Recent Advances in Understanding the Pathogenesis of Lawsonia intracellularis Infections

Proliferative enteropathy is an infectious disease caused by an obligate intracellular bacterium, Lawsonia intracellularis, and characterized by thickening of the intestinal epithelium due to enterocyte proliferation. The disease is endemic in swine herds and has been occasionally reported in various other species. Furthermore, outbreaks among foals began to be reported on breeding farms worldwide within the past 5 years. Cell proliferation is directly associated with bacterial infection and replication in the intestinal epithelium. As a result, mild to severe diarrhea is the major clinical sign described in infected animals. The dynamics of L. intracellularis infection in vitro and in vivo have been well characterized, but little is known about the genetic basis for the pathogenesis or ecology of this organism. The present review focuses on the recent advances regarding the pathogenesis and host-pathogen interaction of L. intracellularis infections.

[1]  JAMES L. Smith,et al.  The role of gastric acid in preventing foodborne disease and how bacteria overcome acid conditions. , 2003, Journal of food protection.

[2]  G. E. Ward,et al.  Recognizing the three forms of proliferative enteritis in swine. , 1990 .

[3]  E. Groisman,et al.  A Salmonella virulence protein that inhibits cellular trafficking , 1999, The EMBO journal.

[4]  G. Lawson,et al.  Intestinal adenomatosis in the pig: immunofluorescent and electron microscopic studies. , 1974, Research in veterinary science.

[5]  M. Ramirez,et al.  Faecal shedding and serological cross-sectional study of Lawsonia intracellularis in horses in the state of Minas Gerais, Brazil. , 2009, Equine veterinary journal.

[6]  C. Gebhart,et al.  PROLIFERATIVE ENTERITIS ASSOCIATED WITH LAWSONIA INTRACELLULARIS IN A JAPANESE MACAQUE (MACACA FUSCATA) , 2004, Journal of zoo and wildlife medicine : official publication of the American Association of Zoo Veterinarians.

[7]  J. Brumell,et al.  Autophagy in immunity against intracellular bacteria. , 2009, Current topics in microbiology and immunology.

[8]  K A Schafer,et al.  The Cell Cycle: A Review , 1998, Veterinary pathology.

[9]  S. McOrist,et al.  Developed and resolving lesions in porcine proliferative enteropathy: possible pathogenetic mechanisms. , 1996, Journal of comparative pathology.

[10]  J. Shea,et al.  Genes encoding putative effector proteins of the type III secretion system of Salmonella pathogenicity island 2 are required for bacterial virulence and proliferation in macrophages , 1998, Molecular microbiology.

[11]  R. Jacoby,et al.  Transmissible ileal hyperplasia of hamsters. II. Ultrastructure. , 1978, The American journal of pathology.

[12]  L. Mølbak,et al.  The microbiota of pigs influenced by diet texture and severity of Lawsonia intracellularis infection. , 2008, Veterinary microbiology.

[13]  R. Monckton,et al.  Replication of Australian porcine isolates of Ileal symbiont intracellularis in tissue culture. , 1996, Veterinary microbiology.

[14]  R. Jacoby,et al.  Transmissible ileal hyperplasia. , 1981, Advances in experimental medicine and biology.

[15]  S. Barns,et al.  Ileal symbiont intracellularis, an obligate intracellular bacterium of porcine intestines showing a relationship to Desulfovibrio species. , 1993, International journal of systematic bacteriology.

[16]  S. Wattanaphansak,et al.  An Alternative Method for Cultivation of Lawsonia intracellularis , 2012, Journal of Clinical Microbiology.

[17]  A. Collins,et al.  Re-challenge of pigs following recovery from proliferative enteropathy. , 2007, Veterinary microbiology.

[18]  C. Gebhart,et al.  Equine proliferative enteropathy – a review of recent developments , 2013, Equine veterinary journal.

[19]  遠藤 祥郎,et al.  Lawsonia intracellularis , 2022, CABI Compendium.

[20]  B. B. Jensen,et al.  The influence of diet on Lawsonia intracellularis colonization in pigs upon experimental challenge. , 2004, Veterinary microbiology.

[21]  S. McOrist,et al.  Immunocytological responses in porcine proliferative enteropathies , 1992, Infection and immunity.

