M protein (Streptococcus)

Last updated
Gram_pos_anchor
Identifiers
SymbolGram_pos_anchor
Pfam PF00746
Pfam clan CL0501
InterPro IPR019948
PROSITE PDOC00373
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

M protein is a virulence factor that can be produced by certain species of Streptococcus . [1]

Contents

Viruses, parasites and bacteria are covered in protein and sugar molecules that help them gain entry into a host by counteracting the host's defenses. One such molecule is the M protein produced by certain streptococcal bacteria. At its C-terminus within the cell wall, M proteins embody a motif that is now known to be shared by many Gram-positive bacterial surface proteins. The motif includes a conserved hexapeptide LPXTGE, which precedes a hydrophobic C-terminal membrane spanning domain, which itself precedes a cluster of basic residues at the C-terminus. [2] [3]

M protein is strongly anti-phagocytic and is the major virulence factor for group A streptococci (Streptococcus pyogenes). It binds to serum factor H, destroying C3-convertase and preventing opsonization by C3b. However plasma B cells can generate antibodies against M protein which will help in opsonization and further the destruction of the microorganism by the macrophages and neutrophils. Cross-reactivity of anti-M protein antibodies with heart muscle has been suggested to be associated in some way with rheumatic fever.

It was originally identified by Rebecca Lancefield, [4] who also formulated the Lancefield classification system for streptococcal bacteria. Bacteria like S. pyogenes, which possess M protein are classified in group A of the Lancefield system.

Therapeutic Approaches

In recent years, the emergence of antibiotic resistance among streptococcal bacteria, particularly Group A Streptococcus (GAS) or Streptococcus pyogenes, has posed significant challenges to traditional therapeutic approaches. [5] The M protein, as a major virulence factor of GAS, has been a focal point for developing novel therapeutic strategies aimed at combating streptococcal infections.

Current therapeutic approaches targeting M protein predominantly involve antibiotics and immunomodulatory agents. Antibiotics such as penicillin and amoxicillin have been the mainstay of treatment for streptococcal infections. [5] However, the rise of antibiotic-resistant strains underscores the urgent need for alternative therapies. In this context, immunomodulatory agents, including intravenous immunoglobulin (IVIG), have shown promise in mitigating the inflammatory response associated with severe GAS infections, although their efficacy in targeting M protein specifically remains to be fully elucidated.

Development of Vaccines

The development of vaccines targeting M protein or its associated epitopes represents a promising avenue for the prevention and treatment of streptococcal infections. Vaccines designed to induce protective immune responses against M protein have the potential to confer long-term immunity and reduce the incidence of GAS-related diseases, including pharyngitis, impetigo, and invasive infections such as necrotizing fasciitis and streptococcal toxic shock syndrome. [6]

Several vaccine candidates targeting M protein have been explored in preclinical and clinical studies. [6] These vaccines aim to elicit antibodies that recognize and neutralize M protein, thereby preventing bacterial attachment and invasion. Furthermore, efforts have been made to enhance vaccine efficacy by incorporating conserved epitopes of M protein or employing novel adjuvants to boost immune responses.

One promising approach involves the use of multi-epitope vaccines that target multiple antigenic sites on M protein, thereby reducing the likelihood of immune evasion by GAS strains expressing variant M protein isoforms. [6] Additionally, advances in vaccine delivery systems, such as nanoparticle-based platforms and mucosal vaccination routes, hold potential for enhancing vaccine immunogenicity and efficacy against streptococcal infections.

Despite these advancements, several challenges remain in the development and implementation of M protein-based vaccines. These include the identification of highly conserved epitopes capable of eliciting protective immune responses across diverse GAS strains, as well as addressing potential autoimmunity associated with molecular mimicry between M protein and host tissues, particularly in the context of rheumatic fever.

Future Perspectives

Targeting M protein represents a promising approach for the development of novel therapeutics and vaccines against streptococcal infections. By leveraging advances in immunology, vaccinology, and molecular biology, researchers are poised to overcome existing challenges and realize the potential of M protein-based interventions in combating this significant public health threat.

