Submitted to: Review Article
Publication Type: Review Article
Publication Acceptance Date: September 24, 2004
Publication Date: August 29, 2005
Citation: Witter, R.L. 2005. Marek's disease: the continuing struggle between pathogen and host. Review Article. Available: http://authors.elsevier.com/sd/article/S1090023304002199. Technical Abstract: As Marek's disease (MD) has slowly transformed from a current to a potential disease problem, attention is rightfully focused on the evolution of MD virus (MDV). In this issue of The Veterinary Journal Venugopal Nair presents a scholarly and instructive review of the process by which MDV has gained virulence in the past and, by extension, might continue to gain virulence in the future. Nair documents that MDV has evolved greatly in the past 60 years and that this process will likely continue. This is a critical thesis as it provides much of the justification for continued study of this intriguing and complex virus. He cites my earlier work that MDV is continuing to become more virulent for chickens immunized with Rispens vaccine (Witter 2001). However, this trend could not be confirmed in later studies by our group. We found that vv+MDV strains isolated in the United States from 1990 through 1999 showed no evidence of increasing virulence (Witter et al. 2005). This, of course, does not exclude the possibility that greater virulence in Rispens-vaccinated chickens will be or has been acquired, especially in Europe where the Rispens vaccine has been used for more than 30 years. For example, the EU1 isolate, an Italian strain isolated in 1992 (Schumacher et al. 2002), is considered exceptionally virulent. Nair identifies vaccines as the most likely trigger for evolutionary change and cites interesting work on malaria by Gandon (Gandon et al. 2001) showing that vaccines which partially suppress viral growth may cause exceptionally high levels of evolutionary change in the wild type pathogen. This suggests that the defining feature of virulence is not oncogenicity, but rather an increased potential for replication and/or transmission in the chicken. This hypothesis may be credible and deserves to be tested. Tumor induction and mortality, the classical hallmarks of virulence, may simply be a byproduct of enhanced replication. The interesting paper by Andrew Read, colleague of Gandon, which was presented at the 7th International Symposium on Marek's Disease in July, 2004, made a strong case for application of these general principles of virulence evolution to MDV. However, many critical questions relevant to the evolution of MDV have yet to be answered. Since the process of virulence evolution in MDV was initiated prior to the introduction of commercial vaccines, factors other than vaccination may also be important. A better understanding of the forces influencing the future virulence of MDV strains should indeed be a priority. Nair correctly points out that several discrete 'waves' of evolutionary change in MDV have occurred. This observation spawns important unanswered questions. Just why does evolution of MDV occur in waves? Why have these waves become apparent in different continents at about the same time? Nair cites sequence analysis of several MDV strains, including 2 that have been newly sequenced, to predict that virulence may be a complex trait, making it less susceptible to influence by single point mutations. Recent work by Reddy's group (Lupiani et al. 2004) has established a role for the viral gene meq in tumor induction but a comprehensive understanding of the genetic changes linked to virulence are not known. Nair implies that another wave of increased virulence will occur but makes no prediction as to when. By past standards, the next wave may already be overdue. Nair discusses the biological markers associated with MDV virulence. He points out the apparent linkage between virulence and immunosuppression, as evidenced by the induction of early atrophy of lymphoid organs by highly virulent isolates (Calnek et al. 1998). In recent collaborative studies with Calnek and others (Witter, Calnek, Buscaglia, Gimeno, & Schat 2005), the linkage between virulence and organ atrophy does not appear to be as tight as previously thought. Nair reports extensive cytolytic disease induced by recent 'hypervirulent' isolates. However, cytolytic disease is also induced by earlier isolates of the vv pathotype (Witter, Sharma, & Fadly 1980). The acute mortality may also reflect the induction of brain pathology consistent with acute transient paralysis (Witter et al. 1999). Nonetheless, cytolytic disease and transient paralysis are obviously correlated with virulence to some degree. Nair's suggestion that virulence may be linked to macrophage tropism, which may produce suppression of macrophage-mediated, non-specific immunity, is novel and deserves additional study. The role of immunodepression in virulence clearly deserves a better understanding. Finally, Nair looks to the future of MD control and concludes that more effective vaccines are needed. Although a specific strategy is not offered, Nair suggests that molecular technologies may well lead the way to providing immunity against future MDV strains, perhaps through the use of cytokines that enhance immune responses. The question of how much immunity can be induced against MD by vaccination was not addressed. Given that present MD vaccines are among the most effective vaccines known and that repeated efforts to produce vaccines superior to the Rispens strain (used since 1971) have thusfar failed, the existence of some kind of threshold of vaccinal immunity may need to be considered (Witter & Kreager 2005). The issues outlined by Nair in this excellent paper are important and suggest paths that may lead us to greater understanding and improved long term control of MD.