Conserved patterns hidden within group A Streptococcus M protein hypervariability recognize human C4b-binding protein

Buffalo, Cosmo Z.; Bahn-Suh, Adrian J; Hirakis, Sophia P.; Biswas, Tapan; Amaro, Rommie E.; Nizet, Victor; Ghosh, Partho

doi:10.1038/nmicrobiol.2016.155

Cited by 50 publications

(113 citation statements)

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“…Due to the pronounced hypervariability of the N-terminal domain (B-repeats included) across M proteins, a single common pattern for the M proteins that activates IL-1β is unlikely. However, it has recently been recognized by x-ray crystallography that the three-dimensional structure of different M proteins in complex with host factors may reveal conserved sequence patterns hidden within hypervariability 42 .…”

Section: Discussionmentioning

confidence: 99%

Group A streptococcal M protein activates the NLRP3 inflammasome

et al. 2017

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Group A Streptococcus (GAS) is among the top 10 causes of infection-related mortality in humans. M protein is the most abundant GAS surface protein, and M1 serotype GAS strains are associated with invasive infections including necrotizing fasciitis and toxic shock syndrome. Here we report that released, soluble M1 protein triggers programmed cell death in macrophages (Mϕ). M1 served as a second signal for caspase-1-dependent NLRP3 inflammasome activation, inducing maturation and release of proinflammatory cytokine IL-1β and macrophage pyroptosis. The structurally dynamic B-repeat domain of M1 was critical for inflammasome activation, which involved K+ efflux and M1 protein internalization by clathrin-mediated endocytosis. Mouse intraperitoneal challenge showed that soluble M1 was sufficient and specific for IL-1β activation, which may represent an early warning to activate host immunity against the pathogen. Conversely, in systemic infection, hyperinflammation associated with M1-mediated pyroptosis and IL-1β release could aggravate tissue injury.

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Section: Discussionmentioning

confidence: 99%

Group A streptococcal M protein activates the NLRP3 inflammasome

et al. 2017

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“…Unlike some previous reports of structure based vaccine design, we have focused only on the array of native peptide structures expressed by GAS. The feasibility of this approach is partly supported by the observation that the structures of the N-terminal regions of M proteins are constrained by their function(s) in virulence, including binding of the complement regulatory proteins C4BP [25, 26], factor H (and factor H-like protein) [27] and protection from proteolytic digestion [28]. Thus, the new cluster-based system predicts groups of related peptide structures whose diversity is limited by functional constraints.…”

Section: Discussionmentioning

confidence: 99%

Structure-based design of broadly protective group a streptococcal M protein-based vaccines

Dale

Smeesters

Courtney

et al. 2017

Vaccine

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Background A major obstacle to the development of broadly protective M protein-based group A streptococcal (GAS) vaccines is the variability within the N-terminal epitopes that evoke potent bactericidal antibodies. The concept of M type-specific protective immune responses has recently been challenged based on the observation that multivalent M protein vaccines elicited cross-reactive bactericidal antibodies against a number of non-vaccine M types of GAS. Additionally, a new “cluster-based” typing system of 175 M proteins identified a limited number of clusters containing closely related M proteins. In the current study, we used the emm cluster typing system, in combination with computational structure-based peptide modeling, as a novel approach to the design of potentially broadly protective M protein-based vaccines. Methods M protein sequences (AA 16–50) from the E4 cluster containing 17 emm types of GAS were analyzed using de novo 3-D structure prediction tools and the resulting structures subjected to chemical diversity analysis to identify sequences that were the most representative of the 3-D physicochemical properties of the M peptides in the cluster. Five peptides that spanned the range of physicochemical attributes of all 17 peptides were used to formulate synthetic and recombinant vaccines. Rabbit antisera were assayed for antibodies that cross-reacted with E4 peptides and whole bacteria by ELISA and for bactericidal activity against all E4 GAS. Results The synthetic vaccine rabbit antisera reacted with all 17 E4 M peptides and demonstrated bactericidal activity against 15/17 E4 GAS. A recombinant hybrid vaccine containing the same E4 peptides also elicited antibodies that cross-reacted with all E4 M peptides. Conclusions Comprehensive studies using structure-based design may result in a broadly protective M peptide vaccine that will elicit cluster-specific and emm type-specific antibody responses against the majority of clinically relevant emm types of GAS.