[22]  C. Gebhart,et al.  Proliferative Enteritis Associated with Lawsonia Intracellularis (Ileal Symbiont Intracellularis) in White-Tailed Deer , 1996, Journal of veterinary diagnostic investigation : official publication of the American Association of Veterinary Laboratory Diagnosticians, Inc.

[23]  S. Wattanaphansak,et al.  Oral infection of weanling foals with an equine isolate of Lawsonia intracellularis, agent of equine proliferative enteropathy. , 2010, Journal of veterinary internal medicine.

[24]  D. Schauer,et al.  Molecular pathogenesis of Citrobacter rodentium and transmissible murine colonic hyperplasia. , 2001, Microbes and infection.

[25]  T. Landsverk.  Intestinal Adenomatosis in a Blue Fox (Alopex lagopus) , 1981, Veterinary pathology.

[26]  M. Elwell,et al.  Duodenal Hyperplasia in a Guinea Pig , 1981, Veterinary pathology.

[27]  E. Paxton,et al.  Expression by Lawsonia intracellularis of type III secretion system components during infection. , 2009, Veterinary microbiology.

[28]  H. Biester,et al.  Intestinal Adenoma in Swine. , 1931, The American journal of pathology.

[29]  M. Wagner,et al.  Lawsonia intracellularis Contains a Gene Encoding a Functional Rickettsia-Like ATP/ADP Translocase for Host Exploitation , 2008, Journal of bacteriology.

[30]  Induction and evasion of host defenses by type 1-piliated uropathogenic Escherichia coli. , 1998 .

[31]  K. Wilson,et al.  Preliminary study using species-specific oligonucleotide probe for rRNA of Bilophila wadsworthia , 1994, Journal of clinical microbiology.

[32]  F. Sheffield,et al.  Prophylaxis of ‘Wet-Tail’ in Hamsters , 1962, Nature.

[33]  S. Wattanaphansak,et al.  Evaluation of the humoral immune response and fecal shedding in weanling foals following oral and intra-rectal administration of an avirulent live vaccine of Lawsonia intracellularis. , 2009, Veterinary journal.

[34]  J. Agerholm,et al.  Application of a pig ligated intestinal loop model for early Lawsonia intracellularis infection , 2010, Acta veterinaria Scandinavica.

[35]  R. Ducatelle,et al.  Lawsonia intracellularis infection in a 12-monthold colt in Belgium , 2005, Veterinary Record.

[36]  C. Gebhart,et al.  Onset and duration of fecal shedding, cell-mediated and humoral immune responses in pigs after challenge with a pathogenic isolate or attenuated vaccine strain of Lawsonia intracellularis. , 2003, Veterinary microbiology.

[37]  C. Gebhart,et al.  Comparison of intestinal mucosa homogenate and pure culture of the homologous Lawsonia intracellularis isolate in reproducing proliferative enteropathy in swine. , 2003, Veterinary microbiology.

[38]  R. Jacoby,et al.  Experimental transmission of atypical ileal hyperplasia of hamsters. , 1975, Laboratory animal science.

[39]  Juliana de Oliveira,et al.  Intestinal absorption and histomorphometry of Syrian hamsters (Mesocricetus auratus) experimentally infected with Lawsonia intracellularis. , 2010, Veterinary microbiology.

[40]  S. McOrist,et al.  Evaluation of porcine ileum models of enterocyte infection by Lawsonia intracellularis. , 2006, Canadian journal of veterinary research = Revue canadienne de recherche veterinaire.

[41]  M. Jensen-Waern,et al.  Diarrhoea in the growing pig – a comparison of clinical, morphological and microbial findings between animals from good and poor performance herds , 2003, Research in Veterinary Science.

[42]  S. McOrist,et al.  Microarray analysis of differential expression of cell cycle and cell differentiation genes in cells infected with Lawsonia intracellularis. , 2010, Veterinary journal.

[43]  S. Barns,et al.  Comparison of the 16S ribosomal DNA sequences from the intracellular agents of proliferative enteritis in a hamster, deer, and ostrich with the sequence of a porcine isolate of Lawsonia intracellularis. , 1997, International journal of systematic bacteriology.

[44]  A. Blikslager,et al.  Mechanisms of porcine diarrheal disease. , 2007, Journal of the American Veterinary Medical Association.

