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Article ; Online: Variation, Indispensability, and Masking in the M protein.

Ghosh, Partho

2017 Volume 26, Issue 2, Page(s) 132–144

Abstract: The M protein is the major surface-associated virulence factor of group A Streptococcus (GAS) and an antigenically variable target of host immunity. How selection pressures to escape immune recognition, maintain indispensable functions, and mask ... ...

Abstract	The M protein is the major surface-associated virulence factor of group A Streptococcus (GAS) and an antigenically variable target of host immunity. How selection pressures to escape immune recognition, maintain indispensable functions, and mask vulnerabilities have shaped the sequences of the >220M protein types is unclear. Recent experiments have shed light on this question by showing that, hidden within the antigenic variability of many M protein types, are sequence patterns conserved for recruiting human C4b-binding protein (C4BP). Other host factors may be recruited in a similar manner by conserved but hidden sequence patterns in the M protein. The identification of such patterns may be applicable to the development of a GAS vaccine.
MeSH term(s)	Antigenic Variation ; Antigens, Bacterial/classification ; Antigens, Bacterial/genetics ; Antigens, Bacterial/immunology ; Antigens, Bacterial/metabolism ; Antimicrobial Cationic Peptides/metabolism ; Bacterial Outer Membrane Proteins/classification ; Bacterial Outer Membrane Proteins/genetics ; Bacterial Outer Membrane Proteins/immunology ; Bacterial Outer Membrane Proteins/metabolism ; Carrier Proteins/classification ; Carrier Proteins/genetics ; Carrier Proteins/immunology ; Carrier Proteins/metabolism ; Complement C4b-Binding Protein/metabolism ; Complement Factor H/metabolism ; Histones/metabolism ; Host-Pathogen Interactions/immunology ; Humans ; Protein Binding ; Staphylococcal Vaccines ; Streptococcus pyogenes/metabolism ; Streptococcus pyogenes/pathogenicity ; Virulence Factors/metabolism
Chemical Substances	Antigens, Bacterial ; Antimicrobial Cationic Peptides ; Bacterial Outer Membrane Proteins ; C4BPA protein, human ; Carrier Proteins ; Complement C4b-Binding Protein ; Histones ; Staphylococcal Vaccines ; Virulence Factors ; streptococcal M protein ; ropocamptide (3DD771JO2H) ; Complement Factor H (80295-65-4)
Language	English
Publishing date	2017-08-31
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1158963-2
ISSN	1878-4380 ; 0966-842X
ISSN (online)	1878-4380
ISSN	0966-842X
DOI	10.1016/j.tim.2017.08.002
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Article ; Online: Nonimmune antibody interactions of Group A Streptococcus M and M-like proteins.

Jori O Mills / Partho Ghosh

PLoS Pathogens, Vol 17, Iss 2, p e

2021 Volume 1009248

Abstract: M and M-like proteins are major virulence factors of the widespread and potentially deadly bacterial pathogen Streptococcus pyogenes. These proteins confer resistance against innate and adaptive immune responses by recruiting specific human proteins to ... ...

Abstract	M and M-like proteins are major virulence factors of the widespread and potentially deadly bacterial pathogen Streptococcus pyogenes. These proteins confer resistance against innate and adaptive immune responses by recruiting specific human proteins to the streptococcal surface. Nonimmune recruitment of immunoglobulins G (IgG) and A (IgA) through their fragment crystallizable (Fc) domains by M and M-like proteins was described almost 40 years ago, but its impact on virulence remains unresolved. These interactions have been suggested to be consequential under immune conditions at mucosal surfaces and in secretions but not in plasma, while other evidence suggests importance in evading phagocytic killing in nonimmune blood. Recently, an indirect effect of Fc-binding through ligand-induced stabilization of an M-like protein was shown to increase virulence. Nonimmune recruitment has also been seen to contribute to tissue damage in animal models of autoimmune diseases triggered by S. pyogenes infection. The damage was treatable by targeting Fc-binding. This and other potential therapeutic applications warrant renewed attention to Fc-binding by M and M-like proteins.
Keywords	Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
Subject code	572
Language	English
Publishing date	2021-02-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
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Article ; Online: Nonimmune antibody interactions of Group A Streptococcus M and M-like proteins.

