)

tions corre late with the app earance of immature granu locytes (ba nd cells) in th e per ipher al blood (31). The decrease in LTB..-generat ion precedes the onset of microbial invas ion as assessed by the quantitative ana lysis of wound biopsy specimens an d correlates with the clinical outcome of the patients ; in survivors the generation of LTB.. is fully restor ed. whereas it is completely sup pressed in patients who succumb to their inju ries (30, 31). One may suggest that ther e is an inadequ ate recru itment of pha gocytes at the sites of tissue injury seconda ry to a reduced chemota ctic response thus facilitatin g the microbial invasion. In addition to granu locytes. the mononuclear phagocytes ar e affected by severe injuri es (22). In experimental animals the antigen presentation by adhe rent spleen cells is impaired with in 24 hours post burn . Mononuclear cells from traum a patients express less clas s II tra nsplantation antigens as compared to health y subjects. Phagocytosis. oxidative metabolism I''resplratory burst "). and the production ofi nterJeukin 1 are reduced . In contrast, the generation of the immunosuppressive prostaglandin E, (PGEzl as well as the tu mor necrosis factor 0 (TNFo) is increased (24. 43.

sz).

The spec ific host defense Tvlym phocyt es (( 03 +) which participate in cell-mediated imm une reactions can be functionally subdivided into cells with helper. cytotoxic. and sup pressor activities. T-helper cells (C04 +) interact with Bv lymphocytes which results in the production of antibodies. Moreover , they support the process of matu ratio n in cytotoxic T-cells (( 08 +). T-cells with suppressor activity (C 08 +). B-cells, and macrophages maintain a negati ve regulatory system, A coordinat e cooperation of these cells requires an intercellular communica tion provided by both physical cell-cell conta ct and soluble factor s (e.g. cytokines. inflammatory med iators) (9. 36. 42. 62 ). Cyt okines consist of lnter leuktns. interferons. tumor necrosis factors. and colony-stimulat ing factors (Tab le 5).

u: Konig

plasma cell Fig.1 Cytokinesaresynthesized and released byactrvated T-helper cells(T.J in responseto cellswhich presentantigen in conjunctionwith classII transplantationantigens(Ia).SubseQuently,the cytoknes exert their pleiotropic effectsvia theinteractionwrthvarious immune effectorcells (CTL .. cvtotoncT-cens. T. = I-suppressorcells: B.. Bc eas; Mo = macrophages/monocytes) aswell as nemoooenc cens. n, .. interleukin; GM-esF ~ granulocytemacrophage colonystimulatingfactor; IFN .. interferon; BSF = Bcellstimulatory factor: BCGF = B cell growth factor. Adapted from(42)

They exert multiple biological functions which indu ce the activation. proliferation, and diITer entiation proces ses of immune effector cells and also stimulate hemopoeuc stem cells derived from the bone marrow (Fig. 1). The specificity of a cellular immune response is medi ated via the ant igen specific Tvcell receptor (TCR)-C03 complex which recognizes fore ign antigens in association with the tra nspla ntation antig ens orthe major histocompatibility complex (MHO

Table 5 Cytokinesandtheir t nolog c functions lnterleukm I {Il-Il, lymphocyte ectwatmg factor (LAF)

T-and B-cell activation,inductionof cytoklnes. stimulation of fibroblasts. mediator 01acute phase reactions

Interleukrn 2 (lL-2),T-cell growth factor (TCGF)

t -een proliferation, cosnmctaton of B-cell differentiation. activation of killer cells

Interleukin 3 (ll -3).multipotentcolony-stimulatingfactor(multi-

mast celldevelopment, growthfactor for multipotenthemopoetic stemcells

CS~

Interleukin4 (ll-4 ),Beenstimulatoryfactor 1 (BSF-I). Be en growth factor (BCGFj

costimulation of B-cell proliferation,synergismwith Il-3 onmastcell development.enhancementof IgGl- andIgE-synthesis,stimulationof classII transplantationantigenson T-and 8· cells, costsr uratron of the proliferation of nemocoenc precursor cells

Interleukin 5 {IL-5). T-cell replacing factor (TRFj, B-cell growth factor II (BCGF II)

costimulationof B·cell proliferation,enhancement of IgA-synthesis, differentiation of eosnophils

