Abstract
Louse borne typhus (also called epidemic typhus) was one of man's major scourges, and epidemics of the disease can be reignited when social, economic, or political systems are disrupted. The fear of a bioterrorist attack using the etiologic agent of typhus, Rickettsia prowazekii, was a reality. An attenuated typhus vaccine, R. prowazekii Madrid E strain, was observed to revert to virulence as demonstrated by isolation of the virulent revertant Evir strain from animals which were inoculated with Madrid E strain. The mechanism of the mutation in R. prowazekii that affects the virulence of the vaccine was not known. We sequenced the genome of the virulent revertant Evir strain and compared its genome sequence with the genome sequences of its parental strain, Madrid E. We found that only a single nucleotide in the entire genome was different between the vaccine strain Madrid E and its virulent revertant strain Evir. The mutation is a single nucleotide insertion in the methyltransferase gene (also known as PR028) in the vaccine strain that inactivated the gene. We also confirmed that the vaccine strain E did not cause fever in guinea pigs and the virulent revertant strain Evir caused fever in guinea pigs. We concluded that a single nucleotide insertion in the methyltransferase gene of R. prowazekii attenuated the R. prowazekii vaccine strain E. This suggested that an irreversible insertion or deletion mutation in the methyl transferase gene of R. prowazekii is required for Madrid E to be considered a safe vaccine.
Highlights
Louse borne typhus was one of man’s major scourges from the 1500 s through the mid-20th century and frequently played a decisive role in wars in Europe during this period
Rickettsia prowazekii is listed as a Select Agent with rigorous legal restrictions on its possession and use in research
We recently demonstrated that the SAM-methyltransferase gene was inactivated in E strain by a single nucleotide insertion, which was absent in the Evir strain [14]
Summary
Louse borne typhus ( called epidemic typhus) was one of man’s major scourges from the 1500 s through the mid-20th century and frequently played a decisive role in wars in Europe during this period It has affected the course of European history [1]. Louse-borne typhus occurs in epidemics when social, economic, or political systems are disrupted exposing a large population such as refugees to louse infestation due to lack of hygiene and reactivation of latent infection associated with the harsh and stressful conditions. This situation has been observed in outbreaks of typhus in Burundi, Algeria, Peru, and Russia [2]. During World War II, the Japanese performed human experiments with rickettsial agents for purposes of biologic weapon development during their occupation of China [4]
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