Francisella tularensis, är en Gram negativ bakterie som orsakar sjukdomen harpest, även kallad tularemi. Francisella är en mycket virulent bakterie där en infektionsdos på mindre än 10 bakterier kan orsaka sjukdom.
Förmågan att orsaka infektioner baseras på olika virulensmekanismer, men hos F. tularensis är inte många av dessa faktorer kända. Det finns i huvudsak två underarter av Francisella tularensis som orsakar sjukdom hos människor, den högvirulenta underarten tularensis, även kallad typ A, och den något mindre virulenta underarten holarctica, kallad typ B. Jag har fokuserat mina studier på att analysera några olika stammar av typ A och typ B. Syftet med denna avhandling har varit att öka kunskapen om den förmåga som Francisella har att orsaka sjukdom, med tonvikt på yt- och membranassocierade proteiner och strukturer. Dessutom har jag undersökt den regulatoriska rollen hos ett chaperone liknande protein, Hfq.
Hittills är endast ett fåtal regulatoriska proteiner är kända hos F. tularensis. Jag har visat att Hfq spelar en roll i regleringen av gener associerade till virulens i Francisella. Detta är första gången en reglulator identifieras som negativt reglerar gener lokaliserade i Francisella patogenicitets ön. Ett annat protein identifierades i yttermembranet på Francisella-bakterien. Detta protein är en homolog till ett disulfid oxidoreduktas, DsbA, som krävs för att ett protein ska inta rätt funktionell konformation. Det visade sig att DsbA bidrar till virulens, och dessutom att en dsbA mutant har förmåga att inducera skydd mot Francisella infektioner.
Det finns också andra gener med homologi till kända virulensmekanismer som är identifierade i Francisella genomet, där en sådan mekanism är typ IV pili systemet. I detta system ingår många komponenter, däribland ett pilin, PilA, som konstaterades bidra till virulens i både typ A- och typ B-stammar.
Dessutom är två gener, pilC och pilQ, vilka kodar för proteiner som är involverade i pilits uppbyggande och sekretion, också betydelsefulla för virulensen hos en typ A stam.
Sammanfattningsvis så bidrar dsbA, hfq och typ IV pili associerade gener till virulens i F. tularensis. Vidare är DsbA ett potentiellt objekt för läkemedelsutveckling och en dsbA mutant en kandidat för utveckling av en ny levande vaccinstam. Förutom detta så har identifieringen av Hfq som en ny regulator gett ny kunskap vad gäller det regulatoriska nätverket i Francisella tularensis.
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