Evaluation of Salmonella typhimurium strains harbouring defined mutations in htrA and aroA in the murine salmonellosis model

Chatfield, Steven N.; Strahan, Karen; Pickard, Derek; Charles, Ian G.; Hormaeche, Carlos E.; Dougan, Gordon

doi:10.1016/0882-4010(92)90117-7

Cited by 149 publications

(107 citation statements)

References 24 publications

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“…degP expression in E. coli is co-regulated by sigma (E) and CpxAR, two of the three stress response signal transduction pathways (Raivio, 2005). Inactivation of degP in S. typhimurium, Klebsiella pneumoniae and Streptococcus pneumoniae caused reduced virulence in experimental animals (Chatfield et al, 1992;Hemmer et al, 1999;Ibrahim et al, 2004). The function of DegQ is less well known but in S. typhimurium the protease may promote growth at systemic sites (Farn and Roberts, 2004).…”

Section: Discussionmentioning

confidence: 99%

Relapsing fever spirochaetes produce a serine protease that provides resistance to oxidative stress and killing by neutrophils

Guyard¹,

Battisti

Raffel

et al. 2006

Molecular Microbiology

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SummaryThe spirochaetes that cause tick-borne relapsing fever and Lyme disease are closely related human pathogens, yet they differ significantly in their ecology and pathogenicity. Genome sequencing of two species of relapsing fever spirochaetes, Borrelia hermsii and Borrelia turicatae, identified a chromosomal open reading frame, designated bhpA , not present in the Lyme disease spirochaete Borrelia burgdorferi . The predicted amino acid sequence of bhpA was homologous with the HtrA serine proteases, which are involved with stress responses and virulence in other bacteria. B. hermsii produced an active serine protease that was recognized by BhpA antibodies and the recombinant BhpA proteindegraded b -casein. bhpA was transcribed in vitro at all growth temperatures and transcription levels were slightly elevated at higher temperatures. These results correlated with the synthesis of BhpA during B. hermsii infection in mice. With the exception of Borrelia recurrentis , the bhpA gene, protein and enzymatic activity were found in all relapsing fever spirochaetes, but not in Lyme disease or related spirochaetes. Heterologous expression of bhpA in B. burgdorferi increased the spirochaete's resistance to both oxidative stress and killing by human neutrophils. Therefore, we propose that bhpA encodes a unique and functional serine protease in relapsing fever spirochaetes. This periplasmic enzyme may prevent the accumulation of proteins damaged by the innate immune response and contribute to the ability of the relapsing fever spirochaetes to achieve high cell densities in blood.

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Section: Discussionmentioning

confidence: 99%

Relapsing fever spirochaetes produce a serine protease that provides resistance to oxidative stress and killing by neutrophils

Guyard¹,

Battisti

Raffel

et al. 2006

Molecular Microbiology

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“…The S. typhimurium strain 4\74 used for oral and subcutaneous challenge has been described elsewhere (Jones et al, 1991 ;Rankin & Taylor, 1966). The purE and htrA mutations were introduced into S. typhimurium 4\74 as described by O'Callaghan et al (1988) and Chatfield et al (1992), respectively.…”

Section: Methodsmentioning

confidence: 99%

“…Thus, the murine salmonellosis model has been used to identify candidate mutations to generate attenuated S. typhi for live typhoid vaccine development. Mutations exploited in this way include those associated with aromatic compound dependence (aro) (Hosieth & Stocker, 1981 ;Tacket et al, 2000), purine dependence (pur) (Levine et al, 1987 ;O'Callaghan et al, 1988 ;Everest et al, 1997) and stress resistance (htrA) (Chatfield et al, On: Sun, 13 May 2018 05:32:28 B. VILLARREAL-RAMOS and OTHERS Strahan et al, 1992 ;Tacket et al, 2000). However, not all mutations that attenuate S. typhimurium in the murine model are fully attenuating for S. typhi in man.…”

