Group B Strep and Pregnancy

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This artistic recreation, based on scanning electron microscopy (SEM), depicts a three-dimensional (3D), computer-generated image, of a group of Gram-positive, Streptococcus agalactiae (group B Streptococcus) bacteria. Photo Credit: Alissa Eckert, who is a medical illustrator at the CDC.

By Shawn Ruiz

Group B Strep (GBS), also known as Streptococcus agalactiae, is a Gram-positive, beta-hemolytic, catalase-negative, facultative anaerobe that is a normal component of the gastrointestinal and genitourinary tracts[1]. In fact, GBS colonizes the gastrointestinal and genitourinary tracts of up to 50% of healthy adults[2]. Most healthy adults who are colonized by GBS will not experience any symptoms or GBS-related infections. While the bacteria is usually harmless in healthy adults, it is a major cause of meningitis, pneumonia, and and sepsis in neonates[3]. Moreover, GBS is the leading infectious cause of neonatal mortality and morbidity in the United States; between four and six percent of babies who develop GBS disease die[4][5]. GBS causes both early onset (<7 days old) and late onset (7-90 days old) infections in neonates[4]. The main risk factor for an early-onset GBS infection in a neonate is colonization of a birthing person's genital tract with Group B strep during labor[4]. About one in four pregnant individuals carry GBS in their body[5]. If the bacteria is present in a pregnant person, it can be directly transferred to their baby in a multitude of ways. For example, GBS can travel from the vagina into the amniotic fluid where the baby can ingest it. The baby can also come into contact with the bacteria as they make their way down the birth canal[3]. In the early 1990s, the early GBS infection rate was 1.7 cases per 1,000 births[3]. In an effort to decrease this infection rate, the American Congress of Obstetricians and Gynecologists and the American Academy of Pediatrics recommended screening pregnant individuals for GBS before they go into labor[3]. As a result, it is now common practice to screen pregnant individuals for GBS at some point between 35 and 37 weeks of pregnancy[5]. Pregnant people who test positive for GBS are treated with intravenous antibiotics during labor[5]. Penicillin and ampicillin are the recommended antibiotics for intrapartum GBS prophylaxis[6]. If a pregnant person tests positive for GBS and they are treated with antibiotics during labor, the risk of their neonate developing a serious, life-threatening GBS infection drops by 80% [3]. Early GBS infection rates in the United States have significantly dropped (0.25 cases per 1,000 births) since these preventative measures went into effect around 1995[3]. While intrapartum prophylaxis to prevent GBS transmission from the birthing individual to their neonate during labor and delivery has proven to be effective, this preventative measure does not target in utero infections that occur earlier in pregnancy, and little is known about the mechanisms that result in the infection of the amniotic cavity[7]. In utero GBS infections have devastating effects, including preterm birth and mortality in both the pregnant person and their baby[7]. That said, the it is critical that researchers and public health officials work toward understanding exactly how GBS infects the amniotic cavity.

Section 1

Figure 2. Primary hAECs were isolated from chorioamniotic membranes and the percent adherence of GBS WT, isogenic ΔcovR, ΔcovRΔcylE, and ΔcylE mutants were compared[7].[1].
Figure 3. Primary hAECs were isolated from chorioamniotic the percent invasion of GBS WT, isogenic ΔcovR, ΔcovRΔcylE, and ΔcylE mutants were compared[7]. [2].