Mills, Jori O / Ghosh, Partho

PLoS pathogens

2021 Volume 17, Issue 2, Page(s) e1009248

Abstract	M and M-like proteins are major virulence factors of the widespread and potentially deadly bacterial pathogen Streptococcus pyogenes. These proteins confer resistance against innate and adaptive immune responses by recruiting specific human proteins to the streptococcal surface. Nonimmune recruitment of immunoglobulins G (IgG) and A (IgA) through their fragment crystallizable (Fc) domains by M and M-like proteins was described almost 40 years ago, but its impact on virulence remains unresolved. These interactions have been suggested to be consequential under immune conditions at mucosal surfaces and in secretions but not in plasma, while other evidence suggests importance in evading phagocytic killing in nonimmune blood. Recently, an indirect effect of Fc-binding through ligand-induced stabilization of an M-like protein was shown to increase virulence. Nonimmune recruitment has also been seen to contribute to tissue damage in animal models of autoimmune diseases triggered by S. pyogenes infection. The damage was treatable by targeting Fc-binding. This and other potential therapeutic applications warrant renewed attention to Fc-binding by M and M-like proteins.
MeSH term(s)	Animals ; Antibodies, Monoclonal/metabolism ; Antigens, Bacterial/metabolism ; Bacterial Outer Membrane Proteins/metabolism ; Carrier Proteins/metabolism ; Humans ; Immunoglobulin Fc Fragments/metabolism ; Streptococcal Infections/metabolism ; Streptococcal Infections/microbiology ; Streptococcus pyogenes/metabolism
Chemical Substances	Antibodies, Monoclonal ; Antigens, Bacterial ; Bacterial Outer Membrane Proteins ; Carrier Proteins ; Immunoglobulin Fc Fragments ; streptococcal M protein
Language	English
Publishing date	2021-02-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1009248
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: A conserved 3D pattern in a Streptococcus pyogenes M protein immunogen elicits M-type crossreactivity.

Wang, Kuei-Chen / Kuliyev, Eziz / Nizet, Victor / Ghosh, Partho

The Journal of biological chemistry

2023 Volume 299, Issue 8, Page(s) 104980

Abstract: Coiled coil-forming M proteins of the widespread and potentially deadly bacterial pathogen Streptococcus pyogenes (strep A) are immunodominant targets of opsonizing antibodies. However, antigenic sequence variability of M proteins into >220 M types, as ... ...

Abstract	Coiled coil-forming M proteins of the widespread and potentially deadly bacterial pathogen Streptococcus pyogenes (strep A) are immunodominant targets of opsonizing antibodies. However, antigenic sequence variability of M proteins into >220 M types, as defined by their hypervariable regions (HVRs), is considered to limit M proteins as vaccine immunogens because of type specificity in the antibody response. Surprisingly, a multi-HVR immunogen in clinical vaccine trials was shown to elicit M-type crossreactivity. The basis for this crossreactivity is unknown but may be due in part to antibody recognition of a 3D pattern conserved in many M protein HVRs that confers binding to human complement C4b-binding protein (C4BP). To test this hypothesis, we investigated whether a single M protein immunogen carrying the 3D pattern would elicit crossreactivity against other M types carrying the 3D pattern. We found that a 34-amino acid sequence of S. pyogenes M2 protein bearing the 3D pattern retained full C4BP-binding capacity when fused to a coiled coil-stabilizing sequence from the protein GCN4. We show that this immunogen, called M2G, elicited cross-reactive antibodies against a number of M types that carry the 3D pattern but not against those that lack the 3D pattern. We further show that the M2G antiserum-recognized M proteins displayed natively on the strep A surface and promoted the opsonophagocytic killing of strep A strains expressing these M proteins. As C4BP binding is a conserved virulence trait of strep A, we propose that targeting the 3D pattern may prove advantageous in vaccine design.
MeSH term(s)	Humans ; Antigens, Bacterial/chemistry ; Antigens, Bacterial/immunology ; Bacterial Outer Membrane Proteins/chemistry ; Bacterial Outer Membrane Proteins/immunology ; Carrier Proteins/chemistry ; Carrier Proteins/immunology ; Protein Binding ; Streptococcus pyogenes/immunology ; Cross Reactions
Chemical Substances	Antigens, Bacterial ; Bacterial Outer Membrane Proteins ; Carrier Proteins ; streptococcal M protein
Language	English
Publishing date	2023-06-28
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1016/j.jbc.2023.104980
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Article: Structural Requirements for Reverse Transcription by a Diversity-generating Retroelement.

Handa, Sumit / Biswas, Tapan / Chakraborty, Jeet / Paul, Blair G / Ghosh, Partho

bioRxiv : the preprint server for biology

2023

Abstract: Diversity-generating retroelements (DGRs), which are pervasive among microbes, create massive protein sequence variation through reverse transcription of a protein-coding RNA template coupled to frequent misincorporation at template adenines. For cDNA ... ...

