6 February 2003 15:00 GMT

by Henry Nicholls

[francisella tularensis]

Researchers are closing in on a vaccine against the highly infectious bacterial infection tularemia, which has been singled out as a potential bioterror agent, reports a leading microbiologist.

The microorganism responsible for tularemia, Francisella tularensis, is one of the most infectious bacterial pathogens known. As few as ten organisms are sufficient to cause infection that, if left untreated, can be fatal. The disease is classed in 'category A' by the USA Center for Disease Control and Prevention (CDC) in a shortlist of bioterror agents that includes anthrax, smallpox and plague.

Compared with these other A-list biological threats, little is known about what makes F. tularensis so virulent. Consequently, there is still no effective vaccine against this disease. "There is an urgent need for an improved vaccine against tularaemia," said professor Richard Titball of the Defence Science and Technology Laboratory at Porton Down, UK.

Titball has performed a microarray analysis of 27 strains of F. tularensis that have different degrees of virulence, which he believes could reveal genetic targets for a new vaccine. "This has allowed us to identify genes that appear to be unique to high virulence strains of F. tularensis," write Titball and colleagues in a review published in the March issue of Trends in Microbiology.

Titball's colleague Anders Johansson of the Swedish Defense Research Association, elaborated on their findings: "Eight regions of difference, altogether comprising 21 open reading frames, were identified that distinguished strains of the moderately virulent subspecies holarctica and the highly virulent subspecies tularensis," he said. "One of these regions allowed us for the first time to develop an F. tularensis-specific PCR assay, discriminating each of the four F. tularensis subspecies," he told BioMedNet News.

F. tularensis is usually transmitted to humans by blood-sucking insects, but because it can also infect if inhaled, it poses a significant bioterrorist threat. In 2001, a review of the threat that it posed concluded that F. tularensis was "a dangerous potential biological weapon because of its extreme infectivity, ease of dissemination, and substantial capacity to cause illness and death."

In 1969, a World Health Organization expert-committee estimated that an aerosol dispersal of 50 kg of virulent F. tularensis over a city with five million inhabitants would cause 250,000 incapacitating casualties, including 19,000 deaths. May Chu of the CDC's Division of Vector-Borne Infectious Diseases asserts this is still a valid quantification of the threat it presents.

Nevertheless, as David Dennis, also at the CDC and lead author of the 2001 JAMA report, points out, there is a "high occupational hazard of working with the agent of tularemia in the laboratory." Dennis' view is supported by Johansson: "Culturing the bacterium is difficult and laboratory-acquired infections not unlikely," he said. "F. tularensis [is] more difficult to handle for bioterrorists than, for example, the causative agent of anthrax, B. anthracis," he explained.

Although the pathogen can replicate in a variety of host cell-types, the main site of replication appears to be macrophages. Nevertheless, there is still considerable debate over the details of how this mysterious microorganism wreaks such havoc.

The enigma deepens with phylogenetic research revealing that the Francisella genus has few close relatives from which clues could be gleaned. Furthermore, say Titball and colleagues, "no significant matches with known virulence genes in other pathogens have been reported."

Their approach has been to compare the genetic make-up of subspecies of F. tularensis, some of which are more virulent than others. Titball hopes that this will reveal virulence genes in F. tularensis, which should be a big boost to finding a vaccine. "It is usually the case that virulence determinants are ideal components of a subunit vaccine," he told BioMedNet News.

Photomicrograph of Francisella tularensis bacteria using a methylene blue stain. CDC/Dr. P. B. Smith