Prc Contributes to Escherichia coli Evasion of Classical Complement-Mediated Serum Killing

Wang, Chin Ya; Wang, Shainn Wei; Huang, Wen Liang; Kim, Kwang Sik; Chang, Nan Shan; Wang, Ying Hsiang; Wu, Meng Hsing; Teng, Ching Hao

doi:10.1128/iai.00321-12

Cited by 38 publications

(55 citation statements)

References 48 publications

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“…Another reason for the marginal interference with bactericidal serum activity of miniFH and FH-CR2 may lie in their AP selectivity. Antibody-dependent and independent CP activation on E. coli has been demonstrated (Wang et al, 2012) providing a rationale why AP-specific inhibition interferes to a much lesser extent with the bactericidal serum activity. MiniFH-1 and FH-CR2 show similar dose-dependent interference with lytic serum activities.…”

Section: Discussionmentioning

confidence: 99%

Selectivity of C3-opsonin targeted complement inhibitors: A distinct advantage in the protection of erythrocytes from paroxysmal nocturnal hemoglobinuria patients

et al. 2016

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Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by complement-mediated cell lysis due to deficiency of GPI-anchored complement regulators. Blockage of the lytic pathway by eculizumab is the only available therapy for PNH patients and shows remarkable benefits, but regularly yields PNH erythrocytes opsonized with fragments of complement protein C3, rendering such erythrocytes prone to extravascular hemolysis. This effect is associated with insufficient responsiveness seen in a subgroup of PNH patients. Novel C3-opsonin targeted complement inhibitors act earlier in the cascade, at the level of activated C3 and are engineered from parts of the natural complement regulator Factor H (FH) or complement receptor 2 (CR2). This inhibitor class comprises three variants of “miniFH” and the clinically developed “FH-CR2” fusion-protein (TT30). We show that the approach of FH-CR2 to target C3-opsonins was more efficient in preventing complement activation induced by foreign surfaces, whereas the miniFH variants were substantially more active in controlling complement on PNH erythrocytes. Subtle differences were noted in the ability of each version of miniFH to protect human PNH cells. Importantly, miniFH and FH-CR2 interfered only minimally with complement-mediated serum killing of bacteria when compared to untargeted inhibition of all complement pathways by eculizumab. Thus, the molecular design of each C3-opsonin targeted complement inhibitor determines its potency in respect to the nature of the activator/surface providing potential functionality in PNH.

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Section: Discussionmentioning

confidence: 99%

Selectivity of C3-opsonin targeted complement inhibitors: A distinct advantage in the protection of erythrocytes from paroxysmal nocturnal hemoglobinuria patients

et al. 2016

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“…Recent work by ourselves and others has shown that amino terminal peptidases and CTPs can play an important role in bacterial virulence (Bandara et al, 2008;Carroll et al, 2012Carroll et al, , 2013Lad et al, 2007;Wang et al, 2012). These findings, along with the observation that C-terminal processing peptidases are poorly understood in Gram-positive pathogens, led us to investigate the role of C-terminal processing peptidases in S. aureus.…”

Section: Identification Of Ctpa In S Aureusmentioning

confidence: 99%

“…Several of these studies have shown that mutation of ctpA leads to impaired interactions with components of the host immune system (Bandara et al, 2005(Bandara et al, , 2008Lad et al, 2007;Wang et al, 2012). To investigate if mutation of ctpA affects the interaction of S. aureus with components of the human immune system, we examined the survival of the ctpA 2 mutant in the presence of a variety of immune components.…”

Section: Analysis Of Ctpa Gene Expressionmentioning

confidence: 99%

“…Altered cell morphology, differences in osmotic/thermal stress resistance and altered susceptibility to antibiotics are common phenotypes of mutants from different species (and may result from alterations in the cell-wall integrity) (Hara et al, 1991;Kumru et al, 2011;Seoane et al, 1992). In addition, a number of Gram-negative bacteria, including E. coli, Brucella suis, Chlamydia trachomatis, Salmonella typhimurium, Pseudomonas aeruginosa and Burkholderia mallei, demonstrate reduced virulence upon inactivation of CTP (Bandara et al, 2005(Bandara et al, , 2008Bäumler et al, 1994;Lad et al, 2007;Seo & Darwin, 2013;Wang et al, 2012). An E. coli prc mutant demonstrates decreased resistance to complement-mediated killing, while in Brucella suis, Burkholderia mallei and S. typhimurium, CtpA has been implicated in the ability of bacteria to survive in the intracellular environment.…”

Section: Introductionmentioning

confidence: 99%

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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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“…For example, it was recently shown that an E. coli outer membrane protein, NIpI, contributes in high-level bacteremia by facilitating blockade of classical complement-mediated killing, via C4bp deposition on the bacterial surface 70 . In addition, Prc, another E. coli bacterial periplasmic protease was also found to have a critical role in the evasion of complement-mediated killing 71 . Hence, when immune mechanisms fail to control bacterial spread either due to bacterial evasion of host immune strategies or due to a breach or defect in the otherwise well-orchestrated immune response, bacteremia can develop (Fig.…”

Section: Host Immune Defense Mechanisms To Prevent Bacteremiamentioning

confidence: 99%

The complex pathogenesis of bacteremia

Christaki

Giamarellos‐Bourboulis

2013

Virulence

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Bacteremia develops when bacteria manage to escape the host immune mechanisms or when the otherwise well-orchestrated immune response fails to control bacterial spread due to inherent or acquired immune defects that are associated with susceptibility to infection. The pathogenesis of bacteremia has some characteristic features that are influenced by the genetic signature of the host. In this review, the host defense mechanisms that help prevent bacteremia will be described and the populations who are at risk because of congenital or acquired deficiencies in such mechanisms will be defined. A special mention will be made to novel insights regarding host immune defense against the most commonly isolated organisms from patients with community-acquired bloodstream infections.

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Prc Contributes to Escherichia coli Evasion of Classical Complement-Mediated Serum Killing

Abstract: ABSTRACTEscherichia coliis a common Gram-negative organism that causes bacteremia. Prc, a bacterial periplasmic protease, and its homologues are known to be involved in the pathogenesis of Gram-negative bacterial infections. The present study examined the role of Prc in Show more

Cited by 38 publications

References 48 publications

Selectivity of C3-opsonin targeted complement inhibitors: A distinct advantage in the protection of erythrocytes from paroxysmal nocturnal hemoglobinuria patients

Selectivity of C3-opsonin targeted complement inhibitors: A distinct advantage in the protection of erythrocytes from paroxysmal nocturnal hemoglobinuria patients

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

The complex pathogenesis of bacteremia

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