Streptococcus pyogenes- Group A Streptococcus (GAS)- An Overview

Group A Streptococcus (GAS) is a type of bacteria that belongs to the genus Streptococcus and is classified by the presence of a group A antigen on its cell wall. GAS is also known by its scientific name, Streptococcus pyogenes, which means "pus-producing" in Greek. GAS can cause a variety of infections in humans, ranging from mild to severe and potentially life-threatening.

GAS is commonly found in the throat and on the skin of healthy people, where it usually does not cause any symptoms . However, under certain conditions, such as when the immune system is weakened or when there is a break in the skin barrier, GAS can invade deeper tissues and organs and cause serious infections. Some of the diseases caused by GAS include:

• Strep throat: a sore throat caused by inflammation of the pharynx
• Scarlet fever: a rash that accompanies strep throat and is caused by a toxin produced by some strains of GAS
• Impetigo: a skin infection characterized by blisters and crusts
• Cellulitis: an infection of the skin and underlying tissues that causes redness, swelling, and pain
• Necrotizing fasciitis: a rare but severe infection that destroys the skin, fat, and muscle layers
• Streptococcal toxic shock syndrome: a rare but severe condition that causes shock, organ failure, and death
• Rheumatic fever: an inflammatory disease that affects the heart, joints, skin, and brain
• Post-streptococcal glomerulonephritis: a kidney disease that causes blood and protein in the urine, edema, and high blood pressure

GAS infections are transmitted from person to person through respiratory droplets or direct contact with infected wounds or skin lesions . The incubation period for GAS infections varies depending on the type of infection, but it is usually between 1 to 3 days. The diagnosis of GAS infections depends on the clinical presentation and laboratory tests, such as culture, antigen detection, or serology . The treatment of GAS infections usually involves antibiotics, such as penicillin or erythromycin . The prevention and control of GAS infections include maintaining good hygiene, avoiding close contact with infected people, and seeking medical attention for any signs of infection .

GAS is an important public health problem worldwide because of its high prevalence, morbidity, and mortality. According to the World Health Organization (WHO), GAS causes more than 700 million cases of disease annually, resulting in over 500,000 deaths. GAS infections are more common in children than adults, especially in developing countries where access to health care and hygiene is limited. GAS infections can also cause outbreaks in settings such as schools, nursing homes, military barracks, or prisons . Therefore, it is essential to raise awareness and implement effective strategies to prevent and treat GAS infections.

Streptococcus pyogenes is a bacterium that is commonly found in the throat and skin of humans. It is a part of the normal microbiota of the upper respiratory tract, where it can exist as a commensal or an opportunistic pathogen.

The carrier rate of S. pyogenes in the respiratory tract varies depending on the age and health status of the individual. It is estimated that 1% to 5% of healthy adults and 2% to 17% of healthy children are asymptomatic carriers of S. pyogenes.

S. pyogenes can also colonize other mucosal surfaces, such as the genital and rectal areas, where it can cause infections such as vaginitis and proctitis.

S. pyogenes can be transmitted from person to person through direct contact with infected secretions or lesions, or through inhalation of respiratory droplets. It can also be spread by contact with contaminated objects, surfaces, or dust that harbor the bacteria.

S. pyogenes can survive in the environment for some time, especially in moist and warm conditions. It can also persist in dust for several weeks or months.

S. pyogenes is an aerotolerant bacterium that can grow in the presence or absence of oxygen. It prefers a temperature range of 15°C to 40°C, with an optimum of 37°C. It does not grow at 10°C or 45°C, nor in high salt or bile concentrations. These characteristics help to differentiate S. pyogenes from other streptococcal species.

Streptococcus pyogenes is a gram-positive, spherical or oval bacterium that forms chains of varying lengths . The chains are composed of non-motile, non-sporing cocci that are less than 2 µm in diameter . Some strains of S. pyogenes have a capsule of hyaluronic acid that inhibits phagocytosis by the host immune system . The cell wall of S. pyogenes contains a group-specific carbohydrate antigen (group A) that distinguishes it from other streptococci. The cell wall also contains lipoteichoic acid and M protein, which are important for attachment and virulence. Some strains of S. pyogenes have fimbriae (protein F) that enhance adherence to epithelial cells .

