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Oral infection of mice with Salmonella enterica serovar Typhimurium causes meningitis and infection of… Wickham, Mark E; Brown, Nat F; Provias, John; Finlay, B B; Coombes, Brian K Jun 27, 2007

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ralssBioMed CentBMC Infectious DiseasesOpen AcceResearch articleOral infection of mice with Salmonella enterica serovar Typhimurium causes meningitis and infection of the brainMark E Wickham1,4, Nat F Brown1,5, John Provias2, B Brett Finlay1 and Brian K Coombes*3Address: 1Michael Smith Laboratories, University of British Columbia, Vancouver, BC., Canada, 2Department of Neuropathology, Hamilton Health Sciences Corporation, Hamilton, ON., Canada, 3Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada, and the Laboratory for Foodborne Zoonoses, Public Health Agency of Canada, Guelph, ON., Canada, 4Phillips Ormonde Fitzpatrick, Level 21, 367 Collins Street, Melbourne 3000, Australia and 5Institute for Glycomics, Griffith University-Gold Coast Campus, PMB 50, Gold Coast Mail Centre, Gold Coast, Queensland 9726, AustraliaEmail: Mark E Wickham - m_wickham@mac.com; Nat F Brown - natbrowni@hotmail.com; John Provias - provijoh@hhsc.ca; B Brett Finlay - bfinlay@interchange.ubc.ca; Brian K Coombes* - coombes@mcmaster.ca* Corresponding author    AbstractBackground: Salmonella meningitis is a rare and serious infection of the central nervous systemfollowing acute Salmonella enterica sepsis. For this pathogen, no appropriate model has beenreported in which to examine infection kinetics and natural dissemination to the brain.Methods: Five mouse lines including C57BL/6, Balb/c, 129S6-Slc11a1tm1Mcg, 129S1/SvImJ, B6.129-Inpp5dtm1Rkh were used in the murine typhoid model to examine the dissemination of systemicSalmonella enterica serovar Typhimurium following oral infection.Results: We report data on spontaneous meningitis and brain infection following oral infection ofmice with Salmonella enterica serovar Typhimurium.Conclusion: This model may provide a system in which dissemination of bacteria through thecentral nervous system and the influence of host and bacterial genetics can be queried.BackgroundSalmonella species are Gram-negative, facultative intracel-lular bacteria that are distributed globally. Two recognizedspecies of Salmonella include S. enterica and S. bongori,with S. enterica serovars Typhimurium, Typhi and Enterid-itis causing the vast majority of human infections world-wide. Humans are infected with S. enterica thoughcontaminated food and water and present with a range ofacute symptoms including gastroenteritis, fever, andheadache. Although systemic infections with S. Typhi are[1]. Infections with non-typhoidal strains of Salmonellaare a global burden, with an estimated 1.4 million cases inthe United States alone [2].Salmonella meningitis is an uncommon complication ofsalmonellosis, occurring more frequently in neonates andinfants [3,4], although adult cases are reported. Whileconsidered rare in the developed world, Salmonella is acommon cause of enterobacterial meningitis in Africa,Brazil and Thailand [4,5]. Cases in adults of SalmonellaPublished: 27 June 2007BMC Infectious Diseases 2007, 7:65 doi:10.1186/1471-2334-7-65Received: 4 January 2007Accepted: 27 June 2007This article is available from: http://www.biomedcentral.com/1471-2334/7/65© 2007 Wickham et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Page 1 of 6(page number not for citation purposes)uncommon in developed countries, typhoid remains asignificant public health problem in the developing worldinfection report colonization of the cerebrospinal fluid,fatal brain abscesses caused by intracranial colonizationBMC Infectious Diseases 2007, 7:65 http://www.biomedcentral.com/1471-2334/7/65of S. enterica serotype Typhimurium [6], adult Salmonellameningitis [7] and CSF pleocytosis [7]. Mortality rates aretypically high, especially in infants where rates have been60% [8]. Other major issues concerning Salmonella men-ingitis is a high treatment failure rate, high relapse rateand considerable neurological sequelae in those that sur-vive, including mental retardation, cerebral palsy, and vis-ual and hearing impairment [3,4,8-11]. The treatment ofsuch complicated cases is made more difficult by the lackof a priori knowledge of the pathogen involved, restric-tions in pediatric use of certain antibiotics, the sharp andcontinued rise in antimicrobial resistance and the prolif-eration of multi-drug