ISRAEL JOURNAL OF

VETERINARY MEDICINE
MANNHEIMIA HAEMOLYTICA: PHYLOGENY AND GENETIC ANALYSIS OF ITS MAJOR VIRULENCE FACTORS.
ADAMU J.Y.

Department of Veterinary Microbiology and Parasitology, Faculty of Veterinary Medicine, University of Maiduguri, P.M.B. 10 !, Borno "tate, #igeria.

Abstract Mannheimia haemolytica is t$e causative agent of several economically significant veterinary diseases occurring in ruminants and, muc$ more rarely, in ot$er animal species. %t accounts for appro&imately '0( of t$e total cattle deat$s )orld)ide, and is associated )it$ an annual economic loss of over one billion dollars in #ort$ *merica alone. +$e organism seems to be enigmatic, c$anging its nic$e from commensal to a pat$ogenic bacterium under conditions of stress. +$e bacterium )as a sub,ect of e&tensive reclassification in t$e past and is still under continuous revision. Using a molecular genetic approac$, t$e genes t$at code for t$e various virulence factors of M. haemolytica $ave been cloned and c$aracteri-ed, and t$e full genome se.uence completed recently, enabling an improved understanding of its virulence and pat$ogenesis. +$e genetic tools and tec$ni.ues developed for M. haemolytica )ill be useful in post/se.uencing genetic analyses of t$e organism. %n t$is brief revie), t$e genetic basis of ma,or virulence factors, t$e M. haemolytica genome and t$e application of molecular tec$ni.ues to an understanding of Pasteurellaceae p$ylogeny are presented. Ke !"r#s0 Mannheimia (Pasteurella) haemolytica, pat$ogenicity, virulence factors, p$ylogeny INTRODUCTION Mannheimia (Pasteurella) haemolytica is t$e aetiologic agent of pneumonic pasteurellosis of cattle and s$eep, )$ic$ is infections and may cause

considerable economic losses to t$e cattle and s$eep industries 11,23 )it$ climatic and animal management factors being involved in its pat$ogenesis 12,'3. M. haemolytica is a $eterogeneous bacterial pat$ogen. +$e $eterogeneity of t$is bacterium is evident from t$e fact t$at $istorically, t$ere are t)o recogni-ed biotypes of M. haemolytica / biotype * consisting of isolates t$at ferment 4arabinose, and biotype t$at ferments tre$alose 15,637 toget$er t$ey are represented by 18 serovars 12, 3. +$e 18 recogni-ed serovars of t$e former M. haemolytica comple& $ave recently been s$o)n to represent t$ree genetically distinct species. "erovars ', 5, 10 and 16 represent Pasteurella trehaosi 183, serovar 11 represents M. glucosida, )$ile t$e reference strain for t$e ot$er serovars belong to Mannheimia haemolytica 193. %n addition, about 10( of isolates are untypable 1U+3 123. +$e U+ isolates may represent eit$er capsule/deficient strains or distinct species 1!, 103. Furt$ermore, e&tensive epidemiological studies of M. haemolytica strains using molecular typing tec$ni.ues s$o) some significant level of $eterogeneity even )it$in strains of t$e same serovars isolated from various $osts and also from different geograp$ical areas 111,12,1'3. Potential virulence factors of M. haemolytica $ave been identified and c$aracteri-ed by gene cloning and D#* se.uence analyses 1153. +$ese factors include a ruminant/specific leu:oto&in, an anti/p$agocytic capsule, lipopolysacc$aride, iron/restricted outer membrane proteins, a sialoglycoprotease, a neuraminidase and immunoglobulin proteases. "ince M. haemolytica undergoes a nic$e c$ange from commensal to pat$ogenic, t$e control of its virulence factor e&pression is also of significant interest. %t $as been s$o)n t$at M. haemolytica e&$ibits a system 2 .uorum/sensing mec$anism to regulate gene e&pression under specific conditions 1163. M. haemolytica B**/510, )$ic$ )as isolated from a calf )it$ bovine respiratory disease comple&, )as se.uenced to draft coverage. *nnotation and analysis of t$e genome provided an opportunity to discover ne) features potentially related to virulence. %t also permitted identification of possible transcriptional regulatory net)or:s and a natural competence system. +$e genome se.uence also allo)ed comparisons )it$ ot$er se.uenced Pasteurellaceae genomes and an evaluation of M. haemolytica )it$in t$e Pasteurellaceae lineage 11 3. HISTORICAL $ACKGROUND AND TA%ONOMY OF MANNHEIMIA &PASTEURELLA' HAEMOLYTICA Mannheimia (Pasteurella) haemolytica is a )ea:ly $aemolytic, gram/negative coccobacillus )it$ t$e follo)ing complete ta&onomy0 "uper:ingdom/Bacteria7 P$ylum/Proteobacteria7 ;lass/Gammaproteobacteria7 <rder/Pasteurellales7 Family/ Pasteurellaceae7 =enus/Pasteurella 1 http://www.ncbi.nlm.nih.gov/taxonomy taxonomy ).

