Experimental microsporidiosis in immunocompetent and immunodeficient mice and monkeys.
Microsporidia cause opportunistic infections in AIDS patients and commonly infect laboratory animals, as well. Euthymic C57B1/6 mice experimentally infected with intraperitoneal injections of 1 x 10(6) Encephalitozoon cuniculi Levaditi, Nicolau et Schoen, 1923, Encephalitozoon hellem Didier et al., 1991, or Nosema corneum Shadduck et al., 1990 displayed no clinical signs of disease. Athymic mice, however, developed ascites and died 8-16 days after inoculation with N. corneum, 21-25 days after inoculation with E. cuniculi, and 34-37 days after inoculation with E. hellem. All athymic mice displayed hepatomegaly, dilated intestine and accumulation of ascites fluid. Granulomatous lesions are primarily located in the liver, lung, pancreas, spleen, and on serosal surfaces of abdominal organs. The murine microsporidiosis model also was used to examine immune response that inhibit microsporidia growth in vitro. Recombinant murine interferon-gamma (mIFN-gamma, 100 mu/ml) alone or in combination with lipopolysaccharide (LPS; 10 ng/ml) could activate thioglycollate-induced peritoneal murine macrophages to destroy E. cuniculi. The production of the nitrogen intermediate, NO2-, correlated with parasite destruction. Inhibition of NO2- generation by addition of the L-arginine analogue, NG-monomethyl L-arginine (NMMA), inhibited microsporidia killing, as well. Since microsporidiosis is becoming an important opportunistic infection in AIDS patients, a microsporidiosis model is being developed using SIV/DeltaB670-infected rhesus macaque monkeys (Macaca mulatta). SIV-infected immunocompetent monkeys given E. cuniculi or E. hellem per os developed specific antibodies, and microsporidia could be detected sporadically by calcofluor or antibody fluorescence staining of stool and urine sediment smears. As immunodeficiency progressed, monkeys developed diarrhoea, cachexia, and anorexia, and organisms were detected in urine and stool with greater frequency. Immunodeficient SIV-infected monkeys died approximately 27 days after receiving E. hellem by intravenous inoculation, and approximately 110 days after receiving E. hellem per os. Lesions typical for SIV-infection were observed in both groups of monkeys and microsporidia were detected in kidney and liver of the intravenously-injected monkeys. The murine microsporidiosis model provides an efficient means for studying protective immune responses to microsporidiosis, and may prove useful for screening immunological and chemotherapeutic agents. The pathogenesis of Encephalitozoon microsporidiosis in SIV-infected monkeys appears to parallel encephalitozoonosis in AIDS patients, suggesting that simian microsporidiosis may provide a useful model for evaluating diagnostic methods and therapeutic strategies during various stages of progressing immunodeficiency.
Didier
E S
ES
Department of Microbiology, Tulane Regional Primate Research Center, Covington, LA 70433.
Varner
P W
PW
Didier
P J
PJ
Aldras
A M
AM
Millichamp
N J
NJ
Murphey-Corb
M
M
Bohm
R
R
Shadduck
J A
JA
D000818:Animals; D000913:Antibodies, Protozoan / Q000097:blood; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D016207:Cytokines / Q000494:pharmacology; D004195:Disease Models, Animal; D016819:Encephalitozoon / Q000276:immunology; D016890:Encephalitozoonosis / Q000276:immunology / Q000469:parasitology; D005260:Female; D007121:Immunocompetence; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008253:Macaca mulatta; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism / Q000469:parasitology; D051379:Mice; D008815:Mice, Inbred Strains; D016881:Microsporidiosis / Q000276:immunology* / Q000469:parasitology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000378:metabolism; D016818:Nosema / Q000276:immunology; D009894:Opportunistic Infections / Q000276:immunology*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000382:microbiology; D015302:Simian Immunodeficiency Virus / Q000276:immunology; D019323:omega-N-Methylarginine
D000913:Antibodies, Protozoan; D016207:Cytokines; D008070:Lipopolysaccharides; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D007371:Interferon-gamma; D001120:Arginine