Mechanism and inhibition of Streptococcus pneumoniae IgA1 protease

Wang, Zhiming; Rahkola, Jeremy; Redzic, Jasmina S.; Chi, Ying-Chih; Tran, Norman; Holyoak, Todd; Zheng, Hongjin; Janoff, Edward N.; Eisenmesser, Elan

doi:10.1038/s41467-020-19887-3

Cited by 16 publications

(9 citation statements)

References 41 publications

(68 reference statements)

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“…The advantage of cryo-EM is that the technique is amenable to proteins and protein complexes that are large and have some inherent flexibility, which can present issues with NMR and XRC techniques, respectively. Since 2020, structures of larger IgA1 segments and their complexes have been produced: Fc of secretory IgA1 in complex with J chain and the secretory component of pIgR (dimeric [ 204 , 205 , 206 ], tetrameric [ 204 , 206 ], and pentameric forms of IgA1 [ 204 ]), the dimeric form of IgA1 Fc in complex with pneumococcal adhesion protein, SpsA [ 206 ], and IgA1 in complex with the Streptococcus pneumoniae IgA1 protease [ 207 ]. These structures demonstrate feasibility to determine the structures of large IgA1-associated complexes using cryo-EM.…”

Section: Iga Nephropathy—disease-specific Treatment Approachesmentioning

confidence: 99%

Pathogenesis of IgA Nephropathy: Current Understanding and Implications for Development of Disease-Specific Treatment

Knoppová

Reily

King

et al. 2021

JCM

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IgA nephropathy, initially described in 1968 as a kidney disease with glomerular “intercapillary deposits of IgA-IgG”, has no disease-specific treatment and is a common cause of kidney failure. Clinical observations and laboratory analyses suggest that IgA nephropathy is an autoimmune disease wherein the kidneys are damaged as innocent bystanders due to deposition of IgA1-IgG immune complexes from the circulation. A multi-hit hypothesis for the pathogenesis of IgA nephropathy describes four sequential steps in disease development. Specifically, patients with IgA nephropathy have elevated circulating levels of IgA1 with some O-glycans deficient in galactose (galactose-deficient IgA1) and these IgA1 glycoforms are recognized as autoantigens by unique IgG autoantibodies, resulting in formation of circulating immune complexes, some of which deposit in glomeruli and activate mesangial cells to induce kidney injury. This proposed mechanism is supported by observations that (i) glomerular immunodeposits in patients with IgA nephropathy are enriched for galactose-deficient IgA1 glycoforms and the corresponding IgG autoantibodies; (ii) circulatory levels of galactose-deficient IgA1 and IgG autoantibodies predict disease progression; and (iii) pathogenic potential of galactose-deficient IgA1 and IgG autoantibodies was demonstrated in vivo. Thus, a better understanding of the structure–function of these immunoglobulins as autoantibodies and autoantigens will enable development of disease-specific treatments.

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Section: Iga Nephropathy—disease-specific Treatment Approachesmentioning

confidence: 99%

Pathogenesis of IgA Nephropathy: Current Understanding and Implications for Development of Disease-Specific Treatment

Knoppová

Reily

King

et al. 2021

JCM

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“…25 ). As ZmpA engages the invariant region of its IgA substrate through high affinity interactions that do not involve the C terminal region 58 , 59 , and the ZmpB N terminus shares structural domains with the immunomodulatory PspC protein (Supplementary Fig. 26 ), it seemed likely that ZmpB may directly bind antibodies outside of their variable antigen recognition domains.…”

Section: Resultsmentioning

confidence: 99%

Genomic and panproteomic analysis of the development of infant immune responses to antigenically-diverse pneumococci

Croucher,

Campo,

et al. 2024

Nat Commun

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Streptococcus pneumoniae (pneumococcus) is a nasopharyngeal commensal and respiratory pathogen. This study characterises the immunoglobulin G (IgG) repertoire recognising pneumococci from birth to 24 months old (mo) in a prospectively-sampled cohort of 63 children using a panproteome array. IgG levels are highest at birth, due to transplacental transmission of maternal antibodies. The subsequent emergence of responses to individual antigens exhibit distinct kinetics across the cohort. Stable differences in the strength of individuals’ responses, correlating with maternal IgG concentrations, are established by 6 mo. By 12 mo, children develop unique antibody profiles that are boosted by re-exposure. However, some proteins only stimulate substantial responses in adults. Integrating genomic data on nasopharyngeal colonisation demonstrates rare pneumococcal antigens can elicit strong IgG levels post-exposure. Quantifying such responses to the diverse core loci (DCL) proteins is complicated by cross-immunity between variants. In particular, the conserved N terminus of DCL protein zinc metalloprotease B provokes the strongest early IgG responses. DCL proteins’ ability to inhibit mucosal immunity likely explains continued pneumococcal carriage despite hosts’ polyvalent antibody repertoire. Yet higher IgG levels are associated with reduced incidence, and severity, of pneumonia, demonstrating the importance of the heterogeneity in response strength and kinetics across antigens and individuals.

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“…[ 66 ] Monoclonal antibodies can inhibit its binding and block infection at the host interface. [ 67 ] Immunization using recombinant IgA1 protease protected lab mice against lethal meningococcal and pneumococcal infections. [ 68 ] Choline‐binding protein A (Q8DN05) is a member of a polypeptide family that anchors proteins to choline residues in the cell wall.…”

Section: Resultsmentioning

confidence: 99%

Yields and Immunomodulatory Effects of Pneumococcal Membrane Vesicles Differ with the Bacterial Growth Phase

Mehanny

Kroniger

Koch

et al. 2021

Adv Healthcare Materials

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Streptococcus pneumoniae infections are a leading cause of death worldwide. Bacterial membrane vesicles (MVs) are promising vaccine candidates because of the antigenic components of their parent microorganisms. Pneumococcal MVs exhibit low toxicity towards several cell lines, but their clinical translation requires a high yield and strong immunogenic effects without compromising immune cell viability. MVs are isolated during either the stationary phase (24 h) or death phase (48 h), and their yields, immunogenicity and cytotoxicity in human primary macrophages and dendritic cells have been investigated. Death-phase vesicles showed higher yields than stationary-phase vesicles. Both vesicle types displayed acceptable compatibility with primary immune cells and several cell lines. Both vesicle types showed comparable uptake and enhanced release of the inflammatory cytokines, tumor necrosis factor and interleukin-6, from human primary immune cells. Proteomic analysis revealed similarities in vesicular immunogenic proteins such as pneumolysin, pneumococcal surface protein A, and IgA1 protease in both vesicle types, but stationary-phase MVs showed significantly lower autolysin levels than death-phase MVs. Although death-phase vesicles produced higher yields, they lacked superiority to stationary-phase vesicles as vaccine candidates owing to their similar antigenic protein cargo and comparable uptake into primary human immune cells.

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Mechanism and inhibition of Streptococcus pneumoniae IgA1 protease

Cited by 16 publications

References 41 publications

Pathogenesis of IgA Nephropathy: Current Understanding and Implications for Development of Disease-Specific Treatment

Pathogenesis of IgA Nephropathy: Current Understanding and Implications for Development of Disease-Specific Treatment

Genomic and panproteomic analysis of the development of infant immune responses to antigenically-diverse pneumococci

Yields and Immunomodulatory Effects of Pneumococcal Membrane Vesicles Differ with the Bacterial Growth Phase

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