+$e bacterium $as been a sub,ect of e&tensive reclassification in t$e past7 first called Bacterium bipolare multocidum by +$eodore >itt in 1996. +$e genus name Pasteurella )as first suggested by %talian ;ount +revisan to commemorate 4ouis Pasteur?s )or: )it$ t$e causative agent of fo)l c$olera in tur:eys 1!3. %t )as renamed Pasteurella haemolytica in 1!'2 1183 and classified into t)o biotypes * and +, based on its ability to ferment arabinose and tre$alose respectively, t$oug$ ot$er biovariates $ave been revealed 119,1!,203. +$ere are 1' * serotypes and 5 + serotypes identified 1213, t$e latter being reclassified as Pasteurella trehalosi in 1!!0 18,223. #ine years later, studies based on D#*/D#* $ybridi-ation and 1 "@#* se.uencing led to renaming previous * serotypes 1*1, *2, *6, * , *8, *9, *!, *12, *1', *15, *1 and *183 as Mannheimia haemolytica )$ile t$e remaining *11 serotype became M. glucosida 193. "tudies of genomic D#* or ribosomal @#* $ave revealed lac: of $omologies acceptable for inclusion of some organisms at t$e genus or species level 12', 25, 263. +$e name Mannheimia )as given in tribute to Aalter Mann$eim, a =erman biologist )$ose researc$ $as improved t$e understanding of t$e ta&onomy of t$e Pasteurellaceae family 193. *lt$oug$ P. haemolytica is no) classified as t$ree distinct species/ M. haemolytica M. glucosida and P. trehalosi for t$e purpose of identification and serotyping t$ey are still treated as one species 12 3. %n addition to isolates )$ic$ fall into one of t$e above serotypes, appro&imately 10( of disease isolates from ruminants are untypable 128,293. +$e ta&onomy of Pasteurellaceae is not )ell settled and is under continuous revision. +$e ta&onomy $as involved mainly p$enotypic c$aracteri-ation, including t$e determination of polyamine patterns 12!,'03. * fe) t$oroug$ studies $ave also been carried out at t$e genotypic level. A$ole genome D#*BD#* $ybridi-ations )ere carried out some time ago on Pasteurellaceae 1'13 and genetic relatedness )as investigated by D#*Br@#* $ybridi-ation 1253. De)$irst et al. 126,'23 investigated t$e p$ylogenetic relations$ips )it$in t$e family by 1 " rD#* se.uence comparisons and a full p$ylogenetic tree )as publis$ed recently 1''3. Cedegaard et al. 1'53 used in!B se.uences to investigate in more detail t$e genetic relations$ips of t$e genus "aemophilus. Co)ever, ot$er p$ylogenetic mar:er genes are needed to clarify t$e ta&onomy )it$in t$e Pasteurellaceae, to provide additional tools for genetic identification and to give insig$t into t$e evolution of t$is group of bacteria. +$e rpoB gene $as been used successfully for t$e elaboration of p$ylogenetic relations$ips in several groups of bacteria, and normally $as a $ig$er discriminatory po)er t$an 1 " rD#* se.uences 1'6, ' 3. Besides t$e use of partial rpoB se.uences for delineating p$ylogenetic relations$ips 1'8, '93 t$e gene $as also been applied for improving diagnosis 1'!,503. Cence, rpoB gene se.uence analysis in con,unction )it$ 1 " rD#* se.uencing is a valuable tool for p$ylogenetic studies of t$e Pasteurellaceae and may also prove useful in reorgani-ing its current ta&onomy 1513. PATHOGENICITY Mannheimia (Pasteurella) species are common commensals on mucous membranes of most domestic animals )orld)ide 1523. Most animals are asymptomatic carriers of M. haemolytica and P. trehalosi and also carry

