Aside from the possibility of a pandemic caused by the H5N1 variant of the avian flu, the coronavirus that causes severe acute respiratory syndrome is probably the virus that is being eyed most warily by public health officials concerned with emerging infectious diseases.

Though no one can say whether H5N1 will ultimately cross over and cause a pandemic, it is not any less threatening, but the history of SARS - such as it is - is more baffling. The virus seemed to come out of nowhere during the winter of 2002-2003, causing about 8,000 known infections and just less than 800 fatalities worldwide (most of them in China, Hong Kong, and Canada) before it was brought under control by public health intervention. After the initial wave of infections, many experts expected that SARS would settle into an annual pattern, much like influenza, with a new wave of infections expected about a year after the initial outbreak.

Instead, SARS has disappeared. While there were sporadic SARS cases reported in 2003 and 2004, those cases represented direct infections from palm civets, a cat-like animal that is the SARS coronaviruses' main animal reservoir. The virus strain that caused the 2002-2003 epidemic initially jumped to humans from palm civets, but was then spread by direct human-to-human transmission afterward. Subsequent strains of the virus have not able to spread between humans, which is a prerequisite for it to become an epidemic.

In an interview conducted in January, Gary Nabel, the director of the vaccine research center at the National Institute of Allergy and Infectious Diseases in Bethesda, Md., told BioWorld Today that although it was impossible to predict whether a more infectious version of SARS will return, it would be best to assume that it might: "The wise thing now is to be prepared, so that if [SARS] should arise at any point in the future, we won't be caught flat-footed like we were."

Researchers have been heeding that advice, and a number of recent papers reported advances on both basic science and medical approaches to SARS.

In the Sept. 16, 2005, issue of Science, researchers from Harvard Medical School published the atomic structure of the spike protein, which is the part of the SARS coronavirus that attaches to the cells it infects, bound to its receptor, the angiotensin-converting enzyme 2 (ACE2).

In their paper, the researchers showed that the viral strain that caused the 2002-2003 scare differed from less infectious (to humans) SARS coronavirus in only four amino acids. Of those, they identified two that were responsible for the increased infectivity of the strain, and possibly its ability to spread directly between humans, as well. The researchers noted those amino acids "are not, of course, the only ones critical" for the tight binding of SARS to its civet or human receptor, but said they "are simply the positions at which there are differences among isolates and receptors important for binding and entry."

Senior author Stephen Harrison said that "one of the critical issues in a SARS epidemic would be to predict whether a given variant of the virus will jump species or move laterally from one human to the other. Understanding the structure of this complex will help us understand what these mutations in the spike protein mean in terms of infectivity." Given that a change in only two amino acids made a 1,000- to 10,000-fold difference in virus infectivity, it appears that Nabel's counsel to assume that we have not seen the last of SARS was prudent.

In the September 2005 issue of Nature Medicine, scientists from Rockville, Md.-based Intradigm Corp., with colleagues from the Biotechnology Research Center of Sun Yatsen University, Guangzhou Top Genomics Ltd. and the Guangzhou Institute of Respiratory Diseases, all of Guangzhou, China; Hong Kong University; and the Chinese Academy of Medical Sciences & Peking Union Medical College of Beijing reported on a vaccine that protected monkeys against SARS. Macaques inhaled the vaccine, which consisted of short interfering RNAs (siRNAs) targeting the spike protein and an enzyme SARS uses for replication, respectively. Regardless of whether it was given before or after exposing the monkeys to the SARS virus, the vaccine induced an antibody response, reduced fever, and protected against the lung damage that is the hallmark of SARS.

Finally, it might be a severe acute respiratory syndrome, but in about 4 percent to 5 percent of cases, the SARS coronavirus apparently is not content to wreak its damage in the lungs. Those patients show nervous system symptoms including vision problems and delirium. In a case study published in the Oct. 15, 2005, issue of Clinical Infectious Diseases, now available online, scientists from the Guangzhou Institute of Respiratory Diseases and the Key Laboratory of Functional Proteomics of Guangdong Province, both in Guangzhou, China, examined the brain tissue of one such patient and found that his brain had been directly infected with SARS. The authors note that physicians need to be aware of the possibility that SARS can infect the brain directly, and tailor their therapeutic regimens accordingly.

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