Structural determinants of host specificity of complement Factor H recruitment by <i>Streptococcus pneumoniae</i>

Achila, David; Liu, Aizhuo; Banerjee, Rahul; Li, Yue; Martı́nez-Hackert, Erik; Zhang, Jing Ren; Yan, Honggao

doi:10.1042/bj20141069

Cited by 16 publications

(19 citation statements)

References 74 publications

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“…PspC from various strains of S. pneumoniae was reported to bind to diverse segments of FH, for example CCPs 8–11, CCPs 13–15, and CCPs 19 and 20 ( 44 , 45 , 47 , 48 ). To further map the FH-binding site of D39 PspCN, we flowed, in an SPR experiment, our existing library of rFH fragments ( 16 ) ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Complement Evasion Mediated by Enhancement of Captured Factor H: Implications for Protection of Self-Surfaces from Complement

Herbert

Makou

Chen

et al. 2015

The Journal of Immunology

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In an attempt to evade annihilation by the vertebrate complement system, many microbes capture factor H (FH), the key soluble complement-regulating protein in human plasma. However, FH is normally an active complement suppressor exclusively on self-surfaces and this selective action of FH is pivotal to self versus non-self discrimination by the complement system. We investigated whether the bacterially captured FH becomes functionally enhanced and, if so, how this is achieved at a structural level. We found, using site-directed and truncation mutagenesis, surface plasmon resonance, nuclear magnetic resonance spectroscopy, and cross-linking and mass spectrometry, that the N-terminal domain of Streptococcus pneumoniae protein PspC (PspCN) not only binds FH extraordinarily tightly but also holds it in a previously uncharacterized conformation. Functional enhancement arises from exposure of a C-terminal cryptic second binding site in FH for C3b, the activation-specific fragment of the pivotal complement component, C3. This conformational change of FH doubles its affinity for C3b and increases 5-fold its ability to accelerate decay of the binary enzyme (C3bBb) responsible for converting C3 to C3b in an amplification loop. Despite not sharing critical FH-binding residues, PspCNs from D39 and Tigr4 S. pneumoniae exhibit similar FH-anchoring and enhancing properties. We propose that these bacterial proteins mimic molecular markers of self-surfaces, providing a compelling hypothesis for how FH prevents complement-mediated injury to host tissue while lacking efficacy on virtually all other surfaces. In hemolysis assays with 2-aminoethylisothiouronium bromide–treated erythrocytes that recapitulate paroxysmal nocturnal hemoglobinuria, PspCN enhanced protection of cells by FH, suggesting a new paradigm for therapeutic complement suppression.

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Section: Resultsmentioning

confidence: 99%

Complement Evasion Mediated by Enhancement of Captured Factor H: Implications for Protection of Self-Surfaces from Complement

Herbert

Makou

Chen

et al. 2015

The Journal of Immunology

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“…The trypanosome FHR structure and the FH domain bound are different to each of the three structurally characterized FH-binding proteins from bacteria. These interact with FH domains 6-7 in N. meningitidis 12 , domain 9 in S. pneumoniae 10 or domains 19-20 in B. burgdorferi 11 . The binding of these FHRs to domains 6-7 and 19-20 mimic self-surface interactions and to domain 9 produces a high-affinity interaction that enhances activity of FH for C3b in one strain 9 .…”

Section: Discussionmentioning

confidence: 99%

“…FH recruitment by diverse pathogens has been shown to be an effective strategy to inactivate complement in the host, but the molecular basis has only been characterized for three bacteria: Streptococcus pneumoniae, Borrelia burgdorferi and Neisseria meningitidis [9][10][11][12] . These recruit FH by mimicry of mammalian host interactions with FH or by increasing activity of FH.…”

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confidence: 99%

A receptor for the complement regulator factor H increases transmission of trypanosomes to tsetse flies

et al. 2020

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Persistent pathogens have evolved to avoid elimination by the mammalian immune system including mechanisms to evade complement. Infections with African trypanosomes can persist for years and cause human and animal disease throughout sub-Saharan Africa. It is not known how trypanosomes limit the action of the alternative complement pathway. Here we identify an African trypanosome receptor for mammalian factor H, a negative regulator of the alternative pathway. Structural studies show how the receptor binds ligand, leaving inhibitory domains of factor H free to inactivate complement C3b deposited on the trypanosome surface. Receptor expression is highest in developmental stages transmitted to the tsetse fly vector and those exposed to blood meals in the tsetse gut. Receptor gene deletion reduced tsetse infection, identifying this receptor as a virulence factor for transmission. This demonstrates how a pathogen evolved a molecular mechanism to increase transmission to an insect vector by exploitation of a mammalian complement regulator.

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“…Although remained to be clarified, the mechanism behind this observation may have involved some spatial and temporal factors. If the regional diversity persisted, the design of future conjugate vaccines covering more serotypes may be difficult, and other vaccine targets should be considered 35 36 .…”

Section: Discussionmentioning

confidence: 99%

Evolving pneumococcal serotypes and sequence types in relation to high antibiotic stress and conditional pneumococcal immunization

Kuo

Chia

et al. 2015

Sci Rep

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In Taiwan, beginning in 2013, the 13-valent pneumococcal conjugate vaccine (PCV13) was provided free of charge to children 2–5 years of age. In 2014, this was extended to children 1–5 years old. During 2012–2014, 953 cases of culture-confirmed pneumococcal disease (CCPD), including 104 invasive pneumococcal disease (IPD), were prospectively identified and analyzed at a 3,700-bed hospital in Taiwan. From 2012 to 2014, the incidence per 10,000 admissions decreased from 26.7 to 20.4 for CCPD (P < 0.001) and from 3.2 to 1.9 for IPD (P < 0.05). Significant reduction of PCV13 serotypes was firstly noted in children in 2013 and extended to both paediatric and adult populations in 2014. Simultaneously, the incidence per 10,000 admissions of non-PCV13 serotypes increased from 6.1 in 2012 to 9.3 in 2014 (P < 0.005). The most prevalent non-PCV13 serotypes were 15A, 15B, and 23A, each containing a predominant clone, ST6315A, ST8315B, and ST33823A. From 2012 to 2014, isolates with penicillin minimum inhibitory concentrations >2 mg/L decreased from 27.8% to 8.1% (P < 0.001) among all isolates. PCV13 immunization in young children demonstrated an early protective effect in all ages. However, in the elderly, the effect was compromised by an emergence of non-PCV13 serotypes.

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Structural determinants of host specificity of complement Factor H recruitment by Streptococcus pneumoniae

Cited by 16 publications

References 74 publications

Complement Evasion Mediated by Enhancement of Captured Factor H: Implications for Protection of Self-Surfaces from Complement

Complement Evasion Mediated by Enhancement of Captured Factor H: Implications for Protection of Self-Surfaces from Complement

A receptor for the complement regulator factor H increases transmission of trypanosomes to tsetse flies

Evolving pneumococcal serotypes and sequence types in relation to high antibiotic stress and conditional pneumococcal immunization

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