The morphology of S. pyogenes can be observed by gram staining, which reveals purple cocci in chains. However, older cultures may lose their gram-positive character and appear gram-variable or gram-negative. The morphology can also be observed by microscopy after staining with methylene blue or crystal violet, which show blue cocci in chains.

The morphology of S. pyogenes can also be inferred from its cultural characteristics on different media. S. pyogenes is an aerobic or facultatively anaerobic bacterium that grows best at 37°C and pH 7.4-7.6 . It requires enriched media with blood, serum or sugars for optimal growth. On blood agar, S. pyogenes produces large zones of beta-hemolysis (clear, complete lysis of red blood cells) around its colonies, which are circular, pinpoint, light yellow to golden, and vary in surface texture depending on the strain . On nutrient agar, S. pyogenes produces similar colonies but without hemolysis. On crystal violet blood agar, a selective medium that inhibits the growth of gram-negative bacteria, S. pyogenes grows well and shows beta-hemolysis. On PNF medium, another selective medium that contains polymyxin B, neomycin and fusidic acid to suppress the growth of other bacteria, S. pyogenes also grows well and shows beta-hemolysis. In liquid media such as nutrient broth or glucose broth, S. pyogenes produces granular turbidity with a powdery deposit due to the heavy chains of bacteria that settle down.

The genome of Streptococcus pyogenes is a circular chromosome that consists of about 1.85 million base pairs and encodes about 1,752 predicted protein-coding genes. The genome has a G+C content of 38.5%, which is lower than most other streptococci. The genome also contains five prophage regions, which are integrated viral DNA that can affect the virulence and diversity of the bacteria.

One of the most important features of the genome of S. pyogenes is the presence of a CRISPR-Cas system, which is a type of adaptive immune system that can recognize and destroy foreign DNA, such as plasmids or phages. The CRISPR-Cas system consists of two main components: CRISPR arrays and Cas genes. CRISPR arrays are sequences of repeated DNA interspersed with spacers, which are derived from previous encounters with foreign DNA. Cas genes encode for proteins that can use the CRISPR arrays as guides to target and cleave the matching foreign DNA.

The CRISPR-Cas system of S. pyogenes belongs to the type II-A subtype, which uses a single Cas protein called Cas9 as the effector nuclease. Cas9 can bind to a short RNA molecule called tracrRNA, which hybridizes with another RNA molecule called crRNA, which is transcribed from the CRISPR array. The Cas9-tracrRNA-crRNA complex can then recognize and cut foreign DNA that contains a sequence complementary to the crRNA spacer and a short motif called protospacer adjacent motif (PAM).

The CRISPR-Cas system of S. pyogenes has been extensively studied and exploited for genome editing applications in various organisms, due to its simplicity, specificity and versatility. However, the system also plays an important role in the natural biology and evolution of S. pyogenes, as it can provide resistance to phage infection, regulate gene expression, modulate virulence and mediate horizontal gene transfer.

Streptococcus pyogenes is a Gram-positive bacterium that grows best on enriched media containing blood, serum or sugars. It is an aerobic or facultatively anaerobic bacterium that can tolerate high levels of oxygen and can also grow at a low level of oxygen. About 5-10% CO2 during incubation promotes hemolysis on blood agar.

The following are some cultural characteristics of S. pyogenes on different culture media:

Nutrient Agar Medium

The colonies of S. pyogenes on nutrient agar medium appear circular, pinpoint with an average diameter of 0.5-1 mm. The colonies are light yellow to yellow colored, semi-transparent to opaque with low convex or convex elevation and matt surface (in the case of virulent strains) or glossy (in the case of non-virulent strains) and mucoid (in the case of capsule producing strains).