GBS has been isolated from the amniotic fluid of birthing people with intact chorioamniotic membranes, suggesting that GBS is capable of invading and breaching amniotic epithelium and chorioamnion[7][8][9][10][11]. This led Whidbey et al. to hypothesize that “intra-amniotic GBS infections in patients with intact placenta or chorioamniotic membranes may be due to elevated virulence factor expression”[7][8][9][10][11].Previous studies showed that the expression of GBS virulence genes is regulated by a two-component regulatory system: COVR/S[7][12][13][14]. More specifically, COVR/S was described to repress a multitude of GBS virulence genes, including the cyl operon, which contains the cylE gene that is that is important for the production of the pluripotent toxin, hemolysin [7][12][13][14]. In order to test whether or not increased expression of GBS virulence genes promotes the invasion of amniotic epithelium, Whidbey et al. compared the abilities of wild-type (WT) GBS and hyper-hemolytic GBS (ΔcovR) GBS to adhere to and invade human amniotic epithelial cells (hAEC)[7].The hAECs were isolated and cultured from “normal, term placentas obtained immediately after cesarean delivery from” birthing people without labor[7]. Non-hemolytic GBS strains (ΔcovRΔcylE and ΔcylE) were also included in the experiment to investigate hemolysin’s role in GBS strains’ ability to adhere to and invade hAECs[7][15]. The results suggest that all GBS strains adhered to hAECs, as seen in Figure 2.Notably, as shown in Figure 3, WT GBS invaded hAECs (~4% invasion), non-hemolytic GBS showed a significantly decreased invasion when compared to the WT (~0.3% invasion), and the hyper-hemolytic strain (ΔcovR) was significantly more invasive when compared to the WT (~80% invasion)[7].In sum, Whidbey et al. concluded that hemolysin promotes GBS invasion of hAECs.

Next, Whidbey et al. investigated if the increased expression of hemolysin in the hyper-hemolytic GBS strain (ΔcovR) activates an inflammatory response[7]. Whidbey et al. isolated RNA from GBS-infected hAECs four hours after infection, and they used qRT-PCR to examine any changes in the expression of inflammatory genes[7][16]. The results, depicted in Figure 4, suggest that infection with ΔcovR caused a significant increase in the transcription of cytokines (e.g., IL-6 and IL-8) in hAECs[7]The increase in the expression of inflammatory genes in hAECS infected with ΔcovR was abolished in hAECs infected with the non-hemolytic strain, ΔcovRΔcylE. In sum, hAECs that were infected with the hyper-hemolytic GBS strain, ΔcovR, did show an inflammatory response. 

Figure 4. Whidbey et al. isolated RNA from hAECs infected with either WT GBS COH1 or isogenic ΔcovR, ΔcovRΔcylE, and ΔcylE mutants at 4 h after infection. qRT-PCR was performed on the RNA, and to examine the expression of cytokines/chemokines. "Data shown are the mean and SD obtained from hAECs that were isolated from three independent placentas, performed in triplicate (n = 3; **, P = 0.007; *, P = 0.03, Student’s t test, error bars ± SD)[7]."[3].

It is known that microbial toxins use the nuclear transcription factor, NF-𝜅B, which is recruited from the cytoplasm to the nucleus, to activate inflammatory signaling pathways[17]. Given that hAECs that were infected with ΔcovR showed an inflammatory response, Whidbey et al. investigated whether or not the increase in the expression of pro-inflammatory genes was associated with the nuclear recruitment/localization of NF-𝜅B[7].Whidbey et al. isolated total nuclear and cytoplasmic proteins from infected and uninfected hAECs, and they resolved them on 10% SDS-PAGE and Western blots[7]. As shown in Figure 5,hAECs that were infected with the hyper-hemolytic GBS strain (ΔcovR) showed a 2.5 fold increase in the nuclear recruitment of  NF-𝜅B[7].

Figure 5. Whidbey et al. performed Western Blots of nuclear and cytoplasmic proteins in GBS-infected hAECs(NF-𝜅B antibody). N and C stand for nuclear and cytoplasmic[7][4].

Despite finding that hemolysin is associated with an increase in the expression of pro-inflammatory genes, as well as the nuclear recruitment of NF-𝜅B, Whidbey et al. still did not know whether or not the presence of hemolysin accelerates the failure of the human amniotic epithelial barrier[7]. To examine this, Whidbey et al. monitored the changes in transepithelial electrical resistance across hAEC using electric cell-substrate impedance sensing[7][18]. hAECs that were infected with the hyper-hemolytic strain (ΔcovR) showed an accelerated decrease in their barrier resistance compared to hAECs that were infected with WT GBS[7].

Section 3

Include some current research, with at least one figure showing data.

Section 4



Authored for BIOL 238 Microbiology, taught by Joan Slonczewski, 2021, Kenyon College.

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