Abstract	Diversity-generating retroelements (DGRs), which are pervasive among microbes, create massive protein sequence variation through reverse transcription of a protein-coding RNA template coupled to frequent misincorporation at template adenines. For cDNA synthesis, the template must be surrounded by up- and downstream sequences. Cryo-EM revealed that this longer RNA formed an integral ribonucleoprotein (RNP) with the DGR reverse transcriptase bRT and associated protein Avd. The downstream, noncoding (nc) RNA formed stem-loops enveloping bRT and laying over barrel-shaped Avd, and duplexes with the upstream and template RNA. These RNA structural elements were required for reverse transcription, and several were conserved in DGRs from distant taxa. Multiple RNP conformations were visualized, and no large structural rearrangements occurred when adenine replaced guanine as the template base, suggesting energetics govern misincorporation at adenines. Our results explain how the downstream ncRNA primes cDNA synthesis, promotes processivity, terminates polymerization, and stringently limits mutagenesis to DGR variable proteins.
Language	English
Publishing date	2023-10-23
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.10.23.563531
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Article ; Online: An M protein coiled coil unfurls and exposes its hydrophobic core to capture LL-37.

Kolesinski, Piotr / Wang, Kuei-Chen / Hirose, Yujiro / Nizet, Victor / Ghosh, Partho

eLife

2022 Volume 11

Abstract: Surface-associated, coiled-coil M proteins ... ...

Abstract	Surface-associated, coiled-coil M proteins of
MeSH term(s)	Humans ; Membrane Proteins/metabolism ; Streptococcus pyogenes/metabolism
Chemical Substances	Membrane Proteins
Language	English
Publishing date	2022-06-21
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.77989
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Article: Variation, Indispensability, and Masking in the M protein

Ghosh, Partho

Trends in microbiology. 2017,

2017

Abstract	The M protein is the major surface-associated virulence factor of group A Streptococcus (GAS) and an antigenically variable target of host immunity. How selection pressures to escape immune recognition, maintain indispensable functions, and mask vulnerabilities have shaped the sequences of the >220M protein types is unclear. Recent experiments have shed light on this question by showing that, hidden within the antigenic variability of many M protein types, are sequence patterns conserved for recruiting human C4b-binding protein (C4BP). Other host factors may be recruited in a similar manner by conserved but hidden sequence patterns in the M protein. The identification of such patterns may be applicable to the development of a GAS vaccine.
Keywords	Streptococcus ; antigenic variation ; humans ; immunity ; vaccines ; virulence
Language	English
Publishing place	Elsevier Ltd
Document type	Article
Note	Pre-press version
ZDB-ID	1158963-2
ISSN	1878-4380 ; 0966-842X
ISSN (online)	1878-4380
ISSN	0966-842X
DOI	10.1016/j.tim.2017.08.002
Database	NAL-Catalogue (AGRICOLA)

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Z 2005/714: Show issues

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Article ; Online: An M protein coiled coil unfurls and exposes its hydrophobic core to capture LL-37

Piotr Kolesinski / Kuei-Chen Wang / Yujiro Hirose / Victor Nizet / Partho Ghosh

eLife, Vol

2022 Volume 11

Abstract: Surface-associated, coiled-coil M proteins of Streptococcus pyogenes (Strep A) disable human immunity through interaction with select proteins. However, coiled coils lack features typical of protein–protein interaction sites, and it is therefore ... ...

Abstract	Surface-associated, coiled-coil M proteins of Streptococcus pyogenes (Strep A) disable human immunity through interaction with select proteins. However, coiled coils lack features typical of protein–protein interaction sites, and it is therefore challenging to understand how M proteins achieve specific binding, for example, with the human antimicrobial peptide LL-37, leading to its neutralization. The crystal structure of a complex of LL-37 with M87 protein, an antigenic M protein variant from a strain that is an emerging threat, revealed a novel interaction mode. The M87 coiled coil unfurled and asymmetrically exposed its hydrophobic core to capture LL-37. A single LL-37 molecule was bound by M87 in the crystal, but in solution additional LL-37 molecules were recruited, consistent with a ‘protein trap’ neutralization mechanism. The interaction mode visualized crystallographically was verified to contribute significantly to LL-37 resistance in an M87 Strep A strain and was identified to be conserved in a number of other M protein types that are prevalent in human populations. Our results provide specific detail for therapeutic inhibition of LL-37 neutralization by M proteins.
Keywords	coiled coils ; Streptococcus pyogenes ; M protein ; antimicrobial peptide ; cathelicidin ; LL-37 ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2022-06-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Determinants of adenine-mutagenesis in diversity-generating retroelements.