resistant organisms in communitysettings. The 1970's to early 1990's witnessed the emer-gence of Salmonella isolates resistant to the front-line anti-microbial chloramphenicol, as well as cotrimoxazole,ampicillin and amoxicillin [12]. In more contemporarymedicine, multi drug-resistant Salmonella such as S. Typh-imurium strain DT104 is a constant reminder that newanti-infectives against novel targets are in demand. DT104is commonly resistant to ampicillin, chloramphenicol,florfenicol, streptomycin, spectinomycin, sulfonamidesand tetracycline [13] and infections with multi-drugresistant S. enterica isolates are associated with highermortality rates than infection with susceptible strains[14]. This apparent link between drug resistance and viru-lence is not well understood but deserves considerableattention.The mechanisms of how Salmonella gains access to theCNS and brain are not known. Outstanding questionsinclude (i) how does Salmonella disseminate from theintestinal mucosa to the CNS? (ii) how do bacteria gainaccess to the brain? (iii) what cell types are utilized fortransport to the brain and intracellular replication withinthis compartment? (iv) what role does host genetics andimmune repertoire play in this process? Lack of an appro-priate animal model has made it difficult to address thesequestions. An animal model in rabbits of experimental S.enterica serotype Enteriditis meningitis has been reported[15], although this model involved direct inoculation ofthe cerebral spinal fluid using an intracisternally placedneedle. Currently there is a dearth of reports that describethe natural progression of salmonellosis from the intesti-nal mucosa, though the CNS and to the brain. Here wereport that the widely used oral infection model of salmo-nellosis fulfills the criteria of natural disseminationthough a susceptible host animal from the intestinalmucosa to the brain. This is accompanied by meningitisand a reproducible behavioral manifestation of intracra-nial infection that occurs in at least five genetically distinctmouse lines and that correlates significantly with the bac-terial load in the brain. The development of animal mod-terial dissemination, the kinetics of natural disease pro-gression, and the influence of host genetics on thisprocess. Such models will also be necessary for testinginvestigational antimicrobials and vaccines for therapeu-tic value against bacterial meningitis.MethodsBacteria and culture conditionsSalmonella enterica serovar Typhimurium strain SL1344[16] was used throughout this study. Bacteria were rou-tinely cultured in LB broth and on solid LB agar platescontaining streptomycin at 50 µg ml-1. Prior to animalinfections, bacteria were cultured overnight in LB broth,washed in a buffer containing 0.1 M HEPES (pH 8.0) and0.9% sodium chloride, and resuspended in the samebuffer to ~107 – 109 colony forming units (cfu) per ml.Experimental animalsExperimental animals were female mice between 8 weeksto 12 weeks of age. Five different mouse strains were usedin these experiments and include: C57BL/6 (Jackson Lab-oratories), Balb/c (Jackson Laboratories), 129S6-Slc11a1tm1Mcg (formerly 129/sv Ity/Nramp-/-) [17], 129S1/SvImJ (Jackson Laboratories), B6.129-Inpp5dtm1Rkh (for-merly 129sv/SHIP-1-/- F1) [18]. Animals were obtainedwith full health reports, were deemed to be healthy andfree of infection and were housed under specific pathogenfree conditions.Animal infections and tissue samplesAll animal experiments were conducted as approved bythe local Animal Ethics Board and pursuant to guidelinesset out by the Canadian Council on Animal Care. Animalinfections were carried out by inoculating mice per osusing a gavage needle with approximately 106 to 108 wildtype S. enterica serotype Typhimurium strain SL1344 in a0.1 ml volume. Infected animals were examined twicedaily for signs of terminal morbidity and animals that hadbecome moribund or that exhibited a balance defect wereeuthanised by cervical dislocation. At necropsy the brainwas removed, dissected into right and left hemisphereswith one hemisphere processed for pathology and theother placed in 1 ml of sterile phosphate buffered saline.This latter sample was homogenized in a tissue homoge-nizer (Polytron, Kinematica) and the homogenate wasdiluted in sterile PBS and plated on solid LB agar contain-ing streptomycin to enumerate S. Typhimurium cfu. Bac-terial load was expressed as cfu/organ.Pathology scoringFor pathologic scoring, brain tissues were fixed in 2%paraformaldehyde in