Streptococcus Agalactiae

By Iris Andrea Garcia and Claudia Cora

Introduction

Streptococcus agalactiae, also known as group B streptococcus (GBS), is an opportunistic gram-positive bacterium that is normally part of the human gut environment; the microbiota. It colonizes 30% of healthy human adults’ gastrointestinal and genitourinary tracts (urinary and vaginal). Normally, S. agalactiae is harmless and many healthy adults live a life without any disease. However, GBS can cause a severe invasive infection in immunocompromised patients like newborns, elderly and patients with underlying diseases such as diabetes, cirrhosis, cancer, AIDS. In dairy cattle, the bacteria is a common pathogen and infects the udder of many cows, leading to inflammation of the udder and reduced milk production, commonly known as mastitis. In humans, GBS infections include urinary tract infection (UTI), skin and soft-tissue infection, meningitis and bacteremia (infection of blood). S. agalactiae is recognized as the leading cause of invasive newborn infections and is transmitted to the fetus via the placenta by the mother during pregnancy or after birth from the external environment.

Figure 1. Streptococcus agalactiae. Source : Public Health Image Library, Centers for Disease Control and Prevention, Ekkert A. (2013) https://phil.cdc.gov/Details.aspx?pid=22882

Disease

S. agalactiae infections in newborns are divided into two categories: early-onset disease (EOD), which affects babies aged 0 to 6 days, and late-onset disease (LOD), which affects babies aged 7 to 90 days. Early-onset infection is caused by the transmission of S. agalactiae from pregnant women to the fetus via the placenta, also referred to as vertical transmission. In vertical transmission, GBS from the maternal gastrointestinal and genitourinary flora infiltrates the uterine compartment and reaches the lungs of the fetus. Once in the lungs, GBS displays a multitude of virulence factors to successfully invade the host cell and reach the bloodstream of the newborn. Early-onset disease symptoms include bloodstream infection, pneumonia, and sepsis; the body’s severe and life-threatening response to infection, which can develop as early as the day of birth. Late-onset infection is mostly acquired horizontally from the mother, as the infant passes through the vaginal tract during birth, or through colonized household contact which causes meningitis and bacteremia. 

In pregnant women even if there are no apparent symptoms, it can cause low birth weight, pre-term delivery and premature ruptures of the membranes. Heavily colonized pregnant women can develop symptoms such as inflammation of the membranes that surround the fetus or the amniotic fluid in which the fetus floats, bacteremia and sepsis.

Figure 2. GBS disease in pregnant mothers and fetuses. GBS ascension into the uterus from the lower genital tract and invasion of the amniotic cavity and fetus. Source: Brokaw et al. 2021. https://www.frontiersin.org/articles/10.3389/fcimb.2021.720789/full

Epidemiology

Streptococcus agalactiae is a very common commensal bacteria of the gut and vaginal tracts of humans and are part of their microbiotas. In an epidemiology study, vaginal colonization of S. agalactiae was found in 16% of pregnant women and 16% of non-pregnant women, as opposed to only 4% in the gut in pregnant and non-pregnant women. As a consequence of a weaker immune system of the mother to tolerate the development of the fetus, this opportunistic pathogen crosses the placental membrane and causes meningitis and sepsis in newborns. There is also an increase in GBS incidence among the elderly causing bacteremia and meningitis. Slotved and Hoffmann study showed that EOD had a higher incidence than LOD, but still remains low and stable in Denmark over a period of 13 years. However, the increasing trend in GBS incidence in elderly is most likely due to the increase in prevalence of comorbidities, mostly chronic diseases, in the aging population of developed countries.

Virulence Factors

Streptococcus agalactiae has many virulence factors which are tools to facilitate colonization and infection of a cell in the gut or in the vaginal tract of the host. S. agalactiae has four main groups of functional virulence factors that aid in infection which are; pore-forming, immune evading, antimicrobial proteins (AMPs) resisting and cell-adhering and invading. The pore-forming factors are proteins that form a pore on the surface of the cell to kill it. In GBS, ꞵ-hemolysin and cytolysin pore-forming proteins can also impair cardiac and liver functions. 

Immune evasion factors such as sialic acid capsular polysaccharide or superoxide dismutase are strategies that make the bacteria invisible to the immune system. Sialic acid can mimic the host cell surface and superoxide dismutase breaks down superoxide produced by macrophages in an attempt to kill the bacteria, as a defense mechanism. Resistance to AMPs is done by the alanylation of lipoteichoic acid, which is a negatively charged molecule on the bacteria surface that is the target of AMPs. Alanylation makes lipoteichoic acid positively charged to repel AMPs that are positively charged, like two north pole magnets. 