Interleukin 6 (IL·6), a·cell stimulatoryfactor II(BSF II). hepatocyte stimulating factor (HSF) lnterleukm 7 (Il- 7)

costimulation ct'l-ceu orouteretton, inductionof Il -2receptors,enhancementof immunoglobulinsynthesis,mediator of acute phase reactions

lnterleukin8 (ll·B), neutrophil activatingpepllde 1(NAP·I )

stimulation of neutroobts (chemotaxis,degranulation.generation of oxygen radicals.CD11bl CDI8 receptor expression)

Tumornecrcsrs factoru (TN Fu).cacnectm

stimulation of neutrocbls (phagocytosiS.microbicidal potency,endothelial adherence), strmulanon ofantibody-dependent cellular cytotoxicity(ADCC).induction of Il -I synthesisand expression of classI transplantationantigens,antiviral activity,mediator 01acutephase reactions

Interferon 'I (IFN'l), macrophage activating factor (MAFj

Inhibitionof VIral replication,inductionof classIItransolantetcn antigens, functional antagonismwith IL4 on B-cell functions

Granulocytemacrophage colony-stimulatingfactor (GM-esFj

growthstimulationofgranulocytes. mecropnages.and bone-marrow.denved precursor cells

stimulationof proliferation of cre.a.cees.thymocytes. and f -ceus. induction of Il-2 and Il-2 receptors

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342

.\ficrohial Pat/ my plI;c;t!! fi nd Host Defe ns e M echanisms

nwrac. cardiol'asc . •r.;urYi'oll .18 (1 (j (j()) Table 6 cutes

molecule

distribution

ligand

oistnbunon

TCR·CD3 C02 (LfA·2)

t -eens. thymocytes

MHC + antigen

all nucleated cells/APC

T· and Nk-cens. thymocytes

all human cells except Ihymocytes

CO'

subpoovanonsof r-cees. thymocytes

Lf A·3 MHCII

COB

subpcpulancns of T-cens. thymocytes all leukocytes

CR3

rnacropnages.mcrocvtes. T-andNKcells. granulocytes actvated T-cens. thymocytes.monocytes. myocytes. fibroblasts, platelets

MHCI ICAM-l iC3b

all nucleated cells

l FA·l

collagen, ?

stroma, connective tissue

VLA 11.2. 4)

:l 4:J

Cell adhesion mote-

activated T· and Bcells, monocvtes.endothelium

B· and t -eens. bone-marrow-denveo cells complement fragment C3

Fig.2 Noxious agentsprovokeInflammatoryreo actions. Monocytes. neutropt nrs.T· and a·cellsas well asendothelial and stromalcellsareactivated. Consequently.cellularmediatorsarereleased Ie.g.cytocnesl.The expressionof cell aohesron molecules[e.g. ICAM- l .lFA·l. HLA·anllgens)is enhanced. These cell surfacemoleculesareactrvelyInvolvedin the inductionand modutatron of the bolog icalresponse totissue injury.Adapted from (62)

' ......URy

, , T CEl l . CTlV. TIOtO • • NTlGEN PRESENTATION BY HLA PLUS IC. ...· 1 PLUS OTHEA . CCESSORY MOLECULES

EtOH"-tOCE;J EtOOOTHH l. l "-OHESIOtO · lC . M·l l F.·1 ADHESIOtO . ItOO UCTION OF OTHER . DHESIVE MECH.tO ISMS

---L-

--'

le UKOCYTE . 0H ESlO... ....0 MIGA. TlO'" ItO TO THE TISSUES

present on antigen-presenting cells IAPC: mecrophages. Bcells). The physical cell-cell contact occurs via the intera ction of adhesion molecules (Table 6) expressed on the cell surface of the respective cell populations. In addi tion. the cell adhesion molecules such as the TCR-CD3 complex are involved in the process of T-cell act ivation upon binding of the adequate ligand s. The role of cell ad hes ion molecules in the host defense agai nst vari ous noxious agent s is summar ized in Fig. 2. An impaired expression of adhes ion molecules may result in life-threateni ng recurrent bacterial infections and in a reduced wound hea ling 121. Cell-mediated immune reactions are impaired following severe trauma (22 1which is demonstrated by the clinical finding of a cutaneous a nergy towards recall an tigens and a prolonged survival of allograft tr an splants. In vitro studies provide evidence for a reduced T-cell proliferati on after antigenic or mitogenic stimulation. The lymphocyt es from patients with the highest risk of sepsis sho w the lowest level of blastogenic res ponses (281. These functional cha nges are accompan ied by an altered release patt ern of various cytokines. The production of inter leukin 2 which is an essent ial T-ceHgrowth factor is markedly decreased (66). Moreover. the num ber of mononuclear cells expressing receptors for interleukin 2 tlL-2Hl is reduced (5S). Our studies demonstrate that the