Handa, Sumit / Reyna, Andres / Wiryaman, Timothy / Ghosh, Partho

Nucleic acids research

2020 Volume 49, Issue 2, Page(s) 1033–1045

Abstract: Diversity-generating retroelements (DGRs) vary protein sequences to the greatest extent known in the natural world. These elements are encoded by constituents of the human microbiome and the microbial 'dark matter'. Variation occurs through adenine- ... ...

Abstract	Diversity-generating retroelements (DGRs) vary protein sequences to the greatest extent known in the natural world. These elements are encoded by constituents of the human microbiome and the microbial 'dark matter'. Variation occurs through adenine-mutagenesis, in which genetic information in RNA is reverse transcribed faithfully to cDNA for all template bases but adenine. We investigated the determinants of adenine-mutagenesis in the prototypical Bordetella bacteriophage DGR through an in vitro system composed of the reverse transcriptase bRT, Avd protein, and a specific RNA. We found that the catalytic efficiency for correct incorporation during reverse transcription by the bRT-Avd complex was strikingly low for all template bases, with the lowest occurring for adenine. Misincorporation across a template adenine was only somewhat lower in efficiency than correct incorporation. We found that the C6, but not the N1 or C2, purine substituent was a key determinant of adenine-mutagenesis. bRT-Avd was insensitive to the C6 amine of adenine but recognized the C6 carbonyl of guanine. We also identified two bRT amino acids predicted to nonspecifically contact incoming dNTPs, R74 and I181, as promoters of adenine-mutagenesis. Our results suggest that the overall low catalytic efficiency of bRT-Avd is intimately tied to its ability to carry out adenine-mutagenesis.
MeSH term(s)	Adenine/chemistry ; Arginine/chemistry ; Bacteriophages/genetics ; Base Sequence ; Bordetella/virology ; Catalysis ; Cell-Free System ; Computer Simulation ; DNA, Complementary/genetics ; Glycine/chemistry ; High-Throughput Nucleotide Sequencing ; Models, Molecular ; Mutagenesis ; Protein Conformation ; RNA-Directed DNA Polymerase/metabolism ; Recombinant Proteins/metabolism ; Retroelements/genetics
Chemical Substances	DNA, Complementary ; Recombinant Proteins ; Retroelements ; Arginine (94ZLA3W45F) ; RNA-Directed DNA Polymerase (EC 2.7.7.49) ; Adenine (JAC85A2161) ; Glycine (TE7660XO1C)
Language	English
Publishing date	2020-12-25
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkaa1240
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Zs.A 1067: Show issues

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Article ; Online: Crystal structure of a Thermus aquaticus diversity-generating retroelement variable protein.

Sumit Handa / Kharissa L Shaw / Partho Ghosh

PLoS ONE, Vol 14, Iss 1, p e

2019 Volume 0205618

Abstract: Diversity-generating retroelements (DGRs) are widely distributed in bacteria, archaea, and microbial viruses, and bring about unparalleled levels of sequence variation in target proteins. While DGR variable proteins share low sequence identity, the ... ...

Abstract	Diversity-generating retroelements (DGRs) are widely distributed in bacteria, archaea, and microbial viruses, and bring about unparalleled levels of sequence variation in target proteins. While DGR variable proteins share low sequence identity, the structures of several such proteins have revealed the C-type lectin (CLec)-fold as a conserved scaffold for accommodating massive sequence variation. This conservation has led to the suggestion that the CLec-fold may be useful in molecular surface display applications. Thermostability is an attractive feature in such applications, and thus we studied the variable protein of a DGR encoded by a prophage of the thermophile Thermus aquaticus. We report here the 2.8 Å resolution crystal structure of the variable protein from the T. aquaticus DGR, called TaqVP, and confirm that it has a CLec-fold. Remarkably, its variable region is nearly identical in structure to those of several other CLec-fold DGR variable proteins despite low sequence identity among these. TaqVP was found to be thermostable, which appears to be a property shared by several CLec-fold DGR variable proteins. These results provide impetus for the pursuit of the DGR variable protein CLec-fold in molecular display applications.
Keywords	Medicine ; R ; Science ; Q
Subject code	612
Language	English
Publishing date	2019-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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