Literature

Related Research Articles

<i>Streptococcus</i> Genus of bacteria

Streptococcus is a genus of gram-positive coccus or spherical bacteria that belongs to the family Streptococcaceae, within the order Lactobacillales, in the phylum Bacillota. Cell division in streptococci occurs along a single axis, so as they grow, they tend to form pairs or chains that may appear bent or twisted. This differs from staphylococci, which divide along multiple axes, thereby generating irregular, grape-like clusters of cells. Most streptococci are oxidase-negative and catalase-negative, and many are facultative anaerobes.

<span class="mw-page-title-main">Group A streptococcal infection</span> Medical condition

Group A streptococcal infections are a number of infections with Streptococcus pyogenes, a group A streptococcus (GAS). S. pyogenes is a species of beta-hemolytic Gram-positive bacteria that is responsible for a wide range of infections that are mostly common and fairly mild. If the bacteria enter the bloodstream an infection can become severe and life-threatening, and is called an invasive GAS (iGAS).

<i>Streptococcus pyogenes</i> Species of bacterium

Streptococcus pyogenes is a species of Gram-positive, aerotolerant bacteria in the genus Streptococcus. These bacteria are extracellular, and made up of non-motile and non-sporing cocci that tend to link in chains. They are clinically important for humans, as they are an infrequent, but usually pathogenic, part of the skin microbiota that can cause Group A streptococcal infection. S. pyogenes is the predominant species harboring the Lancefield group A antigen, and is often called group A Streptococcus (GAS). However, both Streptococcus dysgalactiae and the Streptococcus anginosus group can possess group A antigen as well. Group A streptococci, when grown on blood agar, typically produce small (2–3 mm) zones of beta-hemolysis, a complete destruction of red blood cells. The name group A (beta-hemolytic) Streptococcus is thus also used.

<span class="mw-page-title-main">Scarlet fever</span> Infectious disease caused by Streptococcus pyogenes

Scarlet fever, also known as scarlatina, is an infectious disease caused by Streptococcus pyogenes, a Group A streptococcus (GAS). It most commonly affects children between five and 15 years of age. The signs and symptoms include a sore throat, fever, headache, swollen lymph nodes, and a characteristic rash. The face is flushed and the rash is red and blanching. It typically feels like sandpaper and the tongue may be red and bumpy. The rash occurs as a result of capillary damage by exotoxins produced by S.pyogenes. On darker-pigmented skin the rash may be hard to discern.

<span class="mw-page-title-main">Rheumatic fever</span> Post-streptococcal inflammatory disease

Rheumatic fever (RF) is an inflammatory disease that can involve the heart, joints, skin, and brain. The disease typically develops two to four weeks after a streptococcal throat infection. Signs and symptoms include fever, multiple painful joints, involuntary muscle movements, and occasionally a characteristic non-itchy rash known as erythema marginatum. The heart is involved in about half of the cases. Damage to the heart valves, known as rheumatic heart disease (RHD), usually occurs after repeated attacks but can sometimes occur after one. The damaged valves may result in heart failure, atrial fibrillation and infection of the valves.

<span class="mw-page-title-main">Exotoxin</span> Toxin from bacteria that destroys or disrupts cells

An exotoxin is a toxin secreted by bacteria. An exotoxin can cause damage to the host by destroying cells or disrupting normal cellular metabolism. They are highly potent and can cause major damage to the host. Exotoxins may be secreted, or, similar to endotoxins, may be released during lysis of the cell. Gram negative pathogens may secrete outer membrane vesicles containing lipopolysaccharide endotoxin and some virulence proteins in the bounding membrane along with some other toxins as intra-vesicular contents, thus adding a previously unforeseen dimension to the well-known eukaryote process of membrane vesicle trafficking, which is quite active at the host–pathogen interface.

<i>Streptococcus pneumoniae</i> Species of bacterium

Streptococcus pneumoniae, or pneumococcus, is a Gram-positive, spherical bacteria, alpha-hemolytic member of the genus Streptococcus. They are usually found in pairs (diplococci) and do not form spores and are non motile. As a significant human pathogenic bacterium S. pneumoniae was recognized as a major cause of pneumonia in the late 19th century, and is the subject of many humoral immunity studies.