cellular expression of the CD25 ant igen which is part of the (L-2H complex is enhanced after severe ther mal injuries (52). One may suggest tha t this mechanism is directed towar ds the restoration of the immune reactivity of the patients' lymphocytes. However . the lack of an adequate blastogen ic respon se after exogenous addition of interleukin 2 to lymphocyt e cultures of burn patients a rgues for the expression of func tionally inactive IL-2 receptors. Apart from IL-2 the production of IFl'\y, 11.-3, and 11.-5 is altered following traum a or hemor rhage (1I. Our studies on localized surgical infections such as chron ic posttraumatic csteom velitis indicate that Tvcell dvsfunctlons occur both in vtvo 10TH-reactivity) and in vitro (T-cell proliferati on ) to a minor extent as compared to their occurrence in ac ute traum a (53). After severe inju ries the specific hum oral immu nity is affected as well although se ru m immunoglobulins are decrea sed only in the ea rly posttr aumatic phase (31. The local host defense of the intestinal mucosa is impaired secondary to the redu ction of hepatic IgA secretion (27). The systemic alterat ions involve the activation. prolifer ation. and differentiation of Bvlym p hocyt es (54). Apart from the redu ced B-cell blast ogenesis and ant ibody synthesis after stimulation with inactivated Stap hylococcus aureus (SAC)

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Abbreviations: CD - cluster of differentiation. TR .. t -een receptor. lFA - lymphocyte function associated antigen. CR = complement receptor. VLA - very late actweuon antigen, MHC = major histocompatibility complex. ICAM .. intercellular adhesion molecule. NK - natural killer cell. APe- antigen presentingcell.Modifiedaccordingto (9)

IJ. Schluter, It: Konig

Thome. eardiot'use. Surgeon 38 ' 199OJ

the activat ion of B-cells with the interl eukins 2 and 4 is impair ed . The state of Becell activation can be asses sed by the cell surface marker C0 23 which is only expres sed during the ea rly phas es of the B-cell development (slgM and sIgO positive Bvcells} prior to the class-specific immunoglobulin switch (19). CD23 is also regarded as a receptor for the low-molecular-weight B-cell growt h factor IL\ 1\\'BCGFI. Mor eover , its soluble prot eolytic cleavage product (sCD23) ha s auto crine growth-promoting activity. Our studi es on B-cell dysfunctions in severely burned patients indicate that the cytokine-induced expression of CD23 and the release ofsC D23 ar e markedly decreased in comparison to health y subjects. Concomitantly. the abso lute B-cell counts are within the normal ra nge (54). Thus . the data provide evidence that intrinsic B-cell dysfunctions occur in burn patient s. In contrast. B-cell dysfunctions in patients suffering from chronic posttraumatic osteomyelitis are likely to be secondary to the lack of adequate T-cell help. This can be concluded from the experimental finding tha t direct B-cell stimu lati on elicits nor mal B-cell responses whereas the T-cell depend ent stimulation lead s to a suppressed proliferation and differ entiation ofB-ce lls f531. The mechanisms of the se complex immunological alterat ions are curre ntly being discussed (22): humoral su ppresslve factors (PGE2• den atured complement fragments e.g. C1q, collagen. or a newly occurring serum peptide SAP) as well as the gener ation of suppressor cells tCD8+) have to be considered.

