ANIMAL MODEL OF HUMAN DISEASE
Yersinia Enteritis
Animal Model: Oral Y'ersinia enterocolitica Infection of Mlice
Contributed by: Philip B. Carter, PhD, Trudeau Institute, Inc., Saranac Lake, New York, 12981.
Biologic Features
Human disease related to infection with Yersinia enterocolitica (svn. Bacteritunm enterocoliticum, Pasteurella X) was first observed in the 1930s in New York State 1 and has since assumed increasing world wide importance.23 The most common manifestation of this infection in humans is acute enterocolitis, sometimes masquerading as appendicitis in patients wvith acute terminal ileitis, with fever and diarrhea most often appearing as the clinical svmptoms.4'5 Mesenteric lvmphadenitis often appears in patients with severe gastrointestinal involvement. The disease can potentially develop into an enteric fever, mimicking typhoid,6 but this is an uncommon occurrence. Secondarv manifestations often include arthritis and ervthema nodosum.45 The development of diagnostic and bacterial isolation technique for this disease, as well as studies of its pathogenesis and mode of transmission, have been hampered by the lack of an experimental laboratorv animal model.7 Recently, however, strains have been isolated which demonstrate virulence for laboratory rats and mice.8`9 A particularlv virulent strain, Y. enterocolitica WA, isolated from the blood of a human patient who acquired the infection from stream water,6'8 proved capable of producing disease in mice by aerogenic, parenteral, and oral routes,'0 giving rise to a svndrome very similar to that observed in humans." The primarv pathologic manifestation in the orally infected animal is that of a svstemic pyogenic infection leading to multiple abscess formation, primarilv Publication sponsored by the Registnr of Comparative Pathology of the Arned Forces Institute of Pathology and supported bv Public Health Service Grant RR 00301 from the Division of Research Resources, US [epartment of Health, Education and WVelfare, under the auspices of Universities Associated for Research and Education in Pathology, Inc. 703
704
CARTER
American Journal of Pathology
in the Pever's patches, mesenteric lymph nodes, spleen, liver, and lungs. The primarv lesion, characterized by a massive neutrophil infiltrate, occurs in the ileal Peyer's patches. These lesions enlarge with time, ultimatelv ulcerating into the intestinal lumen, and in some cases, causing perforation through the serosa into the peritoneal cavity. The lesions in the mesenteric lymph nodes, spleen, and liver are well-organized abscesses. A systemic infection of these proportions is often, but not always, fatal. Animals which survive such an infection show a clearance of fluid from the infected portions of lung and a resolution of almost all of the splenic and hepatic abscesses. Comparison Wft Hum Infutio
Oral infection of mice with Y. enterocolitica, strain WA, gives rise to a disease of the gastrointestinal tract which is verv similar to that observed in humans. The initial lesions occur in the distal ileum and cecum which correlates well with the terminal ileitis and pseudoappendicitis so often seen in the human. Evidence in humans for focal ulcerations in the ileum has been reported;`2"3 the occurrence of such was often observed in the mouse infection. Systemic infection in humans is not uncommon,6"' and its occurrence has been related to a decreased immune capability in the host.4 As in the mouse model, its occurrence leads to a granulocytosis 13 and multiple abscess formation, primarily in the mesenteric lymph nodes, liver, and spleen,,2"14 but also in joints.6 The striking pyroninophilic response observed in the lymph nodes of some human cases 12 is also observed in lymph nodes of mice which drain abscessed organs.1' Preliminary evidence suggests that Y. enterocolitica infection in mice can produce a low grade hemolytic anemia such as that observed in some human cases.6"5 Although arthritis and erythema nodosum are considered common sequelae to Y. enterocolitica infections,4'5 these have not been observed in the mouse; however, arthritis is commonly manifest in the intravenously infected rat.16 Potential or Demonstrated Usefulness of the Model
