M protein is a virulence factor that can be produced by certain species of Streptococcus.[1] The protein plays an important role in adhesion to and colonization of host tissues[2] and especially in evading phagocytosis by immune cells.[1][2]
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.[4] 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.[4] 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.[5]
Several vaccine candidates targeting M protein have been explored in preclinical and clinical studies.[5] 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.[5] 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.
Structure of the M protein
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.
The future of M protein
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.
References for structure
Dale, J. B., et al. (2013). Vaccine, 31(Suppl 2), B216–B222.
Carapetis, J. R., et al. (2005). The Lancet Infectious Diseases, 5(11), 685–694.
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
Center; 2016.
McMillan, D. J., et al. (2013). Clinical Microbiology and Infection, 19(5), E222–E229.
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.
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
References for future of M protein
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.
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.
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.
Literature
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. PMID2287281.
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. PMID20347595.
References for overview, therapeutic approaches, and future perspectives
1 2 Oehmcke, Sonja; Shannon, Oonagh; Morgelin, Matthias; Herwald, Heiko (2010-09-06). "Streptococcal M proteins and their role as virulence determinants". Clinica Chimica Acta. 411 (17–18): 1172–1180. doi:10.1016/j.cca.2010.04.032. PMID20452338.
↑ Fischetti, Vincent A. (Jul 1989). "Streptococcal M protein: Molecular design and biological behavior". Clinical Microbiology Reviews. 2 (3): 285–314. doi:10.1128/cmr.2.3.285. PMID2670192.
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. ISSN1473-3099. PMID16253886.
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. ISSN1873-2518. PMID23598485.
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