INTRODUCTION

Pathogen evolution poses the critical challenge for infectious disease management in the twenty-first century. As is already painfully obvious in many parts of the world, the spread of drug-resistant and vaccine-escape (epitope) mutants can impair and even debilitate public and animal health programs. But there may also be another way in which pathogen evolution can erode the effectiveness of medical and veterinary interventions. Virulence- and transmission-related traits are intimately linked to pathogen fitness and are almost always genetically variable in pathogen populations. They can therefore evolve. Moreover, virulence and infectiousness are the target of medical and veterinary interventions. Here, we focus on vaccination and ask whether large-scale immunization programs might impose selection that results in the evolution of more-virulent pathogens.

The word virulence is used in a variety of ways in different disciplines. We take a parasite-centric view as follows. We use “disease severity” (morbidity and/or mortality) to mean the harm to the host following infection. Disease severity is thus a phenotype measured at the whole-organism (host) level that is determined by host genes, parasite genes, environmental effects, and the interaction between those factors. One component of this is virulence, a phenotypic trait of the pathogen whose expression depends on the host. Thus, virulence is the component of disease severity that is due to pathogen genes, and it can be measured only on a given host. We assume no specificity in the interaction between host and pathogen (more-virulent strains are always more virulent, whatever host they infect).

Introduction

Malaria, a disease caused by protozoan parasites of the genus Plasmodium, can substantially reduce host fitness in wild animals (Atkinson and Van Riper 1991; Schall 1996). In humans, the major disease syndromes – severe anemia, coma, and organ failure, as well as general pathology such as respiratory distress, aches, and nausea – cause considerable mortality and morbidity (Marsh and Snow 1997).

Biomedical research attributes malaria to red cell destruction, infected cell sequestration in vital organs, and the parasite-induced release of cytokines (Marsh and Snow 1997). But mechanistic explanations are just one type of explanation for any biological phenomenon, and, in recent years, evolutionary biologists have become interested in offering evolutionary explanations of infectious disease virulence. This is entirely appropriate (Read 1994). In the context of malaria, for example, the clinical outcome of infection has an important impact on parasite and host fitness and is – at least in part – determined by heritable variation in host and parasite factors (Greenwood et al. 1991). Yet in the recent rush to provide evolutionary explanations of disease, there has been, in our view, too little interaction between the models built by evolutionary biologists and reality. There is unlikely to be a simple, general model of virulence: the causes of disease and the fitness consequences for host and parasite are too variable. Instead, different models, and even different frameworks, will be relevant in different contexts.

Continuing research on tardive dyskinesia has considerably broadened the classic hypothesis of dopamine-receptor supersensitivity, proposed more than 20 years ago (Klawans, 1973). Roles for other neurotransmitter systems (GABA and norepinephrine) have been postulated (Tamminga, Crayton, & Chase, 1979; Wagner et al., 1982; Fibiger & Lloyd, 1984; Gunne, Haggstrom, & Sjoquist, 1984; Jeste, Doongaji, & Linnoila, 1984; Stahl et al., 1985; Kaufman et al., 1986; Thaker et al., 1987; Andersson et al., 1989; Thaker, Nguyen, & Tamminga, 1989), and there is a newer hypothesis suggesting that cellular damage mediated by free radicals underlies tardive dyskinesia (Lohr et al., 1988, 1990; Cadet & Lohr, 1989). Demographic and psychiatric variables, such as gender, age, and concomitant affective disorder, have also been identified as risk factors (Smith & Baldessarini, 1980; Jeste & Wyatt, 1982; Kane & Smith, 1982; Richardson et al., 1985; Kane et al., 1986; Weiner & Lang, 1989). Increasingly, these disparate variables support the concept that tardive dyskinesia, like most brain dysfunctions, may involve multiple abnormalities and that vulnerability to it may be multifactorial. In this chapter we summarize our findings concerning risk factors for tardive dyskinesia that suggest that amino acid metabolism – particularly that of the large neutral amino acid phenylalanine (Phe) – may play a role in vulnerability to tardive dyskinesia.