The studv of human Y. enterocolitica infections, particularly the extent of subelinical infection among the world population, has been inhibited bv the lack of acceptable diagnostic techniques. The specific pathogenfree mouse infected with Y. enterocolitica WA now allows the development and testing of better isolation procedures for Y. enterocolitica in feces in these known infected animals. The mouse model will serve as a
Vol. 81, No. 3 December 1975
YERSINIA ENTERITIS
705
system for testing the potential usefulness of various Y. enterocolitica antigens in serologic diagnosis, since preinfection and postinfection serum would be available. Versinia enterocolitica septicemia is refractory to treatment with commonly used antimicrobial agents,6 and the mouse model wrill now allow testing of the efficacy of potential therapeutic agents in divo. Avalabiity
The use of V-ersinia enteroco-litica WN'A for experimental animal infection has been facilitated by its deposition in major culture collections (ATCC No. 27729; NCTC No. 10938; Pasteur Institute No. Ye 2705). The V. enterocolitica strain isolated from the stream water which infected Patient WNIA 6 is also available from the American Type Culture Collection (ATCC No. 27739). Although these strains have infected all mouse strains tested, it is recommended that investigators passage the organism in their ow n strain of mouse by the intravenous route as a preliminary procedure. References 1. Schleifstein JI, Coleman MB: An unidentified microorganism resembling B. lignieri and Past. pseudotuberculosis, and pathogenic for man. NY State J Med 39:1749-1753, 19:39 2. Nilehn B: Studies on Y-ersinia enterocolitica with special reference to bacterial diagnosis and occurrence in human acute enteric disease. Acta Pathol Microbiol Scand [Suppl] 206:1-48, 1969 3. Ahvonen P: Human versiniosis in Finland. II. Clinical features. Ann Clin Res 4:39-48, 1972 4. Mollaret HH: L'infection humaine a 'Yersinia enterocolitica' en 1970. a la lumiere de 642 cas recents: Aspects cliniques et perspectives epidemiologiques. Pathol Biol (Paris) 19:189-205, 1971 5. Knapp W\, Lysy J, Knapp C, Stille W, Goll U: Enterale Infektionen beim Menschen durch Yersinia enterocolitica und ihre Diagnose. Infection 1:113-125, 1973 6. Keet EE: Yersinia enterocolitica septicemia: Source of infection and incubation period identified. NY State J Med 74:2226-22:30. 1974 7. Mollaret HH, Guillon JC: Contribution a l'etude d'un nouveau groupe de germes (Yersinia enterocolitica) proches du bacille de Malassez et V'ignal. II. Pouvoir pathogene experimental. Ann Inst Pasteur (Paris) 109:608-61:3, 1965 8. Carter PB, \'arga CF, Keet EE: New- strain of Y'ersinia enterocolitica pathogenic for rodents. Appl Microbiol 26:1016-1018, 1973 9. Quan TJ, NMeek JL, Tsuchiva KR, Hudson BWN, Bames AM: Experimental pathogenicitv of recent North American isolates of Y'ersinia enterocolitica. J Infect Dis 129::341-344, 1974 10. Carter PB, Collins FM: Experimental Versinia enterocolitica infection in mice: Kinetics of growth. Infect Immun 9:&51-857. 1974 11. Carter PB: Pathogenicity of Y'ersinia enterocolitica for mice. Infect Immun 11:164-1170, 1973
706
CARTER
American Journal of Pathology
12. Ahlquist J, Ahvonen P, Rasanen JA, W'allgren GR: Enteric infection with Yersinia enterocolitca: Large py,roninophilic cell reaction in mesenteric lymph nodes associated with early production of specific antibodies. Acta Pathol Microbiol Scand [A] 779:109-122, 1971 13. Gutmann LT, Ottesen EA, Quan TJ, Noce PS, Katz SL: An interfamilial outbreak of Yersinia enterocolitica enteritis. N Engl J Med 288:1372-1377. 1973 14. Rabson AR, Hallett AF, Koornhof HJ: Generalized 1Yersinia enterocolitica infection. J Infect Dis 131:447-451, 1975 13. von Knorring J, Pettersson T: Haemolytic anemia complicating Y'ersinia enterocolitica infection: Report of a case. Scand J Haematol 9:149-152, 1972 16. McGregor DD: Personal communication
Yersinia Enteritis
Animal Model: Oral Y'ersinia enterocolitica Infection of Mlice
Contributed by: Philip B. Carter, PhD, Trudeau Institute, Inc., Saranac Lake, New York, 12981.