Blood Agar Medium

On blood agar medium, S. pyogenes form circular, pinpoint colonies that are similar in morphology to the colonies formed on other solid agar media. Light golden yellow colonies are formed that are surrounded by a clear zone exhibiting β-hemolysis. The surface of the colonies differs in different species based on their virulence and production of the capsule .

Crystal Violet Blood Agar Medium

Crystal violet blood agar medium is a selective medium for S. pyogenes that inhibits the growth of other Gram-positive bacteria. The colonies of S. pyogenes on this medium are similar to those on blood agar medium, except that they are more transparent and have a smaller zone of hemolysis.

PNF Medium

PNF medium is another selective medium for S. pyogenes that contains polymyxin B sulfate, neomycin sulfate and fusidic acid to suppress the growth of commensal respiratory microbiota, including the species of the same genus. The colonies of S. pyogenes on this medium are circular, pinpoint, yellow-colored and produce β-hemolysis around the colonies.

Streptococcus pyogenes is a highly virulent pathogen that can cause various diseases ranging from mild pharyngitis to severe invasive infections such as necrotizing fasciitis and toxic shock syndrome. To achieve this, S. pyogenes produces a wide array of virulence factors that help it to adhere to host tissues, evade host immune defenses, damage host cells and tissues, and spread within the host. Some of the major virulence factors of S. pyogenes are:

• Hyaluronic acid capsule: This is a polysaccharide layer that surrounds the bacterial cell wall and protects it from phagocytosis and complement-mediated lysis. The capsule is composed of hyaluronic acid, which is also found in human connective tissues, making it non-immunogenic and camouflaging the bacteria from host recognition .
• M protein: This is a surface-exposed protein that extends from the cell wall and forms hair-like structures. M protein is the most important virulence factor of S. pyogenes, as it confers resistance to phagocytosis, opsonization, and complement activation. M protein also binds to fibrinogen and blocks the binding of neutrophils to endothelial cells, impairing neutrophil recruitment and inflammation. M protein also mimics host antigens and induces cross-reactive antibodies that can cause autoimmune diseases such as rheumatic fever and glomerulonephritis . There are more than 200 serotypes of M protein based on antigenic variation.
• Hemolysins: These are toxins that lyse red blood cells and other host cells by forming pores in their membranes. S. pyogenes produces two types of hemolysins: streptolysin O (SLO) and streptolysin S (SLS). SLO is oxygen-labile and immunogenic, meaning that it is inactivated by oxygen and induces antibody production. SLO also activates macrophages and induces cytokine release, contributing to inflammation and tissue damage. SLS is oxygen-stable and non-immunogenic, meaning that it remains active in the presence of oxygen and does not elicit an immune response. SLS is responsible for the beta-hemolysis seen around S. pyogenes colonies on blood agar .
• Pyrogenic exotoxins: These are superantigens that stimulate T cells by binding to class II MHC molecules on antigen-presenting cells and T cell receptors, bypassing the normal antigen processing and presentation pathway. This results in massive T cell activation and cytokine release, leading to fever, rash, shock, and organ failure. S. pyogenes produces several types of pyrogenic exotoxins (also called erythrogenic toxins or streptococcal superantigens), such as SpeA, SpeB, SpeC, SpeF, SpeG, SpeH, SpeJ, SpeL, SpeM, SSA, SMEZ, and SmeZ-2 . Some of these toxins are associated with specific diseases caused by S. pyogenes, such as scarlet fever (SpeA), toxic shock syndrome (SpeA, SpeC), and necrotizing fasciitis (SpeB).