Section: Introductionmentioning

confidence: 99%

Susceptibility of calves to challenge with Salmonella typhimurium 4/74 and derivatives harbouring mutations in htrA or purE

et al. 2000

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Salmonella typhimurium 4/74 is highly virulent for cattle after oral challenge, causing severe diarrhoea, which is sometimes associated with systemic spread of the micro-organism. Although susceptible to oral challenge, groups of cattle were found to be relatively resistant to subcutaneous challenge with this strain. The virulence of S. typhimurium 4/74 harbouring mutations in htrA and purE was also assessed in cattle. Although S. typhimurium 4/74 htrA and purE are attenuated following oral challenge in mice, cattle were highly susceptible to oral challenge with these mutants. As with the parent S. typhimurium 4/74 strain, cattle exhibited greater susceptibility to oral compared to subcutaneous challenge with S. typhimurium htrA and purE mutants. Following subcutaneous challenge with sublethal levels of S. typhimurium 4/74, calves produced significant levels of antibodies to S. typhimurium soluble extract. No correlation was detected between interferon gamma levels in sera and susceptibility to infection by any route. The concentrations of the acute-phaseassociated protein haptoglobin were increased in the sera of five of six cattle inoculated subcutaneously, although increases in concentration were smaller in cattle inoculated orally.

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“…In Escherichia coli HtrA is essential for growth above 42 u C (Lipinska et al, 1989). This is not the case in Salmonella, but S. Typhimurium htrA mutants exhibit increased sensitivity to killing by reactive oxygen species and reduced survival and/or replication within macrophages (Baumler et al, 1994;Humphreys et al, 1999;Johnson et al, 1991), and are highly attenuated in the murine model of systemic Salmonella infection (Chatfield et al, 1992;Humphreys et al, 1999). Since the seminal studies in Salmonella, HtrA has been found to play a role in the virulence of a wide range of Gram-negative and Grampositive bacterial pathogens (Bringer et al, 2005;Cortes et al, 2002;Humphreys et al, 1999;Ibrahim et al, 2004;Johnson et al, 1991;Jones et al, 2001;Pallen & Wren, 1997;Pedersen et al, 2001;Rigoulay et al, 2005;Williams et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Salmonella enterica Serovar Typhimurium HtrA: regulation of expression and role of the chaperone and protease activities during infection

Lewis

Škovierová²,

Rowley

et al. 2009

Microbiology

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HtrA is a bifunctional stress protein required by many bacterial pathogens to successfully cause infection. Salmonella enterica serovar Typhimurium (S. Typhimurium) htrA mutants are defective in intramacrophage survival and are highly attenuated in mice. Transcription of htrA in Escherichia coli is governed by a single promoter that is dependent on s E (RpoE). S. Typhimurium htrA also possesses a s E -dependent promoter; however, we found that the absence of s E had little effect on production of HtrA by S. Typhimurium. This suggests that additional promoters control expression of htrA in S. Typhimurium. We identified three S. Typhimurium htrA promoters. Only the most proximal promoter, htrAp3, was s E dependent. The other promoters, htrAp1 and htrAp2, are probably recognized by the principal sigma factor s 70 . These two promoters were constitutively expressed but were also slightly induced by heat shock. Thus expression of htrA is different in S. Typhimurium and E. coli. The role of HtrA is to deal with misfolded/damaged proteins in the periplasm. It can do this either by degrading (protease activity) or folding/capturing (chaperone/sequestering, C/S, activity) the aberrant protein. We investigated which of these functions are important to S. Typhimurium in vitro and in vivo. Point or deletion mutants of htrA that encode variant HtrA molecules have been used in previous studies to investigate the role of different regions of HtrA in C/S and protease activity. These htrA variants were placed under the control of the S. Typhimurium htrAP123 promoters and expressed in a S. Typhimurium htrA mutant, GVB1343. Both wild-type HtrA and HtrA (HtrA S210A) lacking protease activity enabled GVB1343 to grow at high temperature (46 6C). Both molecules also significantly enhanced the growth/survival of GVB1343 in the liver and spleen of mice during infection. However, expression of wild-type HtrA enabled GVB1343 to grow to much higher levels than expression of HtrA S210A. Thus both the protease and C/S functions of HtrA operate in vivo during infection but the protease function is probably more important. Absence of either PDZ domain completely abolished the ability of HtrA to complement the growth defects of GVB1343 in vitro or in vivo.

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Evaluation of Salmonella typhimurium strains harbouring defined mutations in htrA and aroA in the murine salmonellosis model

Cited by 149 publications

References 24 publications

Relapsing fever spirochaetes produce a serine protease that provides resistance to oxidative stress and killing by neutrophils

Relapsing fever spirochaetes produce a serine protease that provides resistance to oxidative stress and killing by neutrophils

Susceptibility of calves to challenge with Salmonella typhimurium 4/74 and derivatives harbouring mutations in htrA or purE

Salmonella enterica Serovar Typhimurium HtrA: regulation of expression and role of the chaperone and protease activities during infection

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