ACLAD NEWSLETTER Vol. 14, No. 2

American Committee on Laboratory Animal Diseases

September 1993

Editor:
Stephen S. Morse The Rockefeller University 1230 York Avenue, Box 120 New York, NY 10021-6399 Telephone: (212) 327-7722 FAX: (212) 327-7172 OR 327-7974 e-mail: morse@rockvax.rockefeller.edu FOR: Items for the Newsletter, general comments

Editorial Assistant: Joan Bailie Section of Comparative Medicine Yale University School of Medicine P.O. Box 208016 New Haven, CT 06520-8016 Telephone: (203) 785-2507; FAX: (203) 785-7499 FOR: Changes of address; questions about mailing or dues

ACLAD Officers 1993-94: PRESIDENT: Bob Jacoby; SECRETARY-TREASURER: Steve Morse COUNCILLORS: Tony Allen, Jim Fox, Pat Manning, Dean Percy, Abbe Smith, Jerry van Hoosier, Pravin Bhatt

ACLAD BUSINESS MEETING (NASHVILLE) SUNDAY, NOVEMBER 14, 5 PM, APPALACHIAN ROOM, OPRYLAND HOTEL ACLAD SCIENTIFIC PROGRAM (NASHVILLE) Annual Seminar and Wallace P. Rowe Lecture TUESDAY, NOVEMBER 16, 8 A.M.--NOON, MEMPHIS BALLROOM, OPRYLAND HOTEL NEXT ISSUE OF THE NEWSLETTER: MARCH 1994.

PLEASE SEND CONTRIBUTIONS FOR THE NEXT ISSUE BY FEBRUARY 3, 1994 --------

EDITORIAL

The world is in a state of flux, so why should ACLAD be an exception? ACLAD has gone along happily for 14 years, but we all know that an organization can be strong only if it serves its membership well. So this is a time for re-evaluation and renewal. Looking to the future, several new committees have been formed [see President's Message, next page] to evaluate how ACLAD can grow and better serve its members. At the Annual Business Meeting, the future of ACLAD will be discussed, and members recruited for the new committees. This is your invitation to attend and to participate in the decision making process. If you will be in Nashville, do plan to attend the Business meeting on Sunday, bring your ideas and participate actively. This is the only way that ACLAD can be democratic and reflect your needs. The future of this organization is the membership. Let me also urge you to come to the scientific program. I admit I'm biased, but this year's ACLAD scientific program is especially exciting. How could anyone ask for more timely topics? With the recent outbreak of a "new" disease in the Four Corners area of the Southwest, now attributed to a Hantavirus in wild rodents, the seminar subject is as current as the Nightly News. This virus, and other infections of equal concern, many with zoonotic potential, will be the focus of this year's seminar. This is the place to get the latest on all the diseases you will be seeing on the Nightly News (and that your colleagues will be asking about)! Who knows, we may even get a step ahead of the press on this one. Next, this year's Wallace P. Rowe lecturer is Dr. Peter Doherty, whose pioneering work on "killer" T cells has become one of the cornerstones of modern immunology. With the continuing importance of T cells in AIDS, and recent suggestions that killer T cells could be important in protective responses against HIV infection, the subject remains in the forefront. But with the enormous literature in this field, and its specialized vocabulary, keeping up on T cells is really a hard job. Here is a rare opportunity to get an understanding of this important subject, straight from a leader in the field. Elsewhere in this issue, you will find notices for the Business Meeting and scientific program at Nashville this November. For those who couldn't come to Nashville, watch this space for updates. (In the meantime, there is a brief summary of the current hantavirus outbreak on page 5.) Finally, let me remind you that your comments and contributions for this Newsletter are always welcome.
Cordial best wishes, Steve Morse

PRESIDENT'S MESSAGE

Fellow Members, ACLAD has matured admirably since its inception 14 years ago. We are valued contributors to AALAS and the Newsletter has garnered a progressively wider readership. The Executive Committee, in reflecting on ACLAD's accomplishments, knows that it is also important to plan for ACLAD's future. To this end, 3 committees have been established to look, respectively, at: 1) PUBLICATIONS (chaired by Steve Morse); 2) PROGRAMS (chaired by Jim Fox); 3) BY-LAWS (chaired by Bob Jacoby). Because it is essential that the membership be heard during evaluation and recharting of ACLAD's course, we invite you to attend the annual business meeting, where these critical matters will be discussed. It will be held on Sunday evening, November 14, in conjunction with the National Session of AALAS. Please make a special effort to accommodate this important discussion in your itinerary. Many thanks for your continued enthusiasm and support for ACLAD. I look forward to seeing you at the meeting, and at the ACLAD seminar programs on November 16.
Bob Jacoby, President

ACLAD BUSINESS MEETING "ACLAD'S FUTURE: OPPORTUNITIES AND STRATEGIES" DATE: NOVEMBER 14, 1993 TIME: 5 PM PLACE: APPALACHIAN ROOM, OPRYLAND HOTEL P.S.: DON'T FORGET the Annual Seminar and Wallace P. Rowe lecture on Tuesday, November 16! Further details on next page.