Cell-adhesion and invasion factors like fibrinogen-binding proteins A and B simply aid in the adhesion of the bacteria to the host cell and in the penetration process. The bacteria will mostly bind to fibrinogen molecules which are mostly present in the extracellular matrix (ECM); a physical scaffold on which the host cells adhere and interact with the external environment. By anchoring itself to the ECM, the bacterial cell can bind to the target cell and invade it.

Figure 3. The functions of the virulence factors of S. agalactiae for a successful infection on the host cells. Source : Claudia Cora, 2021 produced with Biorender.

Treatment

Beta-lactam antibiotics, notably penicillin G and ampicillin, are often used to treat Streptococcus agalactiae. As alternatives, penicillin-allergic patients are treated with vancomycin and clindamycin. However, in recent years, there has been a surge in clindamycin resistance in both newborn and adult infections.

Infected newborns are treated with several antibiotic combinations before the presence of S. agalactiae is established, and once the presence of S. agalactiae is confirmed, penicillin G is the medicine of choice. Supportive care, such as ventilatory support, is also provided to infected infants. Currently, there is no vaccination available against S. agalactiae. However, some steps may be taken to reduce the chance of the mother infecting the child. The American College of Obstetricians and Gynecologists recommend that pregnant women get tested for GBS bacteria between weeks 36 to 37 of pregnancy. If the pregnant woman tests positive, the fetus is at significant risk of infection. Antibiotics are thus given during labour rather than before because the bacteria will have time to multiply again before labour begins.

References

Ballard MS, Schønheyder HC, Knudsen JD, Lyytikäinen O, Dryden M, Kennedy KJ, Valiquette L, Pinholt M, Jacobsson G, Laupland KB. 2016. The changing epidemiology of group b streptococcus bloodstream infection: A multi-national population-based assessment. Infect Dis (Lond). 48(5):386-391.

Brimil N, Barthell E, Heindrichs U, Kuhn M, Lütticken R, Spellerberg B. 2006. Epidemiology of streptococcus agalactiae colonization in germany. International Journal of Medical Microbiology. 296(1):39-44.

Slotved H-C, Hoffmann S. 2020. The epidemiology of invasive group b streptococcus in denmark from 2005 to 2018. Frontiers in Public Health. 8(40).

Martins ER, Pedroso-Roussado C, Melo-Cristino J, Ramirez M, Portuguese Group for the Study of Streptococcal I. 2017. Streptococcus agalactiae causing neonatal infections in portugal (2005-2015): Diversification and emergence of a cc17/pi-2b multidrug resistant sublineage. Front Microbiol.8:499-499. https://pubmed.ncbi.nlm.nih.gov/28400757

Patras KA, Nizet V. 2018. Group b streptococcal maternal colonization and neonatal disease: Molecular mechanisms and preventative approaches. Frontiers in Pediatrics. [accessed 2018-February-22];6(27)https://www.frontiersin.org/article/10.3389/fped.2018.00027. doi:10.3389/fped.2018.00027

Puopolo KM, Baker CJ. Oct 12 2021. Group b streptococcal infection in neonates and young infants UpToDate. https://www-uptodate-com.proxy3.library.mcgill.ca/contents/group-b-streptococcal-infection-in-neonates-and-young-infants?search=Group%20B%20streptococcal%20infections%20in%20nonpregnant%20adults&topicRef=3171&source=see_link

Puopolo KM, Baker CJ. Sept 24 2019. Group b streptococcal infection in pregnant womenhttps://www-uptodate-com.proxy3.library.mcgill.ca/contents/group-b-streptococcal-infection-in-neonates-and-young-infants?search=Group%20B%20streptococcal%20infections%20in%20nonpregnant%20adults&topicRef=3171&source=see_link

Puopolo KM, Lynfield R, Cummings JJ, Committee On F, Newborn, Committee On Infectious D, Hand I, Adams-Chapman I, Poindexter B, Stewart DL et al. 2019. Management of infants at risk for group b streptococcal disease. Pediatrics.144(2)https://doi.org/10.1542/peds.2019-1881. doi:10.1542/peds.2019-1881.

Rajagopal L. 2009. Understanding the regulation of group b streptococcal virulence factors. Future Microbiology. 4(2):201-221.

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