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1.
Am J Obstet Gynecol ; 228(4): 463.e1-463.e20, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36126729

RESUMO

BACKGROUND: COVID-19 is caused by the SARS-CoV-2 virus and is associated with critical illness requiring hospitalization, maternal mortality, stillbirth, and preterm birth. SARS-CoV-2 has been shown to induce placental pathology. However, substantial gaps exist in our understanding of the pathophysiology of COVID-19 disease in pregnancy and the long-term impact of SARS-CoV-2 on the placenta and fetus. To what extent a SARS-CoV-2 infection of the placenta alters the placental antiviral innate immune response is not well understood. A dysregulated innate immune response in the setting of maternal COVID-19 disease may increase the risk of inflammatory tissue injury or placental compromise and may contribute to deleterious pregnancy outcomes. OBJECTIVE: We sought to determine the impact of a maternal SARS-CoV-2 infection on placental immune response by evaluating gene expression of a panel of 6 antiviral innate immune mediators that act as biomarkers of the antiviral and interferon cytokine response. Our hypothesis was that a SARS-CoV-2 infection during pregnancy would result in an up-regulated placental antiviral innate immune response. STUDY DESIGN: We performed a case-control study on placental tissues (chorionic villous tissues and chorioamniotic membrane) collected from pregnant patients with (N=140) and without (N=24) COVID-19 disease. We performed real-time quantitative polymerase chain reaction and immunohistochemistