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Authors' Response to Hogan

Posted by plosmedicine on 30 Mar 2009 at 23:57 GMT

Author: Albert D.M.E. Osterhaus
Position: Department of Virology
Institution: Erasmus Medical Center, Rotterdam, The Netherlands
Additional Authors: Bart L. Haagmans
Submitted Date: August 08, 2006
Published Date: August 8, 2006
This comment was originally posted as a “Reader Response” on the publication date indicated above. All Reader Responses are now available as comments.

In response to our perspective on nonhuman primate models for SARS [1], which accompanied the article by Lawler et al., [2], Robert Hogan questions the usefulness of nonhuman primates as good models for SARS.

As demonstrated by several groups, SARS-CoV replicates to high titers in the respiratory tract of a surprisingly broad range of animal species, albeit showing remarkable differences in cell tropism. We have argued that efficient infection of type 1 and 2 pneumocytes as seen in macaques and humans - most likely due to the similarities in the spike protein binding domains of the host SARS-CoV receptor ACE2 - is a prerequisite for the SARS-CoV infection induced pathology observed in humans. So far there is no strong evidence that a similar tropism is observed in other animal species.

However, the tropism of SARS-CoV for pneumocytes may not suffice to induce severe clinical signs in primates. In case of a resolving infection in macaques, pathological changes are evident 4-6 days after infection and may have become inapparant by days 12-14. In addition, in young adult humans, SARS-CoV infection generally causes relatively mild disease. Viral sequence differences in the SARS-CoV isolate HKU 39849 - obtained from and distributed to several groups by Peiris et al., [3] - as compared to other strains used, may determine the outcome of SARS-CoV infection in macaques. Furthermore, recent experiments from our group indicate that clinical signs after infection with this virus are more likely to occur in aged macaques (not published). Clinical signs observed in our earlier experiments were largely characterised by lethargy, whereas respiratory distress was observed in one animal [4,5].

The apparent differences observed in clinical outcome of the infection in macaques, which is not dissimilar to the outcome in humans, may limit the utility of SARS-CoV infected macaques as a model for severe SARS. However, none of the other models available produces clinical disease related to respiratory distress, except for ferrets that are inoculated with the HKU 39849 virus intratracheally [6]. Therefore, we feel that the macaque model may indeed provide important clues to the pathogenesis of SARS. As also argued by Subbarao and Roberts [7], there is no single preferred model for SARS and combining the data obtained in different animal models may help to solve the question why SARS is so devastating in some humans. This also holds true for the development of effective vaccines and other intervention strategies against possible future SARS-CoV outbreaks which may be caused by genetically quite distinct viruses.


1. Haagmans BL, Osterhaus ADME (2006) Nonhuman Primate Models for SARS. PLoS Med 3(5): e194 DOI: 10.1371/journal.pmed.0030194

2. Lawler JV, Endy TP, Hensley LE, Garrison A, Fritz EA et al. (2006) Cynomolgus macaque as an animal model for severe acute respiratory syndrome. PLoS Med 3: e149 DOI: 10.1371/journal.pmed.0030149

3. Peiris J, Lai S, Poon L, Guan Y, Yam L, Lim W, Nicholls J, Yee W, Yan W, Cheung M, Cheng V, Chan K, Tsang D, Yung R, Ng T, Yuen K. (2003) Coronavirus as a possible cause of severe acute respiratory syndrome. Lancet 361: 1319-1325.

4. Fouchier RA, Kuiken T, Schutten M, van Amerongen G, van Doornum GJ, et al. (2003) Koch's postulates fulfilled for SARS virus. Nature 423: 240.

5. Kuiken T, Fouchier RA, Schutten M, Rimmelzwaan GF, van Amerongen G, et al. (2003) Newly discovered coronavirus as the primary cause of severe acute respiratory syndrome. Lancet 362: 263-270.

6. Martina BE, Haagmans BL, Kuiken T, Fouchier RA, Rimmelzwaan GF, et al. (2003) SARS virus infection of cats and ferrets. Nature 425: 915

7. Subbarao K, Roberts A (2006) Is there an ideal animal model for SARS? Trends Microbiology 14: 299-303.

Funding: The authors received no specific funding for this article.

Competing Interests: The authors have declared that no competing interests exist.

No competing interests declared.