Emerging Infections as a Cause of Concern
Defense Sciences Office
Defense Advance Research Projects Agency
US Department of Defense
In a very informal sense, emerging infections are the unexpected—those infections that appear unexpectedly without warning and often rapidly. In a more formal sense, they are infections that rapidly expand in geographic range or in prevalence or that appear suddenly in a population. In the case of laboratory animal colonies in the United States and Japan, the level of infectious diseases has been decreasing over the years.
IMPERFECTLY CONTROLLED ENVIRONMENT
The laboratory animal environment is among the best controlled in the world. Although there are still obvious imperfections, as we heard from Dr. Smith (this volume), they are relatively well controlled. We have seen many infections such as ectromelia become comparatively rare; however, such improvements should also give us cause to maintain our guard—to remember that these infections have not been eradicated. Even smallpox, which was officially eradicated in a great cooperative venture (for which Japanese scientist Esau Arita and others deserve a great share of the credit), is something we argue about as a potential bioterrorist threat. Smallpox is the only infection that has successfully been eradicated even among human beings, and the opportunity exists for any infection to remain in geographically isolated colonies. There are places in the world where ectromelia still exists in rodent colonies, and Dr. Riley has described the traffic and movement of laboratory animals and their products throughout the world, which is one of the many factors that could allow a localized infection to spread if we are not vigilant.
In addition to opportunism, there is risk associated with the vast biodiversity of microorganisms that can be introduced into a laboratory animal colony through
contact with the natural host in the environment. In this respect, hantaviruses are of particular interest. The entire concern about emerging infections actually originated in a very small way about 10 years ago from a question about whether hantaviruses were a risk to laboratory workers. At that time, we knew of hantaviruses as an occupational hazard. In recent years, many more have been discovered, and now we know of literally dozens throughout the world, including a great number discovered only in the last few years throughout North and South America where they are harbored in very common wild rodents. Of course the possibility exists for these new infections to be introduced in facilities where other animals from the outside are brought into contact. Such knowledge of the great, not yet fully tapped biodiversity of microorganisms requires us to avoid complacency and to understand that detection and diagnosis remain essential tools for control.
Why might we be interested or concerned about emerging infections in laboratory animals? One compelling reason for all of us as laboratory animal disease specialists is of course the potential threat to the colonies as described by Dr. Smith and other speakers. The possibility exists that ectromelia could be reintroduced, and it is always a potential danger; many examples of rodent parvoviruses are a cause for concern, and perhaps the most dramatic parvovirus was canine parvovirus 2, which appeared in the late 1970s in dogs. There are still many discussions about how it was introduced, but it may have been an accident in vaccine production, a contaminant by another parvovirus during vaccine. We know from work by Colin Parish and others that once this virus appeared, it was able through essentially one mutation to expand its host range into dogs. It spread rapidly throughout the dog population causing very high mortality in puppies and other rapidly growing young dogs. It was replaced by another variant, and several waves of this process took place until several strains of this virus were distributed throughout the world.
Another emerging infection example is that of callitrichid hepatitis, which was really lymphocytic choriomeningitis (LCM), introduced into tamarins in the zoo. There it spread rapidly with rather fatal results throughout the captive tamarin population, possibly due to the feeding of contaminated material from newborn mice that had not been tested for LCM. The progression of this infection and others indicates the potential for surprise with a great biodiversity of microorganisms in existence.
OPPORTUNITIES TO LEARN
Nevertheless, we should not despair over emerging infections. We know there are factors responsible for emerging infections introduced into a new popu
lation. We have heard that with some methods (such as crossing species), material may be introduced that may be infected from another species or contact with natural hosts through changes. That material may carry previously unfamiliar but possibly severe infections simply by chance through contact with natural hosts that are carrying these infections (such as the hantaviruses).
Another reason for laboratory animal specialists not to despair is related to the many opportunities in comparative medicine as well as is identifying and studying appropriate animal models. Understanding the pathogenesis of infectious disease in many cases is greatly facilitated by having a good animal model. Indeed, as you know, good animal models often are essential.