~li crobi al

pathogen icity fa ctors a nd inflammation

Micro bial infections ca use inflammatorv reactions which ar e due to the biological activities - of inflammatory med iators (Table 7). The varietv of mediators is classified in (36) :



1. mediato rs which are derived from hum oral precursors (e.g. complement. clotting factors. kinins) and 2. .medi ators which are released from cells te.g. phagocytes. lymphocyt es. mas t cells. platelets. endothe lial

cells. fibroblasts); they are either preformed and stored in intracellular granules (e.g. histami ne. lysosomal enzymes) or newly gene rated upon cellular activation (e.g. etcosanolds. platelet-activating factor PAF. oxygen radicals. cyto kine s},

The quantity of releas ed mediators. their composition in the biological environment. and the sensi tivity of the targe t tissues determi ne the biological response (e.g. increase ofvascular permeability. vasodilation. chemotactic cell infiltration. smooth muscle contraction. altered glandu lar secretion ], Inflammatory mediators ar e a prerequi site for protective immunity. For instan ce. phagocytes are attracted to the sites of tissue tra uma by the chemotactic factors C5a or leukotriene 13 4 , The local release of histamine. leukotriene (4 . and prostacyclin facilitates the evas ion ofthe phagocytes from the blood st ream into the tissue by th e increa se of vascular per meabilit y. Subsequently. the phago cytosed microorgan isms ar e intr acellularly killed by lysosomal enzymes and oxygen rad icals. However . inflammatory mediators also induce local or syste mic damage in the host when they occur in excessive amou nts or when their metabolism into inactive compounds is inadequately contr olled 116. 24. 38) .

Microbial pathogenicity factor s interfere with the inflammatory process (371. The cha rac teristics oft he microorganisms determi ne which cells an d mediator systems are pred ominant ly activated (Fig. 31. It has been shown that tumor necrosis factor. histami ne. prostagla ndins. thromb oxanes. leukotrienes. and oxygen radicals are released du ring systemic endotoxin shock (16. 24). In this regard. animal experiments applying inhibitors of leukotr iene synthesis or receptor an tagonists indicate that lipoxygenase produ cts play a major role (29), Polymorp honuclear gra nulocytes which adhere to endothelial cells release Iipoxygenase produ cts (e.g. LTB4 ) upon interaction with staphylococci which results in the opening of the endothelial barrier an d promotes the microbial invasion (60). Our own stud ies with clinical isolates ofS. aureus and P. ae ruginosa which are the major pat hogens obse rved during burn wound sepsis (63. 64) demonstrate that cell-bound as well as soluble path ogenicity factors (hemolysins) induce the medi ator

Table 7 Representativemediators of inflammation

mediator

structure

source

biological actions

histamine

imidazolylethylamine

mast cells. basophils

vasopermeabnty [ .chemotaxis.productionof slime, smooth muscle contraction

bradykinin

ncnaoepuoe

kmmogen

vasodilation.painreaction,vasccermeabmty T.smooth muscle contraction

C3a/C5a

polypeptide

complement components

degranulationof mast cellsand granulocytes,chemotaxis. smooth muscle contraction

PG E2

AA-metabolite (cyclooxygenasel

mcnocytes. macroonages.

vasodilation,enhancement of leukotriene effects,mucosal protection. immune regulation

LTB4

AA·metabolite (Iipoxygenase)

neutroonns. monocytes.

LTC.

AA·metabolite jlipoxygenase)

mastcells, macrophages.

PAF

phospholipid

basophils. neutropt uls. monocytes. macroptages

neutrophils chemotaxis,degranulationofneutrophils, immuneregulation

macrophages smooth musclecontraction, vasopermeability non 01slime

t.prccuc-

eosmopons aggregationandactivationof inflammatorycells.smooth muscle contraction. vasopermeatnhty T .immune regulation

Abbreviations: PG = prostaglandin, LT - leukctnene. PAF - platelet-activating factor. AA = aract ndcmc acid

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344

Thom e. cardiovasc. S urgeo n 38 (1990)

M icrobia l Pa thogenicity and Host Defense Mechan isms lac ultaUve ly Intracellular pathogens

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Fig. 3 The mutual interactions between microbial pathogens and the host defense mechanisms determine the type ofthe tissue reaction. Extracellula rlypersisting microorganisms preferentially nduce pyogenic infections (involvement of grarulocytes and humoral immunity). In contrast. intracetlularlypersisting microorganisms cause granulernaformation (involvement of mecropbeges/ monocytes and cell-mediated immunity)

mast ce lls

h umo ral detense

mononu clear cell tnmuctto n

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release from mast cells (histamine) an d gran ulocytes Ileukotriene B.d (8, 65). Taxonomically identical str ains vary in thei r pat hogenicity. It has been report ed that invasive staphylococci obtained from wound biopsies have an increased cell-bound pathogenicity as compared to non invasive stra ins obta ined from wound swabs. Thus. invasive microorganisms can escap e mor e easily from the local host defense. Our studies with E. coli strai ns demonstrated tha t the release of leukotri enes from granu locytes and monocytes is modulated due to the expression ofgenetically cloned adhesins. fimbriae, and hemolysins by the bacteria (33, 51, 61). Sublytic concentra tions of pur ified bacterial exotoxins (e.g. alveolysin. stre ptolysin O. the ta-toxin) and endotoxins induce the release ofle ukotrienes and PAF from gra nulocytes but reduce mediator formation after sub seque nt cellstimulation ll O, 11). Concomitantly, the metabo lization of leukotriene 8 4 into inactive compounds is markedly enhan ced. These results suggest that bacterial toxins are , at least in part , res ponsible for the altered reactivity of neutrophil gran ulocytes in septic patients. During microb ial invas ion the gran ulocytes are significantly activated. However , whe n the pathogen icity factors per sist within the circulation the gra nulocytes fail to respond any longer (deactivation). The biochemical mechanisms of the cellular dysfunctions are curren tly being investigated. Recent studies indicate that bacter ial toxins and adhesins modulate various elements of the signa l transduction cascad e (e.g . Gproteins, phosphoinosiHurnover, proteinkinase C, calcium influx) (25, 34, 35). In addition, th e involvement of cellular stress proteins Cheat shock proteins") in the reduction of cell reactivity has been suggested (32). These exam ples clearly demonstrate tha t posttraumatic and posto perative infections are due to the complex inte ractions between microbial pathogeni city factors and host defense mechanisms . Thus , it has to be emp hasized that an interdisciplinar y cooperation (clinical medicinemicrobiology-immunology) is required not only in order to optimize the application of curren t therapy but also to develop novel therapeutic strategies for the benefit of traumatized patie nts .

Refer en ces I

2

3

4

5

6

7

8

'I

10

11

12

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B. Sch liuer. W Konig

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40

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42

43

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346

71lOrac. cardiol'asc. Surg eon 38 (1990)

Microbial Pathogenicity and llost. Defe ns e Mechanisms

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Prof. Dr. fli ed. W. Kiiuig

Med. Mikrobiologie und Immu nologie AG Infekta bwehrmechanismen Huhr-Universitat Bochum D-4630 Bochum t

Downloaded by: University of British Columbia. Copyrighted material.

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ad hestns from mannose-reststant Escherichia coli on mediator release from hum a n lymph ocytes. monocytes. and basophtls and from polymorp honu clea r granu locytes. Infect. Immun. 58 ( 990 ) 1500- 1508 Wall'ryk , S. O: 1. R. Noiotnu.L P. ~Vick ers. D. Wilkinson. D. Maher , E. Satoaris. K. Welch. 1. Fecondo. and A. If . Boyd : The role of the LFA- 1/ ICAM-1 inter action in hu man leukocyte homing and adhes ion. lmmunol. Rev. 108 (1989 ) 135- 16 1 Wink ler, u.. G. Erbs, W. Konig, and E E. Miiller, A comparison of met hods for the qua ntitation of bacteria in bu rn wounds. Zentralbl. Bakte riol.llyg. A 265 (1987) 82-97 Winkler. M., G. Erbs, F. E. Muller, and H/. Konig: Epidemiological studies on the microbial colonizat ion in heavily burned patients. Zentralbl. Bakteriol. Hyg. B 184 (1987) 304-320 wmkter. AI. , G. Erbs; F H. Miiller. and W. KOl/ig: In vitro vtrutcnz wund infizier ender Stap hylokokken-lsola te von schwe rbrandverletzten Patienten . Langenbecks Arch. Chir. 374 (1989) 181-184 Wood, J. 1., M. L. Rodrick, 1. /1. o'Mahony. S. IJ. Patder. L Saporo schetz. P. d'Eon. an d 1. A Mal/nick: Inadequate interleukin 2 production. A funda me ntal immunological deficiency in patients with major burns. Ann. Surg. 200 (19841311 - 319 IVoods. D. E.: Hole of fibronectin in the pathogene sis of gra mnega tive bacillary pneumonia. Hev. Infect. Dis. 9 [Suppl. 4 ) 386-390

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Microbial pathogenicity and host defense mechanisms--crucial parameters of posttraumatic infections.

Posttraumatic and postoperative infections which may be either localized or turn into sepsis are a major cause of morbidity and mortality in surgical ...
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