[45]  F. Dewhirst,et al.  Intracellular Campylobacter-like organism from ferrets and hamsters with proliferative bowel disease is a Desulfovibrio sp , 1994, Journal of clinical microbiology.

[46]  D. Miller,et al.  Treatment and prevention of porcine proliferative enteropathy with oral tiamulin , 1996, Veterinary Record.

[47]  M. Welsh,et al.  Crypts are the site of intestinal fluid and electrolyte secretion. , 1982, Science.

[48]  S. McOrist,et al.  Evaluation of protective immunity in pigs following oral administration of an avirulent live vaccine of Lawsonia intracellularis. , 2004, American journal of veterinary research.

[49]  F. Taieb,et al.  Bacterial toxins that modulate host cell-cycle progression. , 2005, Current opinion in microbiology.

[50]  G. Lawson,et al.  Lawsonia intracellularis: getting inside the pathogenesis of proliferative enteropathy. , 2001, Veterinary microbiology.

[51]  C. Gyles,et al.  Pathogenesis of bacterial infections in animals , 2004 .

[52]  A. Rowland,et al.  A haemorrhagic bowel syndrome associated with intestinal adenomatosis in the pig , 1972, Veterinary Record.

[53]  S. McOrist,et al.  Synergism of ileal symbiont intracellularis and gut bacteria in the reproduction of porcine proliferative enteropathy , 1994, Veterinary Record.

[54]  D. Horohov,et al.  Acute deterioration and death with necrotizing enteritis associated with Lawsonia intracellularis in 4 weanling horses. , 2012, Journal of veterinary internal medicine.

[55]  M. Roof,et al.  Proliferative enteropathy: a global enteric disease of pigs caused by Lawsonia intracellularis , 2005, Animal Health Research Reviews.

[56]  S. E. Jorsal,et al.  Comparison of histology, immunohistochemistry and polymerase chain reaction for detection of Lawsonia intracellularis in natural porcine proliferative enteropathy. , 1997 .

[57]  M. Wagner,et al.  ATP/ADP Translocases: a Common Feature of Obligate Intracellular Amoebal Symbionts Related to Chlamydiae and Rickettsiae , 2004, Journal of bacteriology.

[58]  R. Jacoby.  Transmissible ileal hyperplasia of hamsters. I. Histogenesis and immunocytochemistry. , 1978, American Journal of Pathology.

[59]  C. F. Parker,et al.  Terminal ileitis in lambs. , 1973, Journal of the American Veterinary Medical Association.

[60]  S. McOrist,et al.  Infection of cultured rat enterocytes by Ileal symbiont intracellularis depends on host cell function and actin polymerisation. , 1995, Veterinary microbiology.

[61]  S. McOrist,et al.  Reproduction of porcine proliferative enteropathy with pure cultures of ileal symbiont intracellularis , 1993, Infection and immunity.

[62]  Nicola Pusterla,et al.  Equine proliferative enteropathy caused by Lawsonia intracellularis , 2009, Equine veterinary education.

[63]  D. Shaw,et al.  Immunopathogenesis of Experimentally Induced Proliferative Enteropathy in Pigs , 2003, Veterinary pathology.

[64]  H. Boesen,et al.  Early pathogenesis in porcine proliferative enteropathy caused by Lawsonia intracellularis. , 2010, Journal of comparative pathology.

[65]  L. Landraud,et al.  Rho GTPase-activating bacterial toxins: from bacterial virulence regulation to eukaryotic cell biology. , 2007, FEMS microbiology reviews.

[66]  P. Dowling,et al.  The rabbit as an infection model for equine proliferative enteropathy. , 2013, Canadian journal of veterinary research = Revue canadienne de recherche veterinaire.

[67]  S. McOrist,et al.  Reproduction of proliferative enteritis in hamsters with a pure culture of porcine ileal symbiont intracellularis. , 1994, Veterinary microbiology.

[68]  C. Gebhart,et al.  Proliferative enteropathy. , 2019, Journal of comparative pathology.

[69]  T. Bihr,et al.  Protein-losing enteropathy caused by Lawsonia intracellularis in a weanling foal. , 2003, The Canadian veterinary journal = La revue veterinaire canadienne.

[70]  M. Watarai,et al.  Infection of different strains of mice with Lawsonia intracellularis derived from rabbit or porcine proliferative enteropathy. , 2008, Journal of comparative pathology.