strains of P. multocida. M. haemolytica is associated )it$ disease in cattle causing pneumonic pasteurellosis, $aemorr$agic septicaemia and abortion 15', 5537 pneumonia, mastitis and septicaemia in domestic s$eep 123 and isolates in domestic goats 156,5 3. Biovariates of M. haemolytica P. trehalosi and P. multocida $ave been isolated from *merican bison, big$orn s$eep, Dall s$eep, el:, moose, mountain goats, mule, deer and prong$orn 1203. <t$er $osts of animals affected by species of Pasteurella include rabbits, pigs, crocodiles, dogs and cats 1583. @ecently M. haemolytica serotypes *2 and *12 )ere isolated from clinically ill poultry in #igeria 1593. +$is organism $as a -oonotic potential 15!3. Man gets infected by P. multocida, and also by P. dogmatis P. canis and M. haemolytica. %nfections of Pasteurella are spread )orld)ide in )ild and domestic animals. Man contracts it by small animals and farm animals, -oo and )ild animals. People )$o )or: )it$ animals are particularly at ris:. +$e transmission mostly $appens via )ound infection, )$ic$ becomes inflamed and is painful. P$legmons or abscesses in t$e subdermis, infections of t$e tendon s$eat$, t$e tendon and bones can occur, follo)ed by necrosis, periostitis and osteomyelitis. (http://www.veterinary#public# health.de/home$e/au!gaben/%oonosen/ba&terien$e.htm). MOLECULAR ANALYSIS OF VIRULENCE FACTORS OF M. HAEMOLYTICA Ca(s)*ar ("* sacc+ar,#e &CP';apsular polysacc$arides $ave been implicated in t$e pat$ogenesis of Mann$eimiosis. +$e role of ;Ps in t$e virulence of a number of gram/negative pat$ogens $as been )ell documented7 t$ese include ad$erence 1603, prevention of desiccation 1613, resistance to $ost immune defense 162,6'3 and mas:ing cell surface 16'3. +$e M. haemolytica *1 ;Ps is composed of disacc$aride repeats of #/ acetylmannosaminuronic acid 1Man#*c*3D/1,5 lin:ed )it$ #/ acetylmannosamine 1Man#*c3 1653. +$e genes nma' and nmaB, )$ic$ code for UDP/=lc#*c/2/epimerase and UDP/Man#*c/de$ydrogenase, respectively, are involved in capsular polysacc$aride biosynt$esis in M. haemolytica *1 1663. Man#*c* is one of t$e sugar moieties in t$e enterobacterial common antigen 1E;*3 16 3. *capsular isolates $ave occasionally been reported 1683, but t$eir genetic basis $as not been e&amined. #o) t$at t$e genes $ave been cloned, molecular tec$ni.ues are used to create defined acapsular mutants 16'3. Furt$ermore, it )as reported t$at t$e acapsular mutant of M. haemolytica )as more easily p$agocyti-ed t$an t$e capsular strains. +$e capsular material may interact )it$ pulmonary surfactant, t$ereby facilitating local ad$erence of t$e organism to different $ost cells 115, 69, 6!, 03. L,("("* sacc+ar,#e &LP' 4ipopolysacc$aride represents 10/16( of t$e dry )eig$t of M. haemolytica 1 13. +)o genes potentially involved in 4Ps biosynt$esis in M. haemolytica