• Spreading factors: These are enzymes that degrade extracellular matrix components and facilitate the dissemination of S. pyogenes within the host tissues. Some of the spreading factors produced by S. pyogenes are:

  • Streptokinase: This enzyme converts plasminogen into plasmin, a protease that degrades fibrin clots and other proteins . This allows S. pyogenes to escape from blood clots and invade deeper tissues.
  • Deoxyribonucleases (DNases): These enzymes degrade DNA released from dead host cells or neutrophil extracellular traps (NETs), which are web-like structures composed of DNA and antimicrobial proteins that trap and kill bacteria . By degrading DNA, S. pyogenes reduces the viscosity of pus and liquefies infected tissues.
  • Hyaluronidase: This enzyme cleaves hyaluronic acid, a major component of connective tissue . By breaking down hyaluronic acid, S. pyogenes disrupts the integrity of connective tissue and enhances its spread.
  • Proteases: These enzymes degrade various host proteins involved in immunity or tissue structure . For example, streptococcal cysteine protease A (ScpA) degrades immunoglobulins (IgG), complement components (C3b), chemokines (interleukin-8), fibrinogen, fibronectin, laminin, collagen, elastin, etc.. Another protease called Mac degrades IgG specifically at its hinge region. A third protease called SpyCEP (also known as ScpC) cleaves interleukin-8 and impairs neutrophil chemotaxis.

These virulence factors enable S. pyogenes to colonize different niches in the human body, evade or subvert host immune responses, cause tissue damage and inflammation, and disseminate to cause systemic infections.

Streptococcus pyogenes can cause a variety of infections, ranging from mild to severe and life-threatening. The clinical manifestation depends on the site of infection, the virulence of the strain, and the host immune response. Some of the common infections caused by S. pyogenes are:

• Pharyngitis: This is the most common manifestation of S. pyogenes infection, also known as strep throat. It is characterized by sore throat, fever, swollen lymph nodes, and tonsillar exudates. It usually occurs in children and young adults, especially during winter and spring seasons. It can be complicated by scarlet fever, rheumatic fever, or post-streptococcal glomerulonephritis.
• Scarlet fever: This is a systemic infection that results from the production of pyrogenic exotoxins by some strains of S. pyogenes. It is characterized by a diffuse erythematous rash that begins on the chest and neck and spreads to the rest of the body, sparing the palms and soles. The rash is accompanied by fever, chills, headache, nausea, vomiting, and a strawberry tongue. The rash usually fades after a week, followed by desquamation of the skin.
• Impetigo: This is a superficial skin infection that causes vesicles or pustules that rupture and form honey-colored crusts. It usually affects children and occurs on exposed areas of the face and extremities. It can be complicated by cellulitis, lymphangitis, or glomerulonephritis.
• Cellulitis: This is a deeper infection of the skin and subcutaneous tissue that causes pain, swelling, erythema, and warmth. It usually occurs on the lower extremities or face and can be associated with trauma, insect bites, or skin lesions. It can be complicated by necrotizing fasciitis, bacteremia, or septic arthritis.
• Erysipelas: This is a form of cellulitis that affects the upper dermis and superficial lymphatics. It causes a well-demarcated raised erythematous lesion with a sharp border and a peau d`orange appearance. It usually occurs on the face or lower extremities and can be associated with fever, chills, malaise, and leukocytosis. It can be complicated by bacteremia or septic shock.
• Necrotizing fasciitis: This is a rare but severe infection that causes extensive necrosis of the fascia and subcutaneous tissue. It is characterized by severe pain, edema, erythema, bullae, crepitus, and systemic toxicity. It usually occurs after trauma, surgery, or injection and can affect any part of the body. It can be complicated by myonecrosis, gangrene, septic shock, or multiorgan failure.
• Myositis: This is an inflammation of the skeletal muscle that causes pain, swelling, tenderness, and weakness. It usually occurs as a complication of necrotizing fasciitis or bacteremia and can affect any muscle group. It can be complicated by rhabdomyolysis, renal failure, or compartment syndrome.
• Streptococcal toxic shock syndrome: This is a rare but life-threatening condition that results from the production of superantigens by some strains of S. pyogenes. It is characterized by fever, hypotension, rash, multiorgan dysfunction, and soft tissue necrosis. It usually occurs in association with invasive infections such as necrotizing fasciitis or myositis but can also occur in patients with pharyngitis or impetigo.
• Puerperal fever: This is an infection of the uterus that occurs after childbirth or abortion. It is characterized by fever, abdominal pain, uterine tenderness, foul-smelling lochia (vaginal discharge), and leukocytosis. It can be complicated by endometritis (inflammation of the uterine lining), pelvic abscess (collection of pus in the pelvis), septic thrombophlebitis (inflammation of a vein with a blood clot), or septicemia (blood infection).
• Bacteremia and sepsis: This is an infection of the blood that can occur as a complication of any localized S. pyogenes infection or as a primary infection in immunocompromised patients. It is characterized by fever, chills, hypotension, tachycardia (fast heart rate), tachypnea (fast breathing), and organ dysfunction. It can be complicated by endocarditis (inflammation of the heart valves), meningitis (inflammation of the meninges), osteomyelitis (inflammation of the bone), arthritis (inflammation of the joints), or pneumonia (inflammation of the lungs).

