A disruption of ctpA encoding carboxy-terminal protease attenuates Burkholderia mallei and induces partial protection in CD1 mice

Bandara, Aloka B.; DeShazer, David; Inzana, Thomas J.; Sriranganathan, Nammalwar; Schurig, Gerhardt G.; Boyle, Stephen M.

doi:10.1016/j.micpath.2008.05.005

Cited by 25 publications

(31 citation statements)

References 34 publications

(66 reference statements)

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“…The sera previously subjected to the CLH001 (1.5 ϫ 10 5 CFU) prime and two boosts had the highest B. mallei-specific IgG total value for this vaccine and gave values similar to those seen in TMM001-vaccinated mice. Further, the observed Ն4.0 ratio of IgG2a/IgG1 has also been described as being favorable for protection (Table 2) (14,15,28,29). The BALB/c mice vaccinated with the prime and two boosts (PBS at the equivalent of 1.5 ϫ 10 4 CFU or CLH001 at 1.5 ϫ 10 5 CFU) were challenged with 1.5 ϫ10 4 CFU of CSM001.…”

Section: Resultsmentioning

confidence: 99%

“…A number of vaccine studies have examined the correlation between a vaccine's ability to generate high B. mallei-specific IgG titers and a Th1-driven immune response (IgG2a/IgG1 ratio of Ն1) and its ability to provide protection against B. mallei infection (14,15,28,29). Our report supports the results of those studies, with the greatest protection observed in vaccinated mice (1.5 ϫ 10 5 CFU of CLH001) with the highest IgG total titers and IgG2a/ IgG1 ratios.…”

Section: Discussionmentioning

confidence: 99%

“…Live attenuated vaccines, the use of which is regarded as the most viable strategy against B. mallei, have been tested with some success (14)(15)(16)(17). Recently, our laboratory evaluated an iron acquisition-deficient B. mallei ⌬tonB (TMM001) strain for use as a live attenuated vaccine in acute inhalational glanders and melioidosis (B. pseudomallei) murine models.…”

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Burkholderia mallei CLH001 Attenuated Vaccine Strain Is Immunogenic and Protects against Acute Respiratory Glanders

et al. 2016

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Burkholderia mallei is the causative agent of glanders, an incapacitating disease with high mortality rates in respiratory cases. Its endemicity and ineffective treatment options emphasize its public health threat and highlight the need for a vaccine. Live attenuated vaccines are considered the most viable vaccine strategy for Burkholderia, but single-gene-deletion mutants have not provided complete protection. In this study, we constructed the select-agent-excluded B. mallei ⌬tonB ⌬hcp1 (CLH001) vaccine strain and investigated its ability to protect against acute respiratory glanders. Here we show that CLH001 is attenuated, safe, and effective at protecting against lethal B. mallei challenge. Intranasal administration of CLH001 to BALB/c and NOD SCID gamma (NSG) mice resulted in complete survival without detectable colonization or abnormal organ histopathology. Additionally, BALB/c mice intranasally immunized with CLH001 in a prime/boost regimen were fully protected against lethal challenge with the B. mallei lux (CSM001) wild-type strain. Burkholderia mallei, the causative agent of glanders, is a Gramnegative, obligate mammalian pathogen. Glanders is primarily a disease of solipeds, with rare cases occurring among humans (1, 2). Naturally acquired human cases occur in areas of endemicity, particularly among those exposed to infected solipeds (2-4). Additionally, cases have been reported among laboratory workers (5, 6). The World Organization for Animal Health coordinates ongoing efforts toward worldwide eradication; however, regional endemicity still exists in Africa, Asia, the Middle East, and South America (2). Recent equid outbreaks in the Middle East and Asia (7-9) set the stage for possible glanders reintroduction into disease-free regions; as a result, glanders has been classified as a reemerging disease.Glanders is a debilitating and often fatal disease transmitted via cutaneous and respiratory routes. Disease course and severity are route dependent, with respiratory cases being the most severe (3). Respiratory infection is characterized by rapid onset of symptoms, including fever, lymphadenopathy, pulmonary abscesses, pneumonia, disseminated organ infection, and, ultimately, septicemia (3, 5, 10). Because of the high incidence of septicemia following respiratory infection, fatality rates in human respiratory cases have been estimated at 90% without treatment and 40% with aggressive antibiotic therapy (11).The use of B. mallei as a biothreat agent has been documented in different world military conflicts (10,12,13). Its amenability to aerosolization, low infectious dose, high case fatality rate, and high-level antibiotic resistance make B. mallei a top candidate for malevolent use (1, 10). Because of its perceived public health threat, the Department of Health and Human Services has categorized B. mallei as a tier 1 select agent. The lack of effective treatments against these bacteria highlights the need for an effective vaccine. Numerous vaccine strategies have been tested; however, to date there are n...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Burkholderia mallei CLH001 Attenuated Vaccine Strain Is Immunogenic and Protects against Acute Respiratory Glanders