$ave been cloned and c$aracteri-ed. * 2 ' amino acid reading frame encoding a peptide similar to ". in!luen%ae lipooligosacc$aride biosynt$etic gene, lic2 )as identified immediately do)nstream of t$e gene encoding glycoprotease 1 23. +$e 4Ps gene, called lps* is a potential glycosyltransferase involved in core/oligosacc$aride biosynt$esis 1153. %t $as been proposed t$at M. haemolytica. 4Ps can cause immune/mediated $ypersensitivity t$at can e&acerbate inflammation and damage by a locali-ed *rt$us or "$)art-mann reaction in t$e lung 1 '3. +$ey $ave endoto&ic activity and moderate leu:ocyte activity 1 53. +$e 4Ps constitute a ma,or surface antigen and t$e somatic serotype )as defined according to t$eir structural antigenic components.. M. haemolytica serotypes of biotype * possess roug$ type of 4Ps )$ile biotype + contains smoot$ 4Ps. 4Ps )as also found to stimulate tumor necrosis factor 1+#F3 release from bovine alveolar macrop$ages as )ell as cyto:ines 115, 6, 3. M. haemolytica 4Ps induce an inflammatory cyto:ine response and e&pression of t$e D2/integrin 4F*/1 leu:oto&in receptor in t$e $ost 115, 83. O)ter -e-bra.e (r"te,.s &OMP' <uter membrane proteins and lipoproteins of M. haemolytica may be involved in serum sensitivity 1 9, !3 and are believed to be important protective antigens. *ntibodies directed against some of t$ese antigens are capable of inducing p$agocytosis and complement/mediated :illing 1 !3, and $ence are of interest as potential vaccine candidates. <MP profiles vary )it$in and bet)een serotypes 1103. M. haemolytica produces a set of <MP in response to iron depletion 1803. +$e iron/regulated outer membrane proteins 1%@<MPs3 are recogni-ed by convalescent bovine 1and ovine3 serum, )$ic$ s$o)s t$at t$ey are antigenic and e&pressed in vivo 1813. +$ree %@<MPs 1 81, 88 and 100 :Da3 e&pressed by M. haemolytica *1 gro)n in vitro under conditions of iron restriction, $ave been c$aracteri-ed 181, 82, 8'3. +$e 81/ and 100 :D %@<MPs )ere identified as bovinespecific transferin binding proteins 1+bps3 t$at are responsible for iron ac.uisition 1853. +$e genes t$at code for +bp* and +bpB $ave been cloned and c$aracteri-ed 1863. +$e tbp* and tbpB are arranged in an operon, and tbpB precedes tbp*. By genetic manipulation of t$e tbp*FtbpB genes, recombinant +bps $ave been produced in (. coli. +$ese recombinant proteins )ere s$o)n to be effective vaccine candidates in a vaccine trial and c$allenge study 18 3. F,-br,ae a.# A#+es,. Bacterial ad$esions function in coloni-ation by binding to receptor molecules on $ost cell surfaces 11 3. Many ad$esions are pili, and t$e type iv pilus locus pil*B;D )as annotated in M. haemolytica. +ype iv pili are :no)n to function in D#* upta:e, ad$esion, and motility in ". in!luen%ae, P. aeruginosa, and )eisseria species 1883 and may perform t$ese functions in M. haemolytica. "everal predicted non pilus ad$esion proteins and additional proteins t$at could modify $ost mucosal surfaces are also present in M. haemolytica 11 3.