[71]  T. Schoeb,et al.  Enterocecocolitis Associated with Intraepithelial Campylobacter-like Bacteria in Rabbits (Oryctolagus cuniculus) , 1990, Veterinary pathology.

[72]  C. Gebhart,et al.  Comparative genome sequencing identifies a prophage-associated genomic island linked to host adaptation of Lawsonia intracellularis infections , 2013, Veterinary Research.

[73]  A. Rowland,et al.  Necrotic enteritis and regional ileitis in pigs at slaughter , 1978, The Veterinary Record.

[74]  M. Watarai,et al.  Proliferative enteropathy involving Lawsonia intracellularis infection in rabbits (Oryctlagus cuniculus). , 2008, The Journal of veterinary medical science.

[75]  C. J. G. and,et al.  Chapter 26. Lawsonia Intracellularis , 2010 .

[76]  F. Taieb,et al.  Cyclomodulins: bacterial effectors that modulate the eukaryotic cell cycle. , 2005, Trends in microbiology.

[77]  C. Gebhart,et al.  Detection of Lawsonia intracellularis by Real-time PCR in the Feces of Free-living Animals from Equine Farms with Documented Occurrence of Equine Proliferative Enteropathy , 2008, Journal of wildlife diseases.

[78]  J. Zimmerman.  Diseases of swine , 2012 .

[79]  C. Gebhart,et al.  Validation of an Immunoperoxidase Monolayer Assay as a Serologic Test for Porcine Proliferative Enteropathy , 2002, Journal of veterinary diagnostic investigation : official publication of the American Association of Veterinary Laboratory Diagnosticians, Inc.

[80]  J. C. Higgins,et al.  Epidemiological survey on farms with documented occurrence of equine proliferative enteropathy due to Lawsonia intracellularis , 2008, Veterinary Record.

[81]  G. Lawson,et al.  Experimental reproduction of porcine intestinal adenomatosis and necrotic enteritis , 1977, Veterinary Record.

[82]  E. Clark.  Pathogenesis of Bacterial Infections in Animals , 1987 .

[83]  P. Dowling,et al.  Species-specificity of equine and porcine Lawsonia intracellularis isolates in laboratory animals. , 2013, Canadian journal of veterinary research = Revue canadienne de recherche veterinaire.

[84]  C. Gebhart,et al.  Attenuation of virulence of Lawsonia intracellularis after in vitro passages and its effects on the experimental reproduction of porcine proliferative enteropathy. , 2013, Veterinary microbiology.

[85]  D. Foster,et al.  Laser microdissection coupled with RNA-seq analysis of porcine enterocytes infected with an obligate intracellular pathogen (Lawsonia intracellularis) , 2013, BMC Genomics.

[86]  D. Foster,et al.  Comparative Transcriptional Analysis of Homologous Pathogenic and Non-Pathogenic Lawsonia intracellularis Isolates in Infected Porcine Cells , 2012, PloS one.

[87]  K. Schwartz,et al.  Evaluation of antemortem polymerase chain reaction and serologic methods for detection of Lawsonia intracellularis-exposed pigs. , 1998, American journal of veterinary research.

[88]  M. Jensen-Waern,et al.  Porcine proliferative enteropathy: an important disease with questions remaining to be solved. , 2010, Veterinary journal.

[89]  W. Hahn,et al.  T cell adhesion, avidity regulation and signaling: a molecular analysis of CD2. , 1993, Seminars in immunology.

[90]  David G. E. Smith,et al.  LsaA, an Antigen Involved in Cell Attachment and Invasion, Is Expressed by Lawsonia intracellularis during Infection In Vitro and In Vivo , 2002, Infection and Immunity.

[91]  C. Gebhart,et al.  Temporal detection of Lawsonia intracellularis using serology and real-time PCR in Thoroughbred horses residing on a farm endemic for equine proliferative enteropathy. , 2009, Veterinary microbiology.

[92]  C. Fossum,et al.  Microarray and cytokine analyses of field cases of pigs with diarrhoea. , 2011, Veterinary microbiology.

[93]  B. Christensen,et al.  Lawsonia intracellularis infection in the large intestines of pigs , 2006, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[94]  C. Der,et al.  Ras and Rho regulation of the cell cycle and oncogenesis. , 2001, Cancer letters.

