Metronidazole-but not IL-10 or prednisolone-rescues Trichuris muris infected C57BL/6 IL-10 deficient mice from severe disease.
Trichuris muris infected C57BL/6 mice are a frequently studied model of immune mediated resistance to helminths. Our objective was to characterize dose-dependent gastrointestinal (GI) disease and pathology due to Trichuris in C57BL/6 mice with varying degrees of IL-10 sufficiency. These mice can serve as a model for other animals (dogs, cattle) and humans where IL-10 polymorphisms have been associated with disease susceptibility and may affect susceptibility to whipworm. C57BL/6 IL-10(+/+), IL-10(+/-) and IL-10(-/-) mice were infected with T. muris (J strain) in a dose response study. T. muris produced dose-dependent disease in IL-10(-/-) mice. Ninety percent of mice receiving the high dose (75 ova) had severe disease necessitating early euthanasia, while the medium dose (50 ova) resulted in 100% early euthanasia of males/75% of females, and the low dose (25 ova) in 100% early euthanasia of males/25% of females. Having some IL-10 as in heterozygotes did not rescue all infected mice from effects of the high dose. 2/21 IL-10(-/-), 1/17 IL-10(+/-), and 0/17 IL-10(+/+) mice in the high dose group had severe peritonitis and extra-intestinal bacteria confirmed by fluorescent 16S rDNA analysis of peritoneal organ surfaces. Three of twenty one IL-10(-/-) had demonstrable extra-intestinal T. muris adults. Although free from viral pathogens, 12/21 IL-10(-/-), 6/17 IL-10(+/-), and 4/17 IL-10(+/+) infected mice had hepatitis, while control mice of all genotypes did not. Mice had evidence of inflammation of serosal surfaces of liver, spleen and GI tract even when extraintestinal Trichuris were not found. Blinded histopathology scoring revealed that even when infected IL-10(-/-) mice displayed few, if any, clinical signs, levels of gut inflammation did not vary significantly from those mice euthanized early due to severe disease. To examine whether antibiotics or corticosteroids could reverse severe disease and lesions, IL-10(-/-) mice infected with T. muris were treated with metronidazole or prednisolone prior to and throughout 40 days of infection. Mice given prednisolone had severe disease and lesions with the highest mortality rate. Mice given metronidazole had a significantly lower mortality rate than those given prednisolone, but GI lesions were of similar severity and distribution including peritonitis. Mortality was associated with extraintestinal worms and bacteria and further supported a role for enteric bacteria in this pathogenesis.
Cell and Molecular Biology Program, Michigan State University, East Lansing, MI, USA; Comparative Enteric Diseases Laboratory, Department of Large Animal Clinical Sciences, Michigan State University, East Lansing, MI, USA; College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USA.
Jamie J
JJ
Kopper
College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USA; The Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, MI, USA.
Jon S
JS
Patterson
Comparative Enteric Diseases Laboratory, Department of Large Animal Clinical Sciences, Michigan State University, East Lansing, MI, USA; College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USA. Electronic address: mansfie4@cvm.msu.edu.
Linda S
LS
Mansfield
D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D007249:Inflammation; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D007422:Intestines / Q000469:parasitology / Q000473:pathology; D007960:Leukocyte Disorders; D008297:Male; D008795:Metronidazole / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011239:Prednisolone / Q000494:pharmacology*; D013927:Thrombosis; D014257:Trichuriasis / Q000235:genetics / Q000473:pathology*; D014258:Trichuris
D000890:Anti-Infective Agents; D000893:Anti-Inflammatory Agents; D016753:Interleukin-10; D008795:Metronidazole; D011239:Prednisolone
C57BL/6 mice; IL-10 deficiency; Metronidazole and prednisolone; Trichuris muris