* serotype *1/specific antigen 1"sa13 is also t$oug$t to function as an ad$esin 1893. +)o types of fimbrae )ere demonstrated in M. haemolytica a large and rigid one 12nm in )idt$, )$ile t$e smaller and fle&ible 6nm )ide 18!,903. +$ese structures $ave not $o)ever been c$aracteri-ed in detail, and t$eir presence does not appear to be a universal feature of M. haemolytica isolates 1913. * $ig$molecular ad$esion protein 1CMA*P7 G2'0:Da3 $as been identified in M. haemolytica *1 1923. Le)/"t"0,.s &LKT' M. haemolytica secretes a 102 :D leu:oto&in 1l:t*3 t$at is a calcium/ dependent cytoto&in belonging to t$e @+H 1repeats in to&in3 family of to&ins. 4eu:oto&in genes and protein $ave been identified in all serotypes 19'3 and nearly all isolates e&amined secrete t$e to&in 1953. 4:t* is species/specific, $aving leu:oto&ic activity only against ruminant lymp$oid cells 196,9 3. %t is also )ea:ly $aemolytic 1983. +$oug$ t$e leu:oto&in can bind to cells from a variety of species 1993, cytolysis re.uires a specific interaction )it$ t$e lymp$ocyte/function associated antigen 1 14F*/13, or D2 integrin, on t$e target cell 19!,!03. *t $ig$ concentrations, t$e to&in creates pores in t$e cell membrane t$at lead to s)elling and lysis 1!13. *t sub/lytic concentrations, t$e to&in activates neutrop$ils 1 03, induces inflammatory cyto:ine production 1!23, invo:es cytos:eletal c$anges, and causes apoptosis 1!',!53. ;ombined, t$ese activities are t$oug$t to impair primary lung immune defense mec$anisms and participate in inflammation and tissue destruction t$at define pneumonic mann$eimiosis. +$e leu:oto&in is encoded by four/gene cluster t$at includes t$e ! ' amino acid structure gene, l&t*, and genes t$at are re.uired for its post/translational acylation 1l&t;3 and secretion 1l&tB and l&tD3 1!63. G* c"(r"tease *ll types of M. haemolytica produce a -inc metalloglycoprotease t$at $as activity against </sialoglycoprotein 1! ,!83. +$e gcp gene $as been cloned into (. coli and se.uenced 1!93. +$e protease is t$oug$t to act at t$e $ost cell surface to en$ance ad$esion and its activity in vitro can be potentiated by coincubation )it$ t$e leu:oto&in 1!!3. <ne conse.uence of t$is activity is t$e aggregation of platelets leading to t$eir deposition in t$e alveoli of t$e lung 1!!3. Ne)ra-,.,#ase * neuraminidase produced by M. haemolytica $as been suggested to play a role in coloni-ation 1100,1013. %t is produced by all 18 classical M. haemolytica serotypes 11023. +$e production of antineuraminidase serum antibodies by cattle after transt$oracic infection )it$ t$e bacterium is evidence t$at neuraminidase is produced by M. haemolytica in vivo 110'3.