[95]  M. Frazer.  Lawsonia intracellularis infection in horses: 2005-2007. , 2008, Journal of veterinary internal medicine.

[96]  C. Hill,et al.  Acid stress responses in Listeria monocytogenes. , 2008, Advances in applied microbiology.

[97]  B. Sponseller,et al.  Impaired intestinal absorption of glucose in 4 foals with Lawsonia intracellularis infection. , 2009, Journal of veterinary internal medicine.

[98]  M. Vengust,et al.  An outbreak of Lawsonia intracellularis infection in a standardbred herd in Ontario. , 2007, The Canadian veterinary journal = La revue veterinaire canadienne.

[99]  R. Marsboom,et al.  Campylobacter-like bacteria in adenocarcinomas of the colon in two Wistar rats , 1982, Veterinary Record.

[100]  C. Gebhart,et al.  Diagnosis of proliferative enteritis in frozen and formalin-fixed, paraffin-embedded tissues from a hamster, horse, deer and ostrich using a Lawsonia intracellularis-specific multiplex PCR assay. , 1997, Veterinary microbiology.

[101]  A. Jonas,et al.  Enzootic intestinal adenocarcinoma in hamsters. , 1965, Journal of the American Veterinary Medical Association.

[102]  E. Brown,et al.  Actin‐based motility of intracellular bacteria, and polarized surface distribution of the bacterial effector molecules , 2006, Journal of cellular physiology.

[103]  C. Gebhart,et al.  Evidence of cell-mediated immune response and specific local mucosal immunoglobulin (Ig) A production against Lawsonia intracellularis in experimentally infected swine. , 2010, Canadian journal of veterinary research = Revue canadienne de recherche veterinaire.

[104]  S. McOrist,et al.  Entry of the bacterium ileal symbiont intracellularis into cultured enterocytes and its subsequent release. , 1995, Research in Veterinary Science.

[105]  H. Friess,et al.  Human inflammatory bowel disease does not associate with Lawsonia intracellularis infection , 2006, BMC Microbiology.

[106]  G. Lawson,et al.  Intestinal Adenomatosis in the Pig: Occurrence of a Bacterium in Affected Cells , 1973, Nature.

[107]  J. Lavoie,et al.  Equine proliferative enteropathy: An emerging disease of foals , 2009 .

[108]  J. Foster,et al.  Acid stress responses in enterobacteria. , 1997, FEMS microbiology letters.

[109]  T. Tully,et al.  Intracellular Campylobacter-like Organisms Associated with Rectal Prolapse and Proliferative Enteroproctitis in Emus (Dromaius novaehollandiae) , 1997, Veterinary pathology.

[110]  T. Umemura,et al.  Histiocytic Enteritis of Rabbits , 1982, Veterinary pathology.

[111]  S. McOrist,et al.  Reproduction of proliferative enteritis in gnotobiotic pigs. , 1989, Research in veterinary science.

[112]  C. Gebhart,et al.  Lawsonia intracellularis infection and proliferative enteropathy in foals , 2013, Veterinary Microbiology.

[113]  E. Wheeldon,et al.  Intestinal Adenomatosis in a Foal , 1982, Veterinary pathology.

[114]  P. O'Hara.  Intestinal haemorrhage syndrome in the pig , 1972, The Veterinary Record.

[115]  S. Barns,et al.  Characterization of Lawsonia intracellularis gen. nov., sp. nov., the obligately intracellular bacterium of porcine proliferative enteropathy. , 1995, International journal of systematic bacteriology.

[116]  E. Moses,et al.  Identification and sequencing of the groE operon and flanking genes of Lawsonia intracellularis: use in phylogeny. , 1998, Microbiology.

[117]  G. Duhamel,et al.  Fatal outbreaks of proliferative enteritis caused by Lawsonia intracellularis in young colony‐raised rhesus macaques , 1999, Journal of medical primatology.

[118]  S. McOrist,et al.  Intracellular bacteria of porcine proliferative enteropathy: cultivation and maintenance in vitro , 1993, Journal of clinical microbiology.

[119]  M. Libal,et al.  Proliferative enteritis in two pups. , 1983, Journal of the American Veterinary Medical Association.

[120]  H. Stills.  Isolation of an intracellular bacterium from hamsters (Mesocricetus auratus) with proliferative ileitis and reproduction of the disease with a pure culture , 1991, Infection and immunity.