Abstract
Francisella tularensis, a highly infectious, intracellular bacterium possesses an atypical type VI secretion system (T6SS), which is essential for the virulence of the bacterium. Recent data suggest that the HSP100 family member, ClpB, is involved in T6SS disassembly in the subspecies Francisella novicida. Here, we investigated the role of ClpB for the function of the T6SS and for phenotypic characteristics of the human pathogenic subspecies holarctica and tularensis. The ∆clpB mutants of the human live vaccine strain, LVS, belonging to subspecies holarctica, and the highly virulent SCHU S4 strain, belonging to subspecies tularensis, both showed extreme susceptibility to heat shock and low pH, severely impaired type VI secretion (T6S), and significant, but impaired intracellular replication compared to the wild-type strains. Moreover, they showed essentially intact phagosomal escape. Infection of mice demonstrated that both ΔclpB mutants were highly attenuated, but the SCHU S4 mutant showed more effective replication than the LVS strain. Collectively, our data demonstrate that ClpB performs multiple functions in the F. tularensis subspecies holarctica and tularensis and its function is important for T6S, intracellular replication, and virulence.
Highlights
The zoonotic disease tularemia is caused by the virulent, intracellular, Gram-negative coccobacillus designated Francisella tularensis[1]
We demonstrate that the ∆clpB mutants of the LVS strain, subspecies holarctica, and the highly virulent SCHU S4 strain, subspecies tularensis, both are exquisitely susceptible to heat shock and low pH, show defective intracellular growth, concomitantly with impaired T6S
To determine the role of ClpB protein of F. tularensis in stress tolerance, we monitored the survival of LVS and the SCHU S4 ΔclpB mutants under various stress conditions
Summary
The zoonotic disease tularemia is caused by the virulent, intracellular, Gram-negative coccobacillus designated Francisella tularensis[1]. Despite the presence of many functional T6SS homologues, Francisella lacks the two ATPases, IcmF/TssM and ClpV, both of which may provide the energy required for secretion in prototypical T6SS28,29. ClpV, being a class I Clp/Hsp[100] protein, is not involved in thermotolerance, it has been identified in vitro[37] and in vivo[18] as crucial for the disassembly of the contractile sheath in prototypical T6SS37. This disassembly activity contributes to the reassembly of an extended sheath[28,38]. A ΔclpB mutant of the LVS strain has been characterized and observed to induce a more robust proinflammatory response than did the parental strain[46]
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