%n ot$er bacterial respiratory pat$ogens, neuraminidases are t$oug$t to desialate salivary glycoproteins, allo)ing pat$ogenic organisms to escape defenses in t$e orop$aryn& 11053. Based on gel filtration, t$e associated en-ymes are 160/200 >D in si-e and primarily cleave #/acetylneuramin lactose, but some also $ave activities t$at cleave fetuin, alp$a/1/acid glycoprotein, and colominic acid 11023. Furt$ermore, t$e production of neuraminidase by M. haemolytica *1 is ma&imal in vitro 11063, )$ic$ suggests a possible role during infection. T+e MANNHEIMIA (PASTEURELLA) HAEMOLYTICA 1e."-e +$e genome se.uence of M. haemolytica )as recently publis$ed 11 3 under t$e direction of Dr "ara$ Cig$lander of Baylor ;ollege of Medicine, Couston, +e&as )it$ funding provided by t$e U"D* #ational @esearc$ =rant %nitiative 00/'6205/!22!. +$e M. haemolytica genome consists of a D#* )it$ an appro&imate = I ; content of 51(. +$e genome lengt$ is about 2.68Mb. +$e annotated genome includes 29'! coding se.uences, 1! of )$ic$ )ere assigned a function and 5' of )$ic$ are uni.ue to M. haemolytica. +$roug$ genome annotation many features of interest )ere identified, including bacteriop$ages 1JM$aMu1 and JM$aMu23 and genes related to virulence, natural competence and transcriptional regulation. +$e general features of M. haemolytica are given in +able 1. ;omparison of competence loci and D#* upta:e signal se.uences 1U""3 in ot$er species in t$e family Pasteurellaceae indicates t$at M. haemolytica 'ctinobacillus pleuropneumoniae, and "aemophilus ducreyi form a lineage distinct from ot$er Pasteurellaceae. +$is observation )as supported by a p$ylogenetic analysis using se.uences of predicted $ouse:eeping genes 11 3. +$e )$ole genome s$ortgun pro,ect $as been deposited at =enBan: under pro,ect accession number **"*00000000 )$ile t$e draft version $as accession number **"*01000000.

CONCLUSION Mannheimia haemolytica continues to be an enigmatic organism. Ait$ t$e completion of t$e genome se.uencing, our understanding of its virulence and pat$ogenesis )ill improve and t$e genetic tools and tec$ni.ues t$at $ave been developed for M. haemolytica )ill be useful in postse.uencing genetic analyses of t$e organism bearing in mind t$e great economic importance of t$is bacterium. ACKNO2LEDGMENT +$an:s are due to Dr "ara$ Cig$lander of t$e Baylor ;ollege of Medicine, Couston, +e&as and Pat Blac:all of t$e Department of Primary %ndustries, Keerongpili, Victoria, *ustralia for providing some of t$e reprints used in t$is )rite/up.

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82. Morc:, D.7 Ellis, B.7 Domingue, P.7 <slon, M. and ;osterton, L.0 %n vivo e&pression of iron regulated outer/membrane proteins in Pasteurella haemolytica *1. Microb. Pat$og. 110'8'/'89, 1!!1. 8'. ;onfer, *.A.7 ;lin:enbeard, >.D. and Murp$y, =.4.0 Pat$ogenesis and virulence of Pasteurella haemolytica in cattle0 *n analysis of current :no)ledge and future approac$es. %n0 Donac$ie,A.7 4ainson, F.*.7 Codgson L.;. 1eds3 "aemophilus 'ctinobacillus and Pasteurella. #e) Kor:0 Plenim Press, pp 61/ 2, 1!!6. 