routine fashion [19] and sectionedfor histologic examination. Each brain was processed inPage 2 of 6(page number not for citation purposes)els of bacterial meningitis and intracranial infections willpermit a better understanding of the mechanisms of bac-one paraffin block and three sections were cut and stainedwith hematoxylin and eosin (H/E), Gram, and naptholBMC Infectious Diseases 2007, 7:65 http://www.biomedcentral.com/1471-2334/7/65esterase to identify mast cells. A neuropathologist exam-ined all brain sections blindly. The degree of inflamma-tion was scored on a 0 to 4+ scale, 0 representing noinflammation and 4+ representing involvement of theentire contour of the sub-arachnoid space of the section.ResultsObservations on infected miceOur studies on Salmonella enterica pathogenesis involveinfection of the mouse in order to examine bacterial viru-lence factors that are essential during discrete stages ofinfection. During the acute phase of infection, micedevelop overt signs of infection (hunched posture,reduced movement, loss of body weight, piloerection).During the course of these studies over several years, webecame interested in a proportion of mice that developeda neurological abnormality with balance defect followinginfection. These mice exhibited an exaggerated lean to oneside of the body and longitudinal spinning and rotarymotion as the most prominent manifestation of infection.Rolling occurred in either direction (however only unidi-rectional movement was observed for any given mouse)ranging from intermittent rolling through to constant roll-ing (Figure 1, and Additional file 1). Neurological deficitswere not unique to one particular strain of mouse, as weobserved this behaviour in five distinct mouse linesincluding wild type C57BL/6, wild type BALB/c, 129S1/SvImJ, 129S6-Slc11a1tm1Mcg, and B6.129-Inpp5dtm1Rkh.Examination of bacterial load in infected miceThe observed neurological deficits following infectionlead us to speculate that an intracranial infection with Sal-monella was taking place in affected mice. To examine thedissemination of S. Typhimurium in mice exhibiting roll-ing behavior, bacterial load was examined in both rollingand non-rolling infected mice. Brains of mice exhibitingneurological deficit had significantly higher bacterialloads (mean, 2.66 ± 0.66 × 106 cfu/organ) than infectedmice without overt signs of neurological deficit (mean,4.21 ± 1.72 × 103 cfu/organ) (P = 0.0002, Mann Whitney)(Figure 1). Whereas some non-rolling mice had no detect-able cfu in the brain (approximately 10–20% of animals),this was never the case for infected mice that had devel-oped neurological deficits.Pathologic examination of mouse brainsThe finding that a proportion of mice developed neuro-logical deficits following oral infection with S. Typhimu-rium and that these mice had a significantly greaterbacterial load in the brain compared to non-affected micelead us to test whether mice developed meningitis follow-ing infection. Mouse brains that were processed for his-topathology were randomized and coded and scored by aclinical finding was the presence of patchy meningitisconfined to the sub-arachnoid space in all mice with neu-rological deficit (see Table 1). The meningitis was com-posed of a mixture of acute and chronic inflammatorycells, chiefly neurophils and macrophages. In general themeningitis was consistent with a sub-acute time framereflecting a process of a few days to one week in duration.The inflammation was non-necrotizing and no granulo-mas were present. The degree of inflammation was scoredon a 0 to 4+ scale, 0 representing no inflammation and 4+representing involvement of the entire contour of the sub-arachnoid space of the section (data summarized in Table1). Some of the brains had thrombosed sub-arachnoidvessels in areas of meningitis, however none of the casesRolling behavior of Salmonella infected miceFigure 1Rolling behavior of Salmonella infected mice. (A). Still frames of a C57BL/6 mouse infected with Salmonella enterica serovar Typhimurium (plus Additional file 1) which shows rolling behavior as a prominent feature of intracranial infec-tion. Rotation speeds of 1 rotation per 0.3 seconds to 1.5 seconds were observed. Rotary motion was observed in either direction, though only unidirectional motion was observed for any given mouse. (B). Bacterial load in the brains of rolling and non-rolling C57BL/6 mice. Infected mice were sacrificed and the brain removed as described in the text. Brain homogenates were plated