Summer Buzz

Polyxeni Potter

Author affiliation: Centers for Disease Control and Prevention, Atlanta, Georgia, USA

Asynchronous Onset of Clinical Disease in BSE-Infected Macaques

Judith Montag¹, Walter Schulz-Schaeffer, Annette Schrod, Gerhard Hunsmann, and Dirk Motzkus

Author affiliations: German Primate Center, Göttingen, Germany (J. Montag, A. Schrod, G. Hunsmann, D. Motzkus); University of Göttingen, Göttingen (W. Schulz-Schaeffer)

Abstract

To estimate the effect of the variability of prion disease onset on primary bovine spongiform encephalopathy transmission to humans, we studied 6 cynomolgus macaques. The preclinical incubation period was significantly prolonged in 2 animals, implying that onset of variant Creutzfeldt-Jacob disease in humans could be more diverse than previously expected.

Prion diseases, such as bovine spongiform encephalopathy (BSE) in cattle, scrapie in sheep, and Creutzfeldt-Jakob disease (CJD) in humans, are fatal, transmissible, neurodegenerative disorders associated with the aggregation of an infectivity-associated isoform (PrP^Sc) of the cellular prion protein (PrP) (1). Seventeen years ago, it became apparent that the BSE-infectious agent had entered the food chain and was identified as the causative agent for a new variant CJD (vCJD) (2). Since then, several risk assessment studies have investigated the number of expected vCJD cases in human populations (reviewed in [3]). Although thousands to millions of consumers of beef products were estimated to be affected, thus far only a few more than 200 vCJD cases have been observed worldwide.
This discrepancy was assumed to be attributable to the so-called species barrier, defined as the hindrance of an infectious agent to change its natural host. Upon crossing the species barrier, prion diseases often show a low attack rate in conjunction with a high variability in the preclinical incubation time. Thus, the consumption of BSE-contaminated products may have led either to a restricted infection or to a prolonged asymptomatic phase in some exposed persons. Therefore, concerns have been raised that asymptomatic carriers of vCJD might exist, posing a risk for unintentional human-to-human transmission.
First indications that transmission of BSE to primates may lead to variances in the preclinical incubation times were obtained by inoculating cynomolgus macaques with cattle-derived BSE material (4–6), even though in those studies not more than 3 animals were used. We have now used a group of 6 macaques that were infected with BSE at a comparable age and kept under identical and controlled experimental conditions.

The Study

Six captive-bred female cynomolgus macaques (Macaca fascicularis, purchased from the Centre de Recherche en Primatologie, Mauritius) were inoculated intracerebrally with 1 dose of 50 mg brain homogenate (10% wt/vol) derived from 11 BSE-infected cattle. Animal experimentation was performed in accordance with section 8 of the German Animal Protection Law in compliance with Directive 86/609/EEC. Macaques were housed in a social group, and behavioral changes were assessed on a daily basis by experienced animal care takers.
After inoculation, all 6 macaques remained healthy and asymptomatic for >30 months (Table). At 931 days postinfection, 1 animal showed indications of slight coordination disorders. Within a few days, afferent ataxia developed, and when the animal was separated from the others animals, she apparently became tame. After 2 weeks, the animal showed severe dysmetria of the extremities without obvious myoclonia. Dementia was apparent but could not be diagnosed by objective measures. For ethical reasons, the animal was euthanized 17 days after disease onset. Within the next 14 weeks, 3 more animals became symptomatic. After appearance of neurologic symptoms (ataxia, tremors), the affected animals were occasionally separated from the group when symptoms became more severe or attacks from asymptomatic animals occurred. The disease course in these animals was comparable to that of the first animal, but the progression was slower (91–103 days).