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Mousepox Resulting from Use of Ectromelia Virus-Contaminated, Imported Mouse Serum

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Mousepox Resulting from Use of Ectromelia Virus-Contaminated, Imported Mouse Serum Comparative Medicine Vol 50, No 4 Copyright 2000 August 2000 by the American Association for Laboratory Animal Science Mousepox Resulting from Use of Ectromelia Virus-Contaminated, Imported Mouse Serum Neil S. Lipman,1* Scott Perkins,1 Hai Nguyen,1 Martin Pfeffer,2 and Hermann Meyer3 Abstract Mousepox was identified in a single mouse-holding room in early 1999 after a group of 20 CAF1/Hsd mice were inoculated SC with a killed murine spindle cell tumor line, S1509A. The cell line had been used without complications multiple times and was determined to be free of viral contamination on the basis of results of mouse antibody production testing. Of the 20 mice inoculated, 12 mice died by postinoculation day 8. Severe lymphoid and hepatic necrosis was observed in select mice subjected to histologic examination. Ballooning degeneration of epi- thelial cells with intracytoplasmic eosinophilic inclusion bodies was observed in the skin overlying the inoculation site of the single mouse from which this tissue site was evaluated. Presence of ectromelia virus was confirmed by use of immunohistochemical and polymerase chain reaction analyses, and the virus was isolated after serum, pooled from 5 of the index cases, was inoculated into an immune-naive mouse. Investigation into the source of virus con- tamination included inoculating mice with aliquots of various S1509A freeze dates; chemically defined media and supplements, including fetal bovine serum; and two lots of pooled commercial mouse sera, after heat inactivation at 56ЊC for 30 minutes used as a medium supplement. One lot of pooled commercial mouse serum was identified as the source of ectromelia virus. This lot of serum was inadvertently used to feed S1509A cells that were subsequently inoculated into mice. We determined that the contaminated serum, which was purchased in late 1998, originated from China. The serum was imported into the United States as a batch of 43 L in early 1995. The serum was blended into a single lot and filtered (0.2 ␮m) before distribution to major suppliers throughout the country. The serum was sold or further processed to obtain a variety of serum-derived products. Because murine serum is generally sold in small aliquots (10 to 50 ml), we speculate that several thousand aliquots may have been derived from this batch of serum and, if inoculated into mice, would likely result in additional mousepox outbreaks. Mousepox, a potentially devastating disease of murine research yoelii in mice, resulted in the destruction of more than 5,000 colonies, is caused by ectromelia virus (EV), an orthopoxvirus of mice housed in two of four buildings at the NMRI followed by mice. Epizootic EV infection may cause substantial morbidity formaldehyde gas decontamination. Few details were provided and mortality dependent on the strain of virus and the host’s in the report, or have been made available subsequently, as to genotype, age, sex, and immunologic status (1–3). Mousepox can the source of the contaminated serum, except that it was ob- be associated with high mortality and limited clinical signs; tained from a domestic mouse colony. generalized maculopapular rash with scabs and/or conjunctivi- Historically, mousepox has been reported to be enzootic in tis, occasionally associated with appendage loss; or as inappar- Europe, Japan, and China. Today it is less common and is infre- ent infection (2). Considerable effort is exerted to maintain quently reported in Europe and Japan. It is still reported as EV-free mouse colonies as a serious outcome may follow its in- common in China (2). advertent introduction. In early 1999, unexpected mortality was observed in mice in- Mousepox is rare in the United States. The first mousepox oculated with a murine-derived cell line at the Weill Medical epizootic was reported in the 1950s (4). Although there were College of Cornell University (WMC/CU). Evaluation of affected sporadic reports of outbreaks over the subsequent 2 decades, it mice revealed mousepox and subsequent epidemiologic evalua- wasn’t until a major outbreak occurred in the United States in tion traced the source of EV to imported pooled commercial the late 1970s and early 1980s at the National Institutes of murine serum. We describe the clinical features of the outbreak, Health (NIH) and numerous U.S. research institutions, that the the methods used to eradicate the virus, and the source and dis- full impact of a mousepox outbreak was recognized (5–14). The tribution of the contaminated serum. NIH outbreak led to the destruction of tens of thousands of mice at a cost of millions of dollars and lost research (4). After the Materials and Methods NIH