85. <gunnari)o, L.*. and "c$ryvers, *.B.0 %ron ac.uisition in Pasteurella haemolytica0 e&pression and identification of a bovine/specific transferrin receptor. %nfect. %mmun. 690 20!1/20!8, 1!!0. 86. <gunnari)o, L.*.7 Aoo, +.>.A.7 4o, @.K.;.7 =on-ale-, =.;. and "c$ryvers, *.B.0 ;$aracteri-ation of t$e Pasteurella haemolytica transferin receptor genes and t$e recombinant receptor proteins. Microbiol. Pat$ogen. 2'028'/295, 1!!8. 8 . Potter, *.*.7 "c$ryvers, *.B.7 <gunnari)o, L.*.7 Cutc$ins, A.*.7 4o, @.K.;. and Aatts, +.0 Protective capacity of t$e Pasteurella haemolytica transferin/binding proteins +bp* and +bpB in cattle. Microbiol. Pat$ogen. 2801!8/20 , 1!!!. 88. Ba:alet-, 4.<.7 Ba:er, B.D.7 Lurcide:, L.*.7 Carrison, *.7 #ovotny, 4.*.7 Boo:)alter, L.E.7 Mungur, @. and Munson, Lr. @.".0 Demonstration of type iv pilus e&pression and a t)itc$ing p$enotype by "aemophilus in!luen%ae. %nfect. %mmun. 8'01 '6/1 5', 2006. 89. 4i, H.Q.7 and #i:aido, C.0 Efflu&/mediated drug resistance in bacteria. Drugs 5016!/205, 2005. 8!. Morc:, D.A.7 @aybould, +.L.=.7 *cres ".D. et al.0 Electron microscopic description of glycocaly& and fimbrae on t$e surface of Pasteurella haemolytica *1. ;an. L. Vet. @es. 610 9'/99, 1!98. 90. Morc:, D.A.7 <lson, M.E.7 *cres, ".D.7 Daost, P/K. and ;osterton, L.A.0 Presence of bacterial glycocaly& and fimbrae on Pasteurella haemolytica in feedlot cattle )it$ pneumonic pasteurellosis. ;an. L. Vet. @es. 6'0 1 8/181, 1!9!. 91. van *lp$en, 4.0 *d$esion/receptor interaction of "aemophilus in!luen%ae and ot$er bacteria from t$e C*P group. %n0 Donacie, A. 4ainson, F.*.7 Codgson, L.;. 1ed3 "aemophilus 'ctinobacillus and Pasteurella. #e) Kor:0 Plenum Press, pp. 9!/100, 1!!6. 92. 4o, @.K.;.0 Pasteurella. %n0 Disseminating bacterial infections. *cademic Press, pp.!8'/!96, 2001.

9'. Burro)s, 4.4.7 <la$/Ainfield, E. and 4o, @.K.0 Molecular analysis of t$e leu:oto&in determinants from Pasteurella haemolytica serotype 1 to 1 . %nfect. %mmun. 106001/6008, 1!!'. 95. "aadati, M.7 =ibbs, C.*.7 Parton, @. and ;oote, L.=.0 ;$aracteri-ation of t$e leu:oto&in produced by different strains of Pasteurella haemolytica. L. Med. Microbiol. 5 028 /295, 1!!8. 96. 96. "$e)en, P.E. and Ail:ie, B.#.0 ;ytoto&in of Pasteurella haemolytica acting on bovine leu:ocytes. %nfect. %mmun. '60!1/!5, 1!92. 9 . >ae$ler, >.4.7 Mar:$am, @.L.F.? Muscoplat, ;.;. and Lo$nson, D.A.0 Evidence for cytocidal effects of Pasteurella haemolytica on bovine perip$eral blood mononuclear leu:ocytes. *m. L. Vet. @es. 5101 !0/1 !', 1!90. 98. Murp$y, =.4.7 A$it)ort$, 4.;.7 ;lin:enbeard, >.D. and ;lin:enbeard, P.*.0 Caemolytic activity of t$e Pasteurella haemolytica leu:oto&in. %nfect. %mmun. '0'20!/'212, 1!!6. 99. "un, K.7 ;lin:enbeard, >.D.7 ;udd, 4.*.7 ;lar:e, ;.@. and ;lin:enbeard, P.*.0 ;orrelation of Pasteurella haemolytica leu:oto&in binding )it$ susceptibility to into&ication of lymp$oid cells from various species. %nfect. %mmun. 80 2 5/ 2 !, 1!!!. 9!. 4i, L.7 ;lin:enbeard, >.D. and @itc$ey, L.A.0 Bovine ;D19 identified as a species/specific receptor for Pasteurella haemolytica leu:oto&in. Vet. Microbiol. 