et al. 2016

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“…either in Gram-negative bacteria (where many have been shown to affect virulence) or in non-pathogenic Grampositive species (where one example is known to affect sporulation) (Bandara et al, 2008;Lad et al, 2007;Marasco et al, 1996;Ostberg et al, 2004;Pan et al, 2003). In this work we have, for the first time, to our knowledge, identified and characterized a C-terminal protease from a Grampositive, pathogenic bacterial species.…”

Section: Discussionmentioning

confidence: 96%

The lone S41 family C-terminal processing protease in Staphylococcus aureus is localized to the cell wall and contributes to virulence

et al. 2014

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Staphylococcus aureus is a versatile pathogen of humans and a continued public health concern due to the rise and spread of multidrug-resistant strains. As part of an ongoing investigation into the pathogenic mechanisms of this organism we previously demonstrated that an intracellular Nterminal processing protease is required for S. aureus virulence. Following on from this, here we examine the role of CtpA, the lone C-terminal processing protease of S. aureus. CtpA, a member of the S41 family, is a serine protease whose homologues in Gram-negative bacteria have been implicated in a range of biological functions, including pathogenesis. We demonstrate that S. aureus CtpA is localized to the bacterial cell wall and expression of the ctpA gene is maximal upon exposure to conditions encountered during infection. Disruption of the ctpA gene leads to decreased heat tolerance and increased sensitivity when exposed to components of the host immune system. Finally we demonstrate that the ctpA " mutant strain is attenuated for virulence in a murine model of infection. Our results represent the first characterization of a C-terminal processing protease in a pathogenic Gram-positive bacterium and show that it plays a critical role during infection.

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“…E. coli Prc processes penicillin-binding protein 3 (23)(24)(25), degrades the phage repressor (26), and cleaves incorrectly synthesized proteins with a C-terminal Ssr tag (27). Additionally, in some pathogens CTPs affect virulence (28)(29)(30). However, our knowledge of bacterial CTPs is quite limited, and in most cases there has been no explanation for their effects on virulence.…”

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confidence: 99%

The Pseudomonas aeruginosa Periplasmic Protease CtpA Can Affect Systems That Impact Its Ability To Mount Both Acute and Chronic Infections

Seo

Darwin

2013

Infect Immun

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Proteases play important roles in the virulence of Pseudomonas aeruginosa. Some are exported to act on host targets and facilitate tissue destruction and bacterial dissemination. Others work within the bacterial cell to process virulence factors and regulate virulence gene expression. Relatively little is known about the role of one class of bacterial serine proteases known as the carboxyl-terminal processing proteases (CTPs). The P. aeruginosa genome encodes two CTPs annotated as PA3257/Prc and PA5134/CtpA in strain PAO1. Prc degrades mutant forms of the anti-sigma factor MucA to promote mucoidy in some cystic fibrosis lung isolates. However, nothing is known about the role or importance of CtpA. We have now found that endogenous CtpA is a soluble periplasmic protein and that a ctpA null mutant has specific phenotypes consistent with an altered cell envelope. Although a ctpA null mutation has no major effect on bacterial growth in the laboratory, CtpA is essential for the normal function of the type 3 secretion system (T3SS), for cytotoxicity toward host cells, and for virulence in a mouse model of acute pneumonia. Conversely, increasing the amount of CtpA above its endogenous level induces an uncharacterized extracytoplasmic function sigma factor regulon, an event that has been reported to attenuate P. aeruginosa in a rat model of chronic lung infection. Therefore, a normal level of CtpA activity is critical for T3SS function and acute virulence, whereas too much activity can trigger an apparent stress response that is detrimental to chronic virulence.

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A disruption of ctpA encoding carboxy-terminal protease attenuates Burkholderia mallei and induces partial protection in CD1 mice

Cited by 25 publications

References 34 publications

Burkholderia mallei CLH001 Attenuated Vaccine Strain Is Immunogenic and Protects against Acute Respiratory Glanders

Burkholderia mallei CLH001 Attenuated Vaccine Strain Is Immunogenic and Protects against Acute Respiratory Glanders

The lone S41 family C-terminal processing protease in Staphylococcus aureus is localized to the cell wall and contributes to virulence

The Pseudomonas aeruginosa Periplasmic Protease CtpA Can Affect Systems That Impact Its Ability To Mount Both Acute and Chronic Infections

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