Many of our problems in understanding the pathogenesis of, for example, AIDS and HIV infection stem from the fact that we have a great limitation in animal models. In many other infections, a good small animal model would greatly facilitate our understanding of the host-pathogen interaction and our ability to study the natural process of disease and its pathogenesis in a relatively realistic situation. In addition, many zoonotic infections found in rodents and other animals may enable us to understand population dynamics through natural study, study in the laboratory, and comparative study of laboratory animal models. Similarly, there are pathogens not known to be human pathogens that offer interesting opportunities for study because of their existence in laboratory animals. Endogenous retroviruses are examples in that mice and rats have many known murine leukemia-like sequences that at times and under certain circumstances reactivate to give a variety of infective retroviruses, which we do not see in humans. I believe this model will provide interesting insights into some of the threats we may face in the future.
Finally and very importantly is the opportunity to study chronic disease models, often perhaps in their natural or more nearly natural setting that may also closely resemble the human situation. Helicobacter is one example of such a model, and I suspect there are many other chronic disease models that can be found and demonstrated coming from our knowledge about existing infections or those newly introduced in laboratory animal colonies. I will defer to Dr. Fox who has done much outstanding work on that subject.
Similarly, we are sometimes surprised by what we find in laboratory animals. Some years ago we studied a virus called mouse thymic virus (murine herpesvirus 3), which had the interesting property of destroying CD4-positive cells. Recently we collaborated with Drs. Shimo Shakabutshi and Noriko Shakabutshi, who were able to demonstrate and publish in the Journal of Immunology the regeneration of the thymus after these animals had been infected and had actually recovered while shedding virus for most of their lifetime. Their thymuses regenerated; however, often late in life, they would manifest disease,
indicating that disregulation of T cell differentiation could be an underlying mechanism for autoimmunity and possibly other abnormalities. This process was first observed with a fairly mild natural infection of mice. Human herpesvirus 6, which was discovered later, has many properties similar to murine herpesvirus 3 (mouse thymic virus), including its ability to kill T lymphocytes.
Thus, I believe there are many discoveries yet to be made. In addition, given the vast biodiversity of microorganisms and the geographic distribution of animal colonies all over the world, I fear there are possibilities for new, currently unknown infections to emerge. Some may be zoonotic and others (simply, like the examples described, but perhaps not so simply) may be capable of causing serious concern in laboratory animal colonies but either damaging the productivity of the colony or affecting the results. How we deal with these possibilities is the subject of this conference, and I believe the approaches are entirely appropriate. They remain our first line of defense: detection and diagnostics, the identification of disease organisms, that ever-increasing list of ever-dwindling organisms. In addition, it might also be advisable to have some broad, perhaps more generic, strategies for looking at pathogen discovery, such as generic polymerase chain reaction or differential display methods that would more rapidly identify pathogens present in the population for which we cannot yet test.
Briefly, gene expression and host markers also offer interesting possibilities. We now have the technology to look at gene expression in the host in response to pathogens, which may be markers of disease. They may also tell us a great deal about the host-pathogen interaction during experimental studies.
The question of validation has been posed many times, and I believe it remains an essential question with any diagnostic test. I also believe there is much cause for optimism in that context because a number of groups in these areas are cooperating, which I hope will continue along with an exchange of information and validation of reagents and tests.
As a program manager at the Defense Advance Research Projects Agency (DARPA), I could not of course participate in this conference without commenting on DARPA. DARPA is best known for having originated the Internet, then called the ARPAnet (we were then called ARPA, a few years ago). Since that time, DARPA's mission has been to develop new technologies for critical national needs.
A few years ago, our director became particularly concerned about our vulnerability to biowarfare and bioterrorism. The decision was made to take a very broad approach to the diagnosis and identification of pathogens and to dealing
with host-pathogen interaction because although we talk a great deal about lists, the fact to remember is that although lists are a useful place to start, they are not the end point.
In any case, we do have a diagnostics program about which I welcome your comments and questions. For more information about DARPA, please feel free to browse our Web site (< http://www.darpa.mil/DSO/rd/Abmt/Bwd.html >). We are trying to develop new technologies and new approaches for the identification of infection and infectious pathogens that we hope will be useful in the future.