<i>Moraxella catarrhalis</i> Species of bacterium

Moraxella catarrhalis is a fastidious, nonmotile, Gram-negative, aerobic, oxidase-positive diplococcus that can cause infections of the respiratory system, middle ear, eye, central nervous system, and joints of humans. It causes the infection of the host cell by sticking to the host cell using trimeric autotransporter adhesins.

<i>Streptococcus agalactiae</i> Species of bacterium

Streptococcus agalactiae is a gram-positive coccus with a tendency to form chains. It is a beta-hemolytic, catalase-negative, and facultative anaerobe.

Virulence factors are cellular structures, molecules and regulatory systems that enable microbial pathogens to achieve the following:

<span class="mw-page-title-main">Lysin</span>

Lysins, also known as endolysins or murein hydrolases, are hydrolytic enzymes produced by bacteriophages in order to cleave the host's cell wall during the final stage of the lytic cycle. Lysins are highly evolved enzymes that are able to target one of the five bonds in peptidoglycan (murein), the main component of bacterial cell walls, which allows the release of progeny virions from the lysed cell. Cell-wall-containing Archaea are also lysed by specialized pseudomurein-cleaving lysins, while most archaeal viruses employ alternative mechanisms. Similarly, not all bacteriophages synthesize lysins: some small single-stranded DNA and RNA phages produce membrane proteins that activate the host's autolytic mechanisms such as autolysins.

Streptolysins are two homogenous exotoxins from Streptococcus pyogenes. Types include streptolysin O, which is oxygen-labile, and streptolysin S, which is oxygen-stable.

Pneumococcal infection is an infection caused by the bacterium Streptococcus pneumoniae.

<i>Streptococcus dysgalactiae</i> Species of bacterium

Streptococcus dysgalactiae is a gram positive, beta-haemolytic, coccal bacterium belonging to the family Streptococcaceae. It is capable of infecting both humans and animals, but is most frequently encountered as a commensal of the alimentary tract, genital tract, or less commonly, as a part of the skin flora. The clinical manifestations in human disease range from superficial skin-infections and tonsillitis, to severe necrotising fasciitis and bacteraemia. The incidence of invasive disease has been reported to be rising. Several different animal species are susceptible to infection by S. dysgalactiae, but bovine mastitis and infectious arthritis in lambs have been most frequently reported.

<span class="mw-page-title-main">Sortase</span> Group of prokaryotic enzymes

Sortase refers to a group of prokaryotic enzymes that modify surface proteins by recognizing and cleaving a carboxyl-terminal sorting signal. For most substrates of sortase enzymes, the recognition signal consists of the motif LPXTG (Leu-Pro-any-Thr-Gly), then a highly hydrophobic transmembrane sequence, followed by a cluster of basic residues such as arginine. Cleavage occurs between the Thr and Gly, with transient attachment through the Thr residue to the active site Cys residue, followed by transpeptidation that attaches the protein covalently to cell wall components. Sortases occur in almost all Gram-positive bacteria and the occasional Gram-negative bacterium or Archaea, where cell wall LPXTG-mediated decoration has not been reported. Although sortase A, the "housekeeping" sortase, typically acts on many protein targets, other forms of sortase recognize variant forms of the cleavage motif, or catalyze the assembly of pilins into pili.

Perianal cellulitis, also known as perianitis or perianal streptococcal dermatitis, is a bacterial infection affecting the lower layers of the skin (cellulitis) around the anus. It presents as bright redness in the skin and can be accompanied by pain, difficulty defecating, itching, and bleeding. This disease is considered a complicated skin and soft tissue infection (cSSTI) because of the involvement of the deeper soft tissues.