on solid LB microbio-logical agar for enumeration of bacterial colony forming units (cfu). Each data point represents one animal. Shown is the data scatter of log-transformed cfu per organ from each ani-mal, with the horizontal line representing the geometric mean (P = 0.0002, Mann Whitney).VHF VHF VHFVHFVHFVHFVHFVHFVHF VHFQRQUROOLQJ UROOLQJORJ FIXEUDLQ3 %$Page 3 of 6(page number not for citation purposes)neuropathologist who was blinded to the treatment his-tory and clinical outcome of the mouse. The principalhad any cerebral infarction or encephalitis. One of thecases with more intense meningitis also had a ventriculitisBMC Infectious Diseases 2007, 7:65 http://www.biomedcentral.com/1471-2334/7/65(Figure 2). There was no obvious correlation betweendevelopment of meningitis and bacterial load in othersystemic sites of infection including the liver and spleen.Bacterial load in these sites is typically variable in infectedmice and ranged from ~1 × 104 to 5 × 106 cfu per organ(data not shown) regardless of the clinical diagnosis of theanimal.DiscussionThe occurrence of meningitis caused by serovars of Salmo-nella enterica is relatively rare in developed countries [20],but in countries such as Africa, Thailand, and Brazil [3,5],it is a common cause of Gram-negative bacterial meningi-tis in infants with high mortality rates being reported. Astudy of infant Salmonella meningitis in Kuala Lumpurreported an 18% fatality rate with surviving infants expe-riencing considerable long-term neurological dysfunction(57%) and high relapse rates (38%) [3]. Although Salmo-nella meningitis is a rare complication of adult salmonel-losis, the increased incidence of Salmonella bacteremia inHIV-infected patients [21,22], may expose such individu-als to increased risk for more disseminated and protractedinfections. Importantly, alarming increases in multi-drugresistance Salmonella enterica may be a harbinger for morevirulent strains of Salmonella with increased invasivepotential.The ability of S. Typhimurium to infect the mouse brainwas related to functional virulence loci including the typeIII secretion systems encoded in chromosomal genomicislands. In our studies over several years, infection ofC57BL/6 mice with S. Typhimurium containing muta-tions in either of these secretion systems was never foundto produce neurological deficits (over 1000 animals, datanot shown) and mutant bacteria could not be recoveredfrom the brains of representative infected mice (10 ani-mals, data not shown). Neurological deficits were notunique to one particular strain of mouse, as we observedHistopathology of infected brain sectionsFigure 2Histopathology of infected brain sections. (A, B) Coro-nal sections of brain with sub-arachnoid meningeal inflamma-tion (arrowheads). Macrophages are the predominant cellular infiltrate in these fields. Thrombosed sub-arachnoid vessels are marked with arrows. H&E; mag, 100×. (C) Area of ventriculitis seen in the brain of mouse #6. H&E; mag, Table 1: Clinical SummaryMouse Treatment Behaviour Clinical Features a Meningitis score Genetic background1 uninfected non-rolling normal 0 C57BL/62 infected non-rolling normal 0 C57BL/63 infected rolling meningitis, thrombosis 1+ Balb/c4b infected rolling meningitis 2+ C57BL/65 infected rolling meningitis 0.5+ Balb/c6 infected rolling meningitis, thrombosis, ventriculitis2+ Balb/c7 infected rolling meningitis 1+ 129S6-Slc11a1tm1Mcga slides were scored with the observer blinded to mouse historyb mouse shown in Additional file 1Page 4 of 6(page number not for citation purposes)this behavior in five different mouse lines including wildtype C57BL/6, wild type BALB/c, 129S1/SvImJ, 129S6-200×.BMC Infectious Diseases 2007, 7:65 http://www.biomedcentral.com/1471-2334/7/65Slc11a1tm1Mcg, and B6.129-Inpp5dtm1Rkh. Much work hasinvestigated the genetic factors in mice involved in resist-ance to S. Typhimurium infection [23]. These efforts haverevealed a critical role for the Slc11a1 gene (formallyNramp1) in early innate resistance to Salmonella infection[17]. We note that 4 out of the 5 mouse strains used in ourwork carry a non-functional mutant allele of Slc11a1(C57BL/6, BALB/c, 129S6-Slc11a1tm1Mcg, and B6.129-Inpp5dtm1Rkh). While we did observe neurological deficitsin a mouse line that normally resists lethal infection dueto a wild type Slc11a1 allele (129S1/SvImJ), our currentsample size does not permit detailed conclusions to bedrawn regarding the impact of Slc11a1 status on meningi-tis development. Thus, it is possible