ACLAD SCIENTIFIC PROGRAM
Annual Seminar and Wallace P. Rowe Lecture Tuesday, November 16 8 A.M.--Noon, Memphis Ballroom (Opryland Hotel) 8--11 AM SEMINAR: EMERGING AND RE-EMERGING INFECTIONS OF ANIMALS AND MAN Moderators: Robert O. Jacoby, Abbe Smith Stephen S. Morse (The Rockefeller University): Overview: Emerging Infections and Their Causes Beatrice Hahn (University of Alabama, Birmingham): Primate Lentiviruses (SIVs, HIV) C.J. Peters (CDC): Hemorrhagic Fever Viruses Stephanie Ostrowski (CDC): Tuberculosis 11 A.M.--Noon WALLACE P. ROWE LECTURE: Peter C. Doherty Chair, Dept. of Immunology St. Jude Children's Research Hospital, Memphis "Cell-Mediated Immunity in Virus Infections" 11 A.M., Memphis Ballroom (Opryland Hotel)
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HANTAVIRUS OUTBREAK IN THE UNITED STATES Beginning in May 1993, patients were admitted to hospitals in New Mexico, Arizona, and Colorado with fever and acute respiratory distress (ARDS); a number subsequently died from respiratory failure. Serology and detection of genetic sequences by polymerase chain reaction (PCR) provided evidence that a previously unrecognized hantavirus was the cause of the outbreak. By PCR, the same sequences were identified in tissues taken at autopsy from several of the patients and in tissue samples from local rodents. The major reservoir was Peromyscus maniculatus, the deer mouse, which is one of the rodents most commonly trapped near houses in the area. A high proportion (20-30%) of captured Peromyscus maniculatus proved positive by serology or PCR. There were a few positive results from other local rodents (other Peromyscus species and a chipmunk).

Since the start of the current outbreak in the Southwest this year, the Centers for Disease Control and Prevention (CDC) tabulated 30 confirmed cases as of mid-August, with 20 deaths (updating as of September 1, CDC reported 35 cases confirmed, and over 50 additional cases under investigation in 10 states; as of early September, clinicians in the area are reporting 1-2 cases per week). Of the 30 confirmed by mid-August, 23 were in New Mexico, Arizona, and Colorado, in the Four Corners area; 7 were outside that area. The current outbreak began in December 1992, with cases peaking in May 1993. One person in Oregon (outside the area) was identified as being infected in July 1992, and there may have been infected individuals in the Four Corners area as early as August 1992. The virus is likely to be ancient in the rodent hosts, but newly recognized as a cause of human disease, so it is very likely that re-examination of earlier cases of respiratory distress will identify sporadic occurrences of hantaviral infection, and that this virus, as well as other hantaviruses, will be found in testing stored tissue samples from rodents. In June 1993, a man in Louisiana died of a similar adult respiratory distress syndrome. The rodent reservoir in this case is most likely to be Peromyscus gossypinus, the cotton mouse. The hantaviral sequences detected in his lung tissue indicated a virus distinct from the "Four Corners" virus, although closely related. From preliminary data, both of the newly recognized hantaviruses are distinct from those previously identified, but appear most closely related to another North American hantavirus, Prospect Hill, described from meadow voles (Microtus pennsylvanicus) in Maryland and Minnesota but not associated with human disease.

Hantaviruses are natural infections of rodents. Human disease is zoonotic, as a result of contact with infected rodents or infected secretions (usually urine). Anecdotal reports from the Four Corners area suggested that the winter had been unusually wet, resulting in a large crop of nuts as rodent food, and, in turn, an exceptionally large rodent population, offering more opportunities for people to come in contact with infected rodents (and, hence, the virus). This has apparently been confirmed by the University of New Mexico's ecological research station at Sevilleta, which documented a tenfold increase in area rodent populations beginning spring 1993.