The laboratory diagnosis of Streptococcus pyogenes (group A streptococci) infections can be done by different methods, depending on the type and severity of the infection, the availability of resources, and the clinical setting. The main methods are:

• Smear: A smear is prepared from a throat swab or other specimen and stained with Gram stain. The presence of Gram-positive cocci in chains suggests streptococcal infection, but it cannot differentiate S. pyogenes from other streptococci or confirm the diagnosis.
• Culture: Culture is the gold standard method for the identification of S. pyogenes. The specimen is inoculated on blood agar plates and incubated at 35-37°C for 18-24 hours. S. pyogenes produces β-hemolysis, which is a clear zone of hemolysis around the colonies. The colonies are small, grayish-white, and may have a glossy or matte surface. S. pyogenes is also sensitive to bacitracin, which can be used as a presumptive test .
• Antigen detection tests: Antigen detection tests are rapid tests that can detect streptococcal antigens directly from a throat swab or other specimen. These tests use enzyme immunoassay (EIA) or agglutination techniques to show a positive or negative result within 10-20 minutes. Antigen detection tests are more sensitive and specific than smear, but less sensitive than culture. They are useful for screening patients with sore throat and initiating antibiotic therapy if positive .
• Serologic tests: Serologic tests are used to diagnose post-streptococcal diseases, such as rheumatic fever and glomerulonephritis, which occur after a latent period of weeks to months following an acute S. pyogenes infection. Serologic tests measure the levels of antibodies against various streptococcal antigens, such as anti-streptolysin O (ASO), anti-DNase B, anti-hyaluronidase, anti-streptokinase, and anti-M protein. A rise in antibody titers indicates a recent or current infection with S. pyogenes .
• Molecular tests: Molecular tests are based on the detection of specific nucleic acid sequences of S. pyogenes by using DNA probes or nucleic acid amplification techniques (NAAT). These tests are more sensitive and specific than culture and antigen detection tests, but they are also more expensive and require specialized equipment and expertise. Molecular tests are useful for confirming the diagnosis of S. pyogenes infections, especially in cases of negative culture or antigen detection tests, and for typing and epidemiological studies .

Streptococcus pyogenes infections can range from mild to severe and life-threatening. Therefore, prompt and appropriate treatment is essential to prevent complications and reduce the risk of transmission.

The mainstay of treatment for S. pyogenes infections is antibiotics. The antibiotic of choice for most S. pyogenes infections is penicillin or amoxicillin. These drugs are effective, safe, and inexpensive. They can also prevent the development of post-streptococcal sequelae such as rheumatic fever and glomerulonephritis.

Penicillin or amoxicillin should be given for at least 10 days for pharyngitis, 5 days for impetigo, and 14 days for cellulitis. For patients who are allergic to penicillin, alternative antibiotics include erythromycin, clindamycin, or cephalosporins .

Some S. pyogenes infections may require more aggressive treatment, such as hospitalization, intravenous antibiotics, surgical debridement, or amputation. These include necrotizing fasciitis, streptococcal toxic shock syndrome, bacteremia, sepsis, and puerperal fever . These infections are medical emergencies and require immediate attention.

