A Protein Toxin from Pasteurella multocida Type D Causes Acute and Chronic Hepatic Toxicity in Rats

Abstract

Abstract. Pasteurella toxin given subcutaneously to rats caused severe liver damage and growth suppression in doses as low as 15.6 ng. Toxin was lethal at and above 31.25 ng. Survival times were dose-dependent, and lesions differed with time of survival after toxin. Rats dead of acute toxicity had focal hepatic necrosis. Liver lesions were associated with diffuse endothelial damage, intravascular trapping of leukocytes, and degeneration of hepatocytes (characterized by glycogen depletion, development of vacuoles, and eosinophilic cytoplasmic inclusions). Endothelial cells, Kupffer cells, and macrophages had evidence of activation, e.g., increased cellular size with increases in Golgi vesicles, granules, and lysosomes. Rats with chronic toxicity (survival > 150 hr) had cirrhosis, intestinal villous atrophy, and markedly reduced body weight and fat. These data show that the rat is highly sensitive to toxins of Pasteurella multocida, and that even low doses of toxin cause liver injury and growth suppression.Peptide toxins extracted from cultures of Pasteurella multocida type D, a causal bacterium in porcine atrophic rhinitis, 19,22 have been purified by several labo r a t o r i e~.~,~J~ Assays for toxin (dermatonecrotic toxin) include lethality in mice, cytopathic effects in cell cultures, and necrosis after intradermal injection of rodents. Given experimentally to piglets these toxins produce osteoporosis and progressive distortion of the nasal turbinates by causing necrosis of osteoblasts and by accelerating osteoclastic osteolysis.6.s The osseous core of the turbinate is replaced by mesenchymal stroma, and epithelium of the turbinate and its submucosal glands become atrophic. Toxins are active when given locally or parenterally, e.g., toxin purified in our laboratory, when sprayed onto nasal mucosa or injected subcutaneously, causes gross lesions of turbinate atrophy as early as 48 hr after t~eatment.~.'Although not commonly recognized in natural disease, pasteurella toxins (PT) also produce important systemic effects, including damage to liver and kidney.6J1 Experimentally, degeneration of hepatocytes has been reported (but not characterized) in piglets given toxin intraperitoneally (250 pg)22 and by aerosol (125 pg).6 A PT (which also contained endotoxin), when given intradermally to rats, caused "dystrophic alterations" in liver, kidney, adrenal cortex, and lymphoid tissues.21 Recently we have shown that PT given subcutaneously causes acute cell swelling and necrosis of hepatocytes in pigs.3 Although not adequately documented, these lesions suggest that toxins may cause alterations of vascular tissue or in systems that control metabolism in liver, skeletal muscle, or kidney. Hepatocytes, through production of acute phase proteins of inflammation, have the capacity to reduce growth, particularly of muscle tissue.Our long-term goal is to elucidate mechanisms by which low doses of PT affect the liver and, in turn, growth of peripheral tissues. This experiment was designed to evaluate the rat as a model for study...

Pasteurella multocida: from Zoonosis to Cellular Microbiology

“…Symptoms of pasteurellosis in most animals range from mild to severe (44, 178,[189][190][191][192][193][194][195][196][197][198]. Mild symptoms include sneezing, copious mucous secretions, mild rhinitis, mild pneumonia with labored breathing, and fever but can progress to disseminated disease (hemorrhagic septicemia [further discussed in "Pasteurellosis and Hemorrhagic Septicemia" below]) and/or atrophic rhinitis (atrophy of nasal mucosa, seromucinous glands, and turbinate bones) associated with toxinogenic strains.…”

“…Once it was discovered that only certain capsular serotype D and A strains of P. multocida were responsible for chronic turbinate atrophy, a large protein toxin was identified, isolated, and cloned from these strains (148,194,196,461,462). The purified, 146-kDa P. multocida toxin (PMT), encoded by the toxA gene located on a putative lysogenic bacteriophage (463), was subsequently demonstrated to be the primary agent responsible for the symptoms of atrophic rhinitis (461,(464)(465)(466)(467)(468)(469)(470)(471), as well as a number of other clinical symptoms associated with P. multocida infection (189,190,192,461,464,470,(472)(473)(474)(475). PMT-mediated bone atrophy appears to occur through disruption of normal cell signaling processes in bone-generating osteoblasts and macrophage-like osteoclasts (205,206,466,(476)(477)(478)(479)(480)(481)(482).…”

Characterisation of dermonecrotic toxin-producing strains of Pasteurella multocida subsp. multocida isolated from man and swine

“…multocida strains could result from exposure to swine [6,7]. In animals, DNT induces lesions in liver and kidney [3, 8,9] and carriage of toxin-producing strains could be harmful to farmers, especially those suffering from chronic pulmonary disease. Human carriage could be of concern also in the control of atrophic rhinitis in swine.…”

Atrophic rhinitis vaccine composition triggers different serological profiles that do not correlate with protection

“…Acta Veterinaria Hungarica 56, 2008 PMT detoxification Pasteurella multocida toxin purified as described by Cheville and Rimler (1989) was kindly provided by R. B. Rimler (NADC, Ames, Iowa, USA). Detoxification of PMT was performed as established by Rimler (personal communication).…”