Hantaviruses constitute a genus in the family Bunyaviridae; other members include Hantaan (the cause of Korean hemorrhagic fever), and viruses such as Puumala and others in Europe that classically cause hemorrhagic fevers with renal syndrome (fever, bleeding, kidney damage, and shock). Numerous hantaviruses are found worldwide in various rodent species, and a given hantavirus is usually closely associated with a particular rodent host. At present, some 100,000 cases of Korean hemorrhagic fever (Hantaan infection) are diagnosed annually in China alone. The major natural host of Hantaan virus in Asia is the striped field mouse, Apodemus agrarius. A related virus, Seoul, was originally described in rats in Korea and has since been identified in urban rats living in American cities. It has been suggested that rats carried on ships from Asia may have introduced Seoul virus into the U.S. In Korea, Seoul virus has caused hemorrhagic fever with renal syndrome similar to Hantaan virus, but usually considerably milder. In the US, acute disease has not been identified, although seropositive individuals have been found in some inner city areas. There is some evidence for a possible association with chronic renal disease, including renal hypertension. Some foreign rat colonies (e.g., in Japan) contain animals infected with hantavirus, with occasional transmission to researchers. This is not an issue in the United States, where laboratory rodents are generally considered free of hantaviruses. Some colonies of exotic or wild origin rodents might possibly harbor hantaviruses (your Editor, for one, is quite interested in receiving samples from such sources to test by PCR). For those with possible exposure to rodents in the field, the CDC has recently issued recommendations for protective measures (5).

References:

1. Johnson, K. (1986). Hemorrhagic fever -- Hantaan virus. In: Viral and Mycoplasmal Infections of Laboratory Rodents (ed. P.N. Bhatt, R.O. Jacoby, H.C. Morse III, and A.E. New), pp. 193-207 (Chap. 11). Orlando: Academic Press. (Also Chap. 11a: Guidelines for Surveillance,Prevention, and Control of Hantaan Virus Infection in Laboratory Animal Colonies, pp. 209-216.)

2. LeDuc, J.W. (1987). Epidemiology of Hantaan and related viruses. Lab. Anim. Sci. 37:413-418.

3. LeDuc, J.W., J.E. Childs, and G.E. Glass (1992). The Hantaviruses,etiologic agents of hemorrhagic fever with renal syndrome: a possible cause of hypertension and chronic renal disease in the United States.Annu. Rev. Public Health 13:79-98.

4. LeDuc, J.W., J.E. Childs, G.E. Glass, and A.J. Watson (1993). Hantaan (Korean hemorrhagic fever) and related rodent zoonoses. In: Emerging Viruses (ed. S.S. Morse), pp. 149-158 (Chap. 14). New York:Oxford University Press.

5. CDC (1993). Hantavirus infection -- Southwestern United States:Interim recommendations for risk reduction. MMWR 42 (No. RR-11):1-13. [Available from US Government Printing Office, 202 783-3238]

This summary was compiled from various sources, including the CDC's Morbidity and Mortality Weekly Reports (June 11--August 13, 1993) and personal communications. Future issues will contain updates on this evolving situation. The annual symposium will also feature talks on this and related subjects, with latest news.

RESEARCH UPDATES AND FORUM Contributors: Many thanks to Drs. Robert O. Jacoby, Abigail Smith and Steven Weisbroth for abstracts. We welcome contributions of material from the membership! -- Editor