outbreak, reports of mousepox were not published in the Animals: Hybrid (CAF1/Hsd) F1 mice, which subsequently United States until 1996, when the most recent mousepox out- developed mousepox, were purchased from a commercial vendor break was reported from the Naval Medical Research Institute (Harlan Sprague Dawley, Indianapolis, IN) reported to be free of (NMRI), Bethesda, Md (15). The outbreak, traced to pooled com- adventitious virus contamination, including Sendai, mouse mercial murine serum used as a carrier to passage Plasmodium hepatitis virus (MHV), pneumonia virus of mice (PVM), minute 1Research Animal Resource Center, Weill Medical College of Cornell University virus of mice (MVM), mouse parvovirus (MPV), transmissible and Memorial Sloan-Kettering Cancer Center, New York, NY; 2Institute for Medi- encephalomyelitis virus (GDVII), reovirus 3, mouse rotavirus cal Microbiology, Epidemic and Infectious Diseases, Ludwig-Maximilians Univer- sity, Munich, Germany; 3Institute for Microbiology, German Armed Forces Medical (EDIM), ectromelia, lymphocytic choriomeningitis (LCM), mouse Academy, Munich, Germany; *Corresponding Author. adenovirus (Mad), polyoma, mouse cytomegalovirus (MCMV), 426 Mousepox Associated with Contaminated Mouse Serum Hantaan virus, lactate dehydrogenase elevating virus (LDV), K Table 1. Murine sentinel health-monitoring program virus, and mouse thymic virus (MTV), Mycoplasma sp., para- Panel A B C sites, and pathogenic bacteria. On arrival, mice were uncrated Frequency Bimonthly Semiannual Annual in an animal holding room housing mice for a single investiga- Agents MHV Bimonthly plus: Semiannual plus: Sendai Reovirus 3 Mad tive group. They were uncrated on an open bench and placed in MVM LCM Polyoma static isolator cages (Micro-barrier® standard height, Allentown GDVII Ectromelia Hantaan Caging Equipment Co. Inc., Allentown, NJ), using aqueous io- EDIM Cecal/duodenal protozoa MTV PVM Rectal specimen culture MCMV dophor (Wescodyne, AMSCO, Apex, NC)-disinfected forceps. MPV for Clostridium rodentium Clostridium piliforme They acclimated for eight days prior to use. In addition to the Mycoplasma Respiratory tract CAR bacillus pulmonis aerobic culture Encephalitozoon CAF1 mice, the room contained a unique transgenic (Tg) line, cuniculi C57BL/6J, and A/J mice. Skin scraping Examination of cecum and The animal holding room, housing EV-infected mice, was served Pooled fecal colon for helminths flotation by a single corridor and contained three shelf racks. At the time of Anal tape test the outbreak, the room held approximately 80 static isolator MHV = mouse hepatitis virus; MVM = minute virus of mice; GDVII = trans- cages. The corridor served a distinct section of the animal facil- missible encephalomyelitis virus; EDIM = mouse rotavirus; PVM = pneumo- ity in which there were 15 additional holding rooms housing nia virus of mice; MPV = mouse parvovirus; LCM = lymphocytic choriomenin- gitis virus; Mad = mouse adenovirus; MTV = mouse thymic virus; MCMV = predominantly mice, but also rats, guinea pigs, and frogs. Differ- mouse cytomegalovirus; and CAR = cilia-associated respiratory bacillus. ential pressures provided directional airflow so that air flowed from the corridor into the animal rooms. Mice in other holding later, an additional mouse from this group (C99-353) was found rooms within the facility were housed in either static or ventilated dead and was subjected to complete pathologic examination. (Maxi-Miser®, Thoren Caging Systems, Inc., Hazelton, PA) isola- Eight days after inoculation, 6 additional mice were found dead tor cages and were changed on an open bench or in a vertical without a detectable prodrome. At that time, the remaining live flow class-100 HEPA-filtered change station (Max-Miser® Mo- mice (C99-377-1 through C99-377-8) were euthanized (n = 8), blood bile Change Station, Thoren Caging Systems, Inc., Hazelton, was collected for serum antibody determination (n = 5), and the PA), using forceps. Cages contained autoclaved corncob bedding bodies were submitted for gross and histologic (n = 5) evalua- (Bed O’Cobs, The Anderson Co., Maumee, OH) and were changed tion. Histopathologic findings were consistent with EV infec- at least weekly. Mice were fed pelleted feed (Laboratory Rodent tion, and the room was quarantined. Additional testing was Diet 5001, PMI Feeds, Inc., St. Louis, MO) and were provided completed to confirm the presence of EV in tissue sections by tap water in water bottles ad libitum. use of indirect fluorescent antibody (IFA) testing (C99-353) and The animal holding room environment was controlled, main- polymerase chain reaction (PCR) analysis (C99-377-2 and C99- taining temperature at 22 Ϯ 1ЊC, relative humidity between 40 377-4). Subsequently, intensive evaluation was undertaken to and 60%, and provided a photoperiod of 12 hours’ light/12 hours’ identify the source(s) of
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