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Consequences of immune activation during infection with Francisella tularensis

Russo, Brian C (2013) Consequences of immune activation during infection with Francisella tularensis. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Tularemia is a debilitating, febrile illness caused by Francisella tularensis. Delayed activation of host responses is associated with the virulence of F. tularensis. The bacterium can use several signals, including spermine, to adapt to the intracellular environment to limit its stimulation of host cells. However, the bacterial genes responsible for these responses remain unknown. Transposon mutagenesis in F. tularensis subsp. holarctica Live Vaccine Strain (LVS) identified FTL_0883 as important for spermine responsiveness. In-frame deletion mutants of FTL_0883 and FTT_0615c, the homolog of FTL_0883 in F. tularensis subsp. tularensis Schu S4 (Schu S4) were generated. These mutants demonstrated that the spermine response is associated with changes in capsule concentration on the surface of F. tularensis. Additionally, this locus was important for the virulence of LVS and Schu S4 in vitro and in vivo. FTL_0883 and FTT_0615c were needed in F. tularensis to limit the stimulation of host cells, but only LVS required FTL_0883 for its replication within macrophages. This attenuation depended on host responses to elevated levels of pro-inflammatory cytokines. The mutants were biochemically characterized to identify how they stimulated host cells more robustly than wild-type strains. There were not consistent changes in these mutants, which suggested there are divergent roles for the proteins in LVS and Schu S4. Collectively, these data define a novel function of FTL_0883/FTT_0615c in the virulence and evasion of the immune response of F. tularensis.
To further understand the requirements for the host response to virulent strains of F. tularensis, wild-type and MyD88 KO mice were infected with Schu S4. Schu S4 infected MyD88 KO had higher bacterial burdens, decreased pro-inflammatory cytokine responses, increased cell death in the lungs, and accelerated mortality compared to wild-type mice. These data highlight a beneficial role for the innate immune response generally and MyD88 signaling specifically against F. tularensis. Overall, the data presented in this thesis furthers our understanding of the genes required for F. tularensis adaptation to the host intracellular environment to avoid immune detection, a process dependent on the presence of MyD88.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Russo, Brian Cbrr30@pitt.eduBRR30
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorNau, Gerard Jgjnau@pitt.eduGJNAU
Committee MemberNorris, Karen Akan1@pitt.eduKAN1
Committee MemberMcClane, Bruce A.bamcc@pitt.eduBAMCC
Committee MemberSalter, Russell Drds@pitt.eduRDS
Committee MemberEvans, Jaredevansj2@pitt.eduEVANSJ2
Date: 9 July 2013
Date Type: Publication
Defense Date: 14 June 2013
Approval Date: 9 July 2013
Submission Date: 29 June 2013
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 204
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Molecular Virology and Microbiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Francisella tularensis, MyD88, CorC, FTL_0883, FTT_0615c, spermine
Date Deposited: 09 Jul 2013 18:07
Last Modified: 09 Jul 2018 05:15


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