Characterization of acute rat parvovirus infection by in situ hybridization. Diane J. Gaertner, Robert O. Jacoby, Elizabeth A. Johnson, Frank X. Paturzo, Abigail L. Smith, and Janet L. Brandsma [To appear in Virus Research] In situ hybridization and virus titration were used to characterize early stages of rat virus (RV) infection of rat pups after oronasal inoculation. Results suggest that virus enters through the lung and that early viremia leads rapidly to pantropic infection. Cells derived from all three germ layers were infected with RV, but those of endodermal and mesodermal origin were the predominant targets. Infection of vascular endothelium was widespread and was associated with hemorrhage and infarction in the brain. Convalescence from acute infection was accompanied by mononuclear cell infiltrates at sites containing RV DNA. Viral DNA was also detected in endothelium, fibroblasts and smooth muscle myofibers four weeks after inoculation. Further examination of these cells as potential sites of persistent infection is warranted. **********************************************
Rodent parvoviruses, orphans no longer? Steven H. Weisbroth For some time, we have noted that certain mouse and rat serum accessions, drawn from the field, had a reproducible serologic test profile, ELISA or IFA (+) but HAI (-), with MVM (minute virus of mice) or KRV (Kilham rat virus) antigens. Based on a suggestion by Tattersall and Cotmore (1), we theorized that the cross-reaction was to antigenic sites of the non-structural protein (NS-1) shared by many parvoviruses, while the hemagglutinin detected by HAI would be more specific, and (about 10 years ago) we postulated a (then) hypothetical additional parvovirus to account for this profile. Since then, "orphan" parvovirus (OPV) has been identified (2,3), and appears one appropriate candidate. For the serologist wishing to recognize such parvoviruses by their cross-reactions, another permutation of the problem has been recognized in mouse sera from various sources. These are sera that test IFA (+), HAI (-), and that may be either negative or positive by ELISA (typically negative) when tested against MVM antigens. Others are negative (by ELISA) with MVM antigen preparations, but positive with KRV antigen, and are IFA positive with at least one of the antigens. A further complication is that no single MVM or KRV IFA preparation appears equally reactive with all sera. Twenty mouse sera from a single accession were tested in replicate against 3 different IFA antigen sources (2 preparations of MVM, and 1 of KRV), and against an MVM antigen in ELISA. Five sera were negative in all the tests. Fifteen sera were positive in at least one of the tests (of these 15, 13 were ELISA negative); 8 of these 15 reacted with all 3 of the IFA antigen preparations (from different sources), 5/15 with 2 of the preparations, and 2/15 with a KRV antigen preparation only (all 15 did react with the KRV preparation used in IFA). The reasons for these differences are unclear, but the differences do not appear to be artifacts of concentration. From the positive reactions, we would conclude that some of the sera indicate the presence of OPV, but, as long as we are trying to infer the existence of OPV from cross-reactive systems, there are going to be profiles that are difficult to explain. I think it is time to begin the formal recognition and (for serologists) reporting of mouse OPV and rat OPV as separate entities. Until the availability of homologous antigens for these viruses, detection must continue to be based on cross-reactivity with MVM and KRV antigens, especially in IFA. Certainly the future holds promise that the agents we currently designate as mouse OPV and rat OPV are being isolated and characterized (2,3), and that homologous antigen systems will become available. At present, we appear to be in the early stages of characterizing an emerging rodent health problem. As the pieces of this puzzle begin to fill in and more specific diagnostic reagents enter general use, the biology of these agents, and their origin and distribution, will be better understood.

References:

1. Tattersall, P., and S.F. Cotmore (1986). The rodent parvoviruses.In: Viral and Mycoplasmal Infections of Laboratory Rodents (ed. P.N.Bhatt, R.O. Jacoby, H.C. Morse III, and A.E. New), pp. 335-337. Orlando: Academic Press.

2. McKisic, M.D., D.W. Lancki, G. Otto, et al. (1993). Identification and propagation of a putative immunosuppressive orphan parvovirus in cloned T cells. J. Immunol. 150:419-428.

3. Smith, A.L., R.O. Jacoby, E.A. Johnson, et al. (1993). In vivo studies with an "orphan" parvovirus of mice. Lab. Anim. Sci. 43:175-182. **********************************************
Lethal exacerbation of Pneumocystis carinii pneumonia (PCP) in scid mice after infection by pneumonia virus of mice (PVM) John B. Roths, Abigail L. Smith, and Charles L. Sidman [To appear in the Journal of Experimental Medicine] Mice homozygous for the mutant allele scid (severe combined immunodeficiency) have been described as excellent models for Pneumocystis carinii (Pc) pneumonia (PCP), a major health problem in patients with AIDS and other immunodeficiency states. Other opportunistic pathogens have been shown to infect AIDS patients simultaneously with Pc, but whether one opportunist is able to directly influence the pathogenicity of another has not been determined previously. We have deliberately coinfected scid mice (with extant Pc infection) with a variety of primarily pneumotropic viruses and bacteria and have identified Pneumonia Virus of Mice (PVM) as being capable of fatally synergizing with Pc. This finding has clinical significance in the management of PCP, in that the identification and treatment of coinfecting pneumotropic pathogens may be as important as treatment targeted at Pc. A search for other synergistic (or antagonistic) microorganisms and determination of their mechanism(s) of action in altering the progression of PCP is indicated by these findings. **********************************************
**ANNOUNCEMENTS** Samples Wanted! We are very interested in sera or tissue samples (frozen or ethanol-preserved) from any wild murine rodents, or from colonies of "exotic" rodents, and from any wild-caught or feral primates. Our intended use would be testing (by PCR or serology) for several viruses in which we are interested (yes, including mouse thymic virus in mouse samples). Please contact Stephen S. Morse (address on cover).
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