Biologic Features
Human disease related to infection with Yersinia enterocolitica (svn. Bacteritunm enterocoliticum, Pasteurella X) was first observed in the 1930s in New York State 1 and has since assumed increasing world wide importance.23 The most common manifestation of this infection in humans is acute enterocolitis, sometimes masquerading as appendicitis in patients wvith acute terminal ileitis, with fever and diarrhea most often appearing as the clinical svmptoms.4'5 Mesenteric lvmphadenitis often appears in patients with severe gastrointestinal involvement. The disease can potentially develop into an enteric fever, mimicking typhoid,6 but this is an uncommon occurrence. Secondarv manifestations often include arthritis and ervthema nodosum.45 The development of diagnostic and bacterial isolation technique for this disease, as well as studies of its pathogenesis and mode of transmission, have been hampered by the lack of an experimental laboratorv animal model.7 Recently, however, strains have been isolated which demonstrate virulence for laboratory rats and mice.8`9 A particularlv virulent strain, Y. enterocolitica WA, isolated from the blood of a human patient who acquired the infection from stream water,6'8 proved capable of producing disease in mice by aerogenic, parenteral, and oral routes,'0 giving rise to a svndrome very similar to that observed in humans." The primarv pathologic manifestation in the orally infected animal is that of a svstemic pyogenic infection leading to multiple abscess formation, primarilv Publication sponsored by the Registnr of Comparative Pathology of the Arned Forces Institute of Pathology and supported bv Public Health Service Grant RR 00301 from the Division of Research Resources, US [epartment of Health, Education and WVelfare, under the auspices of Universities Associated for Research and Education in Pathology, Inc. 703
704
CARTER
American Journal of Pathology
in the Pever's patches, mesenteric lymph nodes, spleen, liver, and lungs. The primarv lesion, characterized by a massive neutrophil infiltrate, occurs in the ileal Peyer's patches. These lesions enlarge with time, ultimatelv ulcerating into the intestinal lumen, and in some cases, causing perforation through the serosa into the peritoneal cavity. The lesions in the mesenteric lymph nodes, spleen, and liver are well-organized abscesses. A systemic infection of these proportions is often, but not always, fatal. Animals which survive such an infection show a clearance of fluid from the infected portions of lung and a resolution of almost all of the splenic and hepatic abscesses. Comparison Wft Hum Infutio
Oral infection of mice with Y. enterocolitica, strain WA, gives rise to a disease of the gastrointestinal tract which is verv similar to that observed in humans. The initial lesions occur in the distal ileum and cecum which correlates well with the terminal ileitis and pseudoappendicitis so often seen in the human. Evidence in humans for focal ulcerations in the ileum has been reported;`2"3 the occurrence of such was often observed in the mouse infection. Systemic infection in humans is not uncommon,6"' and its occurrence has been related to a decreased immune capability in the host.4 As in the mouse model, its occurrence leads to a granulocytosis 13 and multiple abscess formation, primarily in the mesenteric lymph nodes, liver, and spleen,,2"14 but also in joints.6 The striking pyroninophilic response observed in the lymph nodes of some human cases 12 is also observed in lymph nodes of mice which drain abscessed organs.1' Preliminary evidence suggests that Y. enterocolitica infection in mice can produce a low grade hemolytic anemia such as that observed in some human cases.6"5 Although arthritis and erythema nodosum are considered common sequelae to Y. enterocolitica infections,4'5 these have not been observed in the mouse; however, arthritis is commonly manifest in the intravenously infected rat.16 Potential or Demonstrated Usefulness of the Model
