Cynomolgus macaque as an animal model for severe acute respiratory syndrome

Abstract

Background: The emergence of severe acute respiratory syndrome (SARS) in 2002 and 2003 affected global health and caused major economic disruption. Adequate animal models are required to study the underlying pathogenesis of SARS-associated coronavirus (SARS-CoV) infection and to develop effective vaccines and therapeutics. We report the first findings of measurable clinical disease in nonhuman primates (NHPs) infected with SARS-CoV.

Methods and findings: In order to characterize clinically relevant parameters of SARS-CoV infection in NHPs, we infected cynomolgus macaques with SARS-CoV in three groups: Group I was infected in the nares and bronchus, group II in the nares and conjunctiva, and group III intravenously. Nonhuman primates in groups I and II developed mild to moderate symptomatic illness. All NHPs demonstrated evidence of viral replication and developed neutralizing antibodies. Chest radiographs from several animals in groups I and II revealed unifocal or multifocal pneumonia that peaked between days 8 and 10 postinfection. Clinical laboratory tests were not significantly changed. Overall, inoculation by a mucosal route produced more prominent disease than did intravenous inoculation. Half of the group I animals were infected with a recombinant infectious clone SARS-CoV derived from the SARS-CoV Urbani strain. This infectious clone produced disease indistinguishable from wild-type Urbani strain.

Conclusions: SARS-CoV infection of cynomolgus macaques did not reproduce the severe illness seen in the majority of adult human cases of SARS; however, our results suggest similarities to the milder syndrome of SARS-CoV infection characteristically seen in young children.

Figure 1. Chest Radiographs

Anterior-posterior (AP) (A) and lateral (B) chest radiographs from 8 d postinfection for animal 91–379 show focal airspace disease in the right lower lobe that obscures the right costophrenic angle. Air bronchograms can be seen on the lateral view. Radiographs showing AP (C) and lateral (D) views from day 8 for animal 91–512 demonstrate subtle bilateral perihilar airspace disease visible on the AP film. Radiographs of animal 292Q on day 6 (E, F) reveal airspace disease involving the right lower lobe, left lingula, and perihilar right upper lobe. Lower lobe disease is clearly seen on the lateral view (F).