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“…FGG coding for fibrinogen-gamma was shown to be induced by pro-inflammatory cytokines 34 and to be elevated in lung pneumonia and infection 33 . C4BPA, coding for C4BP and part of the complement system, was found to recognize and bind pneumonia-causing streptococci in the lung epithelium 35,36 . It is noteworthy that many patients with COVID-19 (e.g.…”

Section: Discussionmentioning

confidence: 99%

“…A cutoff of absolute gene expression fold-change >1.2 and an FDR q-value < 0.05 were applied to select DEGs between ACE2-expressing and ACE2-absent AT2 cells. We found genes upregulated in ACE2-expressing AT2 cells that are highly pertinent to lung epithelial biology and disease such as HHIP (lung branching and chronic obstructive pulmonary disease/COPD, 31,32 ), FGG (fibrosis, pneumonia and inflammation, 33,34 ) and C4BPA (complement system, pneumonia and infection, 35,36 ) ( Fig. 3).…”

Section: Abundance and Expression Patterns Of The Sars-cov-2 Receptormentioning

confidence: 98%

Single-cell analysis of human lung epithelia reveals concomitant expression of the SARS-CoV-2 receptor ACE2 with multiple virus receptors and scavengers in alveolar type II cells

Han

Sinjab

Treekitkarnmongkol

et al. 2020

Preprint

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The novel coronavirus SARS-CoV-2 was identified as the causative agent of the ongoing pandemic COVID 19. COVID-19-associated deaths are mainly attributed to severe pneumonia and respiratory failure. Recent work demonstrated that SARS-CoV-2 binds to angiotensin converting enzyme 2 (ACE2) in the lung. To better understand ACE2 abundance and expression patterns in the lung we interrogated our in-house single-cell RNA-sequencing dataset containing 70,085 EPCAM+ lung epithelial cells from paired normal and lung adenocarcinoma tissues. Transcriptomic analysis revealed a diverse repertoire of airway lineages that included alveolar type I and II, bronchioalveolar, club/secretory, quiescent and proliferating basal, ciliated and malignant cells as well as rare populations such as ionocytes. While the fraction of lung epithelial cells expressing ACE2 was low (1.7% overall), alveolar type II (AT2, 2.2% ACE2+) cells exhibited highest levels of ACE2 expression among all cell subsets. Further analysis of the AT2 compartment (n = 27,235 cells) revealed a number of genes co-expressed with ACE2 that are important for lung pathobiology including those associated with chronic obstructive pulmonary disease (COPD; HHIP), pneumonia and infection (FGG and C4BPA) as well as malarial/bacterial (CD36) and viral (DMBT1) scavenging which, for the most part, were increased in smoker versus light or non-smoker cells. Notably, DMBT1 was highly expressed in AT2 cells relative to other lung epithelial subsets and its expression positively correlated with ACE2.We describe a population of ACE2-positive AT2 cells that co-express pathogen (including viral) receptors (e.g. DMBT1) with crucial roles in host defense thus comprising plausible phenotypic targets for treatment of COVID-19.

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Conserved patterns hidden within group A Streptococcus M protein hypervariability recognize human C4b-binding protein

Cited by 50 publications

References 58 publications

Group A streptococcal M protein activates the NLRP3 inflammasome

Group A streptococcal M protein activates the NLRP3 inflammasome

Structure-based design of broadly protective group a streptococcal M protein-based vaccines

Single-cell analysis of human lung epithelia reveals concomitant expression of the SARS-CoV-2 receptor ACE2 with multiple virus receptors and scavengers in alveolar type II cells

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