For decades, temperature-sensitive viruses have been generated by repeated passage at low temperatures and used as live vaccines against diseases such as polio and influenza. Typically, live vaccines against bacterial diseases have used strains with attenuated virulence generated by in vitro passage or deliberate mutagenesis.
Canadian and US scientists have now generated temperature-sensitive bacteria by substituting essential genes in pathogenic bacteria with counterparts from cold-loving C. psychrerythraea bacteria usually found in the subzero temperatures of the Arctic. These cold-adapted bacteria cannot survive at normal body temperatures and the temperature-sensitivity is transferred to the recipient bacteria, in this case F. novicida, which is normally highly virulent in mice. Out of nine temperature-sensitive strains of F. novicida, five were unable to revert to temperature-resistant forms at detectable levels. A temperature-sensitive vaccine is able to take advantage of the difference in temperature between the cooler tissues near the body surface and the warmer body core: the bacteria can grow at sites close to the skin but not at sites deep within the body. When mice were vaccinated s.c. near the tail with one of the temperature-sensitive strains of F. novicida, the bacteria grew close to the site of infection but did not spread to the spleen and the mice were afforded protection against a later lethal intranasal challenge with wild-type bacteria. As well as offering the possibility of live vaccines against important human pathogens such as S. enteric and M. tuberculosis, temperature-sensitive bacterial variants may also allow the biochemical and genetic analysis of dangerous pathogens without the need for full containment facilities.
The study is published in PNAS.