that both bacterialand host genetic factors are involved in infection of thebrain and the development of meningitis. Further workusing larger sample sizes and controls could address theseissues. We cannot exclude hemiparesis in mice with neu-rological deficits and the potential involvement in thisbehaviour of the vestibular system will require additionalinvestigation.The ability of Salmonella to disseminate naturally to thebrain in several mouse lines allows the use of the vastarray of transgenic and knockout mouse strains to addressthe host genetic factors influencing CNS disseminationincluding the mode of bacterial transport from intestinalsites to systemic sites of infection, the role of variousimmune cells in the trafficking of intracellular salmonel-lae to the CNS and brain, and the role of various immunecell migration factors in this process. We suggest that themouse model of Salmonella typhoid could represent a use-ful tool in which to investigate basic mechanisms of CNSinfiltration and brain infection following oral ingestion ofSalmonella. This model could also be exploited to examinethe efficacy of investigational medicines (vaccines, anti-infectives) to treat invasive and protracted Salmonellainfections. Importantly, this model fills a gap in the liter-ature to address meningitis caused by naturally dissemi-nating salmonellae.ConclusionOral infection of mice with Salmonella enterica serovarTyphimurium might represent a useful model in which tostudy the dissemination of a pathogen from the naturalroute of infection to the brain. Infection of the brain is fol-lowed by meningitis and a neurological deficit in a pro-portion of infected animals. Because more virulent strainsof Salmonella are commonly associated with antibioticresistance, the continued global epidemic spread of multi-drug resistant Salmonella isolates in human and animalmedicine (such as S. Typhimurium DT104) presents aserious public health issue. Drug resistance in such iso-infection of mice with S. Typhimurium is an accessiblemodel in which to study the host and bacterial determi-nants that lead to dissemination and progression of infec-tion from the gastrointestinal tract to the brain. Wepropose that this model has utility for testing new antibac-terial chemotherapies to treat complicated, life-threaten-ing Salmonella infections.Competing interestsThe author(s) declare that they have no competing inter-ests.Authors' contributionsMEW, JP, and BKC designed research, MEW, NFB, JP, andBKC performed research, MEW, JP, and BKC analyzeddata, MEW, NFB, JP, BBF, and BKC wrote the paper. Allauthors read and approved the final manuscript.Additional materialAcknowledgementsThe authors wish to thank Jennifer Bishop, Guntram Grassl, Bryan Coburn and Yanet Valdez for contributing mice to this study. MEW was a CIHR and MSFHR postdoctoral fellow and NFB was a postdoctoral fellow of the MSFHR. This work was supported by grants to BBF from the Canadian Institutes of Health Research (CIHR) and to BKC from the Public Health Agency of Canada and the CIHR.References1. Huang DB, DuPont HL: Problem pathogens: extra-intestinalcomplications of Salmonella enterica serotype Typhi infec-tion.  Lancet Infect Dis 2005, 5(6):341-348.2. Voetsch AC, Van Gilder TJ, Angulo FJ, Farley MM, Shallow S, MarcusR, Cieslak PR, Deneen VC, Tauxe RV: FoodNet estimate of theburden of illness caused by nontyphoidal Salmonella infec-tions in the United States.  Clin Infect Dis 2004, 38 Suppl3:S127-34.3. Lee WS, Puthucheary SD, Omar A: Salmonella meningitis and itscomplications in infants.  J Paediatr Child Health 1999,35(4):379-382.4. Chotpitayasunondh T: Bacterial meningitis in children: etiologyand clinical features, an 11-year review of 618 cases.  TheSoutheast Asian journal of tropical medicine and public health 1994,25(1):107-115.5. 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Celum CL, Chaisson RE, Rutherford GW, Barnhart JL, Echenberg DF:Incidence of salmonellosis in patients with AIDS.  J Infect Dis1987, 156(6):998-1002.23. Roy MF, Malo D: Genetic regulation of host responses to Sal-monella infection in mice.  Genes Immun 2002, 3(7):381-393.Pre-publication historyThe pre-publication history for this paper can be accessedhere:http://www.biomedcentral.com/1471-2334/7/65/prepubyours — you keep the copyrightSubmit your manuscript here:http://www.biomedcentral.com/info/publishing_adv.aspBioMedcentralPage 6 of 6(page number not for citation purposes)


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