Judith McNaught

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

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.

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.

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.

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.

The M protein is a fibrillar surface protein found on the bacterial pathogen Streptococcus pyogenes. It contributes to the bacterium's ability to cause disease by interfering with the host immune system and enabling adhesion to host tissues.

The M protein contains four distinct sequence repeat domains with dissimilar size and amino acid composition. It extends outward from the bacterial cell wall, and consists of a highly variable N-terminal, a central coiled-coil, and a conserved C-terminal anchoring domain. The central region’s coiled-coil conformation provides structural rigidity so that the protein can protrude from the cell surface and resist mechanical forces within the host niche.

the N-terminal domain, while immunodominant, is highly variable between strains and therefore it presents difficulties for vaccine design because of its antigenic heterogeneity. The central and C-terminal domains, however, are fairly conserved and therefore more suitable targets for broadly protective vaccines and therapies.

Instabilities and irregularities within the coiled-coil conformation are functionally important; they are significant for the ability of the protein to bind host molecules. These structural properties enable the M protein to bind a number of host proteins, such as fibrinogen, which is an essential component of the blood clotting system. By binding fibrinogen, the M protein interferes with host immune processes and enables the formation of pathological host-pathogen proteinnetworks that allow for bacterial virulence.

New laboratory techniques for the M protein have greatly improved diagnosis and follow-up of Group A Streptococcus (GAS) infection (such as strep throat, APSGN, etc.). Previous blood tests were slower and less precise. Today, polymerase chain reaction (PCR) and DNA sequencing offer faster and more precise typing of GAS strains. The revised model of the M protein will facilitate epidemiological investigations and vaccine development by improving how strains are typed and tracked using genetic methods. These methods can also monitor the spread of specific clones over time and space to improve responses to pandemic outbreaks. They are applied to research and clinical practice.

Considerable advances have also been achieved in M protein vaccine development. Vaccines that can target multiple domains of the M protein are being developed to ensure broader protection. A 26-valent vaccine based on the amino-terminal fragments of the M protein has been shown to be safe and immunogenic in humans, a promising design for better protection. Other candidates are being designed to incorporate conserved areas of the M protein, which would offer protection against more forms of GAS. Novel delivery systems, such as nasal sprays and nanoparticles, are being tested to enhance immune responses and improve access. Synthetic biology is being used to expand the breadth of coverage by incorporating conserved epitopes that limit bacterial immune escape.

1. Dale, J. B., et al. (2013). Vaccine, 31(Suppl 2), B216–B222.
2. Carapetis, J. R., et al. (2005). The Lancet Infectious Diseases, 5(11), 685–694.
3. Fischetti VA. M protein and other surface proteins on streptococci. In: Ferretti JJ, Stevens DL, Fischetti VA, editors. Streptococcus pyogenes: Basic Biology to Clinical Manifestations [Internet]. Oklahoma City (OK): University of Oklahoma Health Sciences
4. Center; 2016.
5. McMillan, D. J., et al. (2013). Clinical Microbiology and Infection, 19(5), E222–E229.
6. McNamara, C., Zinkernagel, A. S., & Macheboeuf, P. et al. (2008). "Coiled-coil irregularities and instability in group A Streptococcus M1 are required for virulence." Science, 319(5868), 1405–1408.
7. Terao, Y., Kawabata, S., & Nakata, M. et al. (2002). "Fibrinogen-binding protein of Streptococcus pyogenes, a coiled-coil M-related protein, interacts with the Aα chain through coiled-coil motifs." Journal of Biological Chemistry, 277(42), 38796–38801

1. McMillan, David J., et al. “Updated Model of Group A Streptococcus M Proteins Based on a Comprehensive Worldwide Study.” Clinical Microbiology and Infection, vol. 19, no. 2013, pp. E222–E229. https://doi.org/10.1111/1469-0691.12134.
2. Carapetis, Jonathan R., et al. “Acute Rheumatic Fever and Rheumatic Heart Disease.”The Lancet, vol. 366, no. 9480, 2005, pp. 155–168. https://doi.org/10.1016/S0140-6736(05)66874-2.
3. Dale, James B., et al. “Potential Coverage of a Multivalent M Protein-Based Group A Streptococcal Vaccine.” Vaccine, vol. 31, no. 6, 2013, pp. 1576–1581. https://doi.org/10.1016/j.vaccine.2012.12.062.

• 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.
• Pierre R. Smeesters; David J. McMillan; Kadaba S. Sriprakash (June 2010). "The streptococcal M protein: a highly versatile molecule". Trends in Microbiology. 18 (6): 275–282. doi:10.1016/j.tim.2010.02.007. PMID 20347595.