80!'/!!, 1!!!. !0. Leyaseelan, ".7 Csuan, ".4.7 >annan, M.".7 Aalc$ec:, B.7 Aang, L.F.7 >e$rli, M.E.7 4ally, E.+.7 "iec:, =.;. and Ma$es)aran, ".>.0 4ymp$ocyte function/associated antigen 1 is a receptor for Pasteurella haemolytica leu:oto&in in bovine leu:ocytes. %nfect. %mmun. 680520/ 526, 2000. !1. ;lin:enbeard, >.D.7 Mosier, D.*.7 and ;onfer, *.A.0 +ransmembrane pore si-e and role of cell s)elling in cytoto&icity caused by Pasteurella haemolytica leu:oto&in. %nfect. %mmun. 680'12 /'1'', 1!9!. !2. Koo, C.".7 @a,agopal, ".7 Ma$es)aran, ".>. and *mes, +.@.0 Purified Pasteurella haemolytica leu:oto&in induces e&pression of inflammatory cyto:ines from bovine alveolar macrop$ages. Microb. Pat$og. 1902'8/262, 1!!6. !'. "tevens, P.>. and ;-upryns:i, ;.L.0 Pasteurella haemolytica leu:oto&in induces bovine leu:ocytes to undergo c$anges consistent )it$ apoptosis in vitro. %nfect. %mmun. 50110/118, 1!! . !5. "un, K.7 ;lin:enbeard, >.D.7 ;lar:e, ;.@7 ;udd, 4.*.7 Cig$lander, ". and Dabo, M.0 Pasteurella haemolytica leu:oto&in induces apoptosis of bovine lymp$ocytes involves D#* fragmentation. Vet. Microbiol. 1 190 1/15, 1!!9.

!6. Cig$lander, ".>.7 ;$idambaram, M.7 Engler, M.L. and Aeinstoc:, =.M.0 D#* se.uence of t$e Pasteurella haemolytica leu:oto&in gene cluster. D#* ;ell Biol. 9016/ 29, 1!9!. ! . *bdulla$, >.M.7 4o, @.K. and Mellors, *.0 Distribution of glycoprotease activity and t$e glycoprotease gene among serotypes of Pasteurella haemolytica. Bioc$em. "oc. +rans. 190!01/!0', 1!!0. !8. <tula:o)s:i, =.4.7 "$e)en, P.E.7 Udo$, *.E.7 Mellors, *. and Ail:e, B.#.0 Proteolysis of sialoglycoprotein by Pasteurella haemolytica cytoto&ic culture supernatant. %nfect. %mmun. 520 5/80, 1!9'. !9. 4o, @.K.;. and M.4.E.0 ;loning, nucleotide se.uence, and e&pression of t$e Pasteurella haemolytica *1 glycoprotease gene. L. bacterial. 18'066!8/ 6 0', 1!!1. !!. #yar:o, >.*.7 ;oomber, B.4.7 Mellors, *. and =entry, .*.0 Bovine platelet ad$esion is en$anced by leu:oto&in and sialoglycoprotease isolated from Pasteurella haemolytica *1 cultures. Vet. Microbiol. 1091/!1, 1!!9. 100. Fran:, =.C. and +abatabai, 4.0 #euraminidase activity of Pasteurella haemolytica isolates. %nfect. %mmun. '20111!/ 1122, 1!91. 101. "a:arya, ". and <ncu, ".0 Bacterial ad$esins and t$e role of sialic acid in bacterial ad$esion. Med. "ci. Monit. !0 @*8 /@*92, 200'. 102. "traus, D.;.7 Lolley, A.4. and Purdy, ;.A.0 ;$aracteri-ation of neuraminidases produced by various serotypes of Pasteurella haemolytica. %nfect. %mmun. 10 5 !/5 85, 1!!'a. 10'. "traus, D.;. and Purdy, ;.A.0 %n vivo production of neuraminidase by Pasteurella haemolytica *1 in goats after intrat$oracic c$allenge. %nfect. %mmun. 20 5 86/ 5 89, 1!!5. 105. =otts$al:, *.0 ;orrelation bet)een composition, structure, s$ape and function of a salivary mucoprotein. #ature. 19 0!5!/!61, 1! 0. 106. "traus, D.;.7 Unbe$agen, P.L. and Purdy, ;.A.0 #euraminidase production by a Pasteurella haemolytica *1 strain associated )it$ bovine pneumonia. %nfect. %mmun. 10 26'/26!, 1!!'b.