<span class="mw-page-title-main">Lancefield grouping</span> System for classifying streptococci bacteria

Lancefield grouping is a system of classification that classifies catalase-negative Gram-positive cocci based on the carbohydrate composition of bacterial antigens found on their cell walls. The system, created by Rebecca Lancefield, was historically used to organize the various members of the family Streptococcaceae, which includes the genera Lactococcus and Streptococcus, but now is largely superfluous due to explosive growth in the number of streptococcal species identified since the 1970s. However, it has retained some clinical usefulness even after the taxonomic changes, and as of 2018, Lancefield designations are still often used to communicate medical microbiological test results.

LPXTGase refers to an endopeptidase enzyme from Streptococci and Staphylococci with the capacity to cleave the carboxy-terminal LPXTG anchor motif of surface proteins similar to Sortase. However, LPXTGase differs significantly from Sortase in several ways: a) it is glycosylated, b) it contains unconventional amino acids, and c) it contains D-amino acids. The latter two characteristics indicate that ribosomes are not involve in the synthesis of LPXTGase. Data suggest that the enzymes responsible for cell wall assembly also assemble LPXTGase.

Vincent A. Fischetti is an American microbiologist and immunologist. He is Professor and Head of the Laboratory of Bacterial Pathogenesis and Immunology at Rockefeller University in New York City. His Laboratory is the oldest continuous laboratory at Rockefeller that started in 1926 and headed by 4 leading scientists over its near 100-year history: Homer Swift, Maclyn McCarty, Emil Gotschlich and Fischetti. Keeping with the historical theme of infectious diseases, Fischetti's primary areas of research are bacterial pathogenesis, bacterial genomics, immunology, virology, microbiology, and therapeutics. He was the first scientist to clone and sequence a surface protein on gram-positive bacteria, the M protein from S. pyogenes, and determine its unique coiled-coil structure. He also was the first use phage lysins as a therapeutic and an effective alternative to conventional antibiotics.

Streptococcosis is an infectious disease caused by bacteria of the genus Steptococcus. This disease is most common among horses, guinea pigs, dogs, cats, and fish with symptoms varying based on the streptococcal species involved. In humans, this disease typically involves a throat infection and is called streptococcal pharyngitis or strep throat.

References

  1. ↑ Chanter N, Talbot NC, Newton JR, Hewson D, Verheyen K (June 2000). "Streptococcus equi with truncated M-proteins isolated from outwardly healthy horses". Microbiology. 146 (Pt 6): 1361–9. doi: 10.1099/00221287-146-6-1361 . PMID   10846214.
  2. ↑ Schneewind O, Jones KF, Fischetti VA (June 1990). "Sequence and structural characteristics of the trypsin-resistant T6 surface protein of group A streptococci". J. Bacteriol. 172 (6): 3310–7. doi:10.1128/jb.172.6.3310-3317.1990. PMC   209141 . PMID   2188957.
  3. ↑ Fischetti VA, Pancholi V, Schneewind O (September 1990). "Conservation of a hexapeptide sequence in the anchor region of surface proteins from gram-positive cocci". Mol. Microbiol. 4 (9): 1603–5. doi:10.1111/j.1365-2958.1990.tb02072.x. PMID   2287281.
  4. ↑ "Streptococcal M protein: molecular design and biological behavior" . Retrieved 2009-06-21.
  5. 1 2 Carapetis, Jonathan R.; Steer, Andrew C.; Mulholland, E. Kim; Weber, Martin (November 2005). "The global burden of group A streptococcal diseases". The Lancet. Infectious Diseases. 5 (11): 685–694. doi:10.1016/S1473-3099(05)70267-X. ISSN   1473-3099. PMID   16253886.
  6. 1 2 3 Dale, James B.; Fischetti, Vincent A.; Carapetis, Jonathan R.; Steer, Andrew C.; Sow, Samba; Kumar, Rajesh; Mayosi, Bongani M.; Rubin, Fran A.; Mulholland, Kim; Hombach, Joachim Maria; Schödel, Florian; Henao-Restrepo, Ana Maria (2013-04-18). "Group A streptococcal vaccines: paving a path for accelerated development". Vaccine. 31 (Suppl 2): B216–222. doi:10.1016/j.vaccine.2012.09.045. ISSN   1873-2518. PMID   23598485.
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