The studv of human Y. enterocolitica infections, particularly the extent of subelinical infection among the world population, has been inhibited bv the lack of acceptable diagnostic techniques. The specific pathogenfree mouse infected with Y. enterocolitica WA now allows the development and testing of better isolation procedures for Y. enterocolitica in feces in these known infected animals. The mouse model will serve as a
Vol. 81, No. 3 December 1975
YERSINIA ENTERITIS
705
system for testing the potential usefulness of various Y. enterocolitica antigens in serologic diagnosis, since preinfection and postinfection serum would be available. Versinia enterocolitica septicemia is refractory to treatment with commonly used antimicrobial agents,6 and the mouse model wrill now allow testing of the efficacy of potential therapeutic agents in divo. Avalabiity
The use of V-ersinia enteroco-litica WN'A for experimental animal infection has been facilitated by its deposition in major culture collections (ATCC No. 27729; NCTC No. 10938; Pasteur Institute No. Ye 2705). The V. enterocolitica strain isolated from the stream water which infected Patient WNIA 6 is also available from the American Type Culture Collection (ATCC No. 27739). Although these strains have infected all mouse strains tested, it is recommended that investigators passage the organism in their ow n strain of mouse by the intravenous route as a preliminary procedure. References 1. Schleifstein JI, Coleman MB: An unidentified microorganism resembling B. lignieri and Past. pseudotuberculosis, and pathogenic for man. NY State J Med 39:1749-1753, 19:39 2. Nilehn B: Studies on Y-ersinia enterocolitica with special reference to bacterial diagnosis and occurrence in human acute enteric disease. Acta Pathol Microbiol Scand [Suppl] 206:1-48, 1969 3. Ahvonen P: Human versiniosis in Finland. II. Clinical features. Ann Clin Res 4:39-48, 1972 4. Mollaret HH: L'infection humaine a 'Yersinia enterocolitica' en 1970. a la lumiere de 642 cas recents: Aspects cliniques et perspectives epidemiologiques. Pathol Biol (Paris) 19:189-205, 1971 5. Knapp W\, Lysy J, Knapp C, Stille W, Goll U: Enterale Infektionen beim Menschen durch Yersinia enterocolitica und ihre Diagnose. Infection 1:113-125, 1973 6. Keet EE: Yersinia enterocolitica septicemia: Source of infection and incubation period identified. NY State J Med 74:2226-22:30. 1974 7. Mollaret HH, Guillon JC: Contribution a l'etude d'un nouveau groupe de germes (Yersinia enterocolitica) proches du bacille de Malassez et V'ignal. II. Pouvoir pathogene experimental. Ann Inst Pasteur (Paris) 109:608-61:3, 1965 8. Carter PB, \'arga CF, Keet EE: New- strain of Y'ersinia enterocolitica pathogenic for rodents. Appl Microbiol 26:1016-1018, 1973 9. Quan TJ, NMeek JL, Tsuchiva KR, Hudson BWN, Bames AM: Experimental pathogenicitv of recent North American isolates of Y'ersinia enterocolitica. J Infect Dis 129::341-344, 1974 10. Carter PB, Collins FM: Experimental Versinia enterocolitica infection in mice: Kinetics of growth. Infect Immun 9:&51-857. 1974 11. Carter PB: Pathogenicity of Y'ersinia enterocolitica for mice. Infect Immun 11:164-1170, 1973
706
CARTER
American Journal of Pathology
12. Ahlquist J, Ahvonen P, Rasanen JA, W'allgren GR: Enteric infection with Yersinia enterocolitca: Large py,roninophilic cell reaction in mesenteric lymph nodes associated with early production of specific antibodies. Acta Pathol Microbiol Scand [A] 779:109-122, 1971 13. Gutmann LT, Ottesen EA, Quan TJ, Noce PS, Katz SL: An interfamilial outbreak of Yersinia enterocolitica enteritis. N Engl J Med 288:1372-1377. 1973 14. Rabson AR, Hallett AF, Koornhof HJ: Generalized 1Yersinia enterocolitica infection. J Infect Dis 131:447-451, 1975 13. von Knorring J, Pettersson T: Haemolytic anemia complicating Y'ersinia enterocolitica infection: Report of a case. Scand J Haematol 9:149-152, 1972 16. McGregor DD: Personal communication