In addition to antibiotics, supportive care such as pain relief, fever control, hydration, and wound care may be needed for some S. pyogenes infections. Patients with strep throat should also avoid irritants such as smoke, alcohol, and spicy foods. Patients with scarlet fever should apply moisturizers to soothe the skin rash.

The treatment of S. pyogenes infections should be guided by the clinical presentation, the results of laboratory tests, and the local patterns of antibiotic resistance. Patients should be advised to complete the full course of antibiotics and to seek medical attention if their symptoms worsen or do not improve within a few days.

Streptococcus pyogenes infections can be prevented and controlled by various measures that aim to reduce the transmission of the bacteria and to treat the infected individuals promptly and effectively. Some of the prevention and control strategies are:

• Maintenance of personal hygiene: Hand-washing is one of the best ways to prevent the spread of common infections, including strep throat. Hand-washing should be done frequently and thoroughly with soap and water, especially before eating, after coughing or sneezing, after touching skin sores or wounds, and after using the bathroom. Hand sanitizer can also be used when soap and water are not available. Other personal hygiene practices include covering the mouth and nose when coughing or sneezing, using disposable tissues or elbows instead of hands, avoiding sharing personal items such as utensils, cups, toothbrushes, or towels, and keeping the skin clean and dry .
• Protection of others in the home: If someone in the household has a strep infection, they should isolate themselves from others as much as possible until they have completed at least 24 hours of antibiotic treatment. They should also avoid close contact with others, such as kissing, hugging, or sharing food or drinks. They should wash their hands frequently and disinfect common surfaces and objects that may be contaminated with the bacteria, such as countertops, doorknobs, faucets, phones, keyboards, or toys.
• Take prescribed medications: If someone is diagnosed with a strep infection, they should take the prescribed antibiotics exactly as directed by their doctor. They should not stop taking the antibiotics even if they feel better, as this may lead to incomplete treatment and recurrence of infection. They should also inform their doctor if they have any allergies or side effects to the antibiotics. Antibiotics can help reduce the symptoms, prevent complications, and prevent the spread of the infection to others.
• Manage symptoms: While taking antibiotics, someone with a strep infection can also take over-the-counter pain relievers such as ibuprofen or acetaminophen to reduce fever, sore throat, or headache. They should also drink plenty of fluids to stay hydrated and soothe the throat. Warm liquids such as tea, broth, or soup can help ease the discomfort. They can also gargle with salt water or use throat lozenges or sprays to relieve the pain.
• Adjust your diet: Someone with a strep infection may have difficulty swallowing due to a sore throat. They should avoid eating spicy, acidic, or hard foods that may irritate the throat further. Instead, they should eat soft foods that are easy to swallow, such as yogurt, mashed potatoes, scrambled eggs, oatmeal, or pudding. They should also avoid alcohol and caffeine, which can dehydrate the body and worsen the symptoms.
• Rest up: Someone with a strep infection should get enough rest and sleep to help their body fight off the infection. They should also avoid strenuous activities that may strain their heart or lungs until they are fully recovered. They should stay home from work or school until they have completed at least 24 hours of antibiotic treatment and have no fever without using fever-reducing medications.
• Chemoprophylaxis: Prophylactic use of antibiotics may be recommended for some people who are at high risk of developing serious complications from strep infections, such as acute rheumatic fever or rheumatic heart disease. This may include people who have a history of these conditions or who have close contact with someone who has them. Chemoprophylaxis can prevent strep reinfection and further damage to the heart.
• Resource distribution: Governments and health authorities should also consider distributing resources to improve the living conditions and access to health care for populations that are disproportionately affected by strep infections, such as developing countries, indigenous communities, and low socioeconomic areas. These populations may face challenges such as overcrowding, poor sanitation, malnutrition, lack of awareness, and limited availability of diagnostic tests and treatments. Resource distribution can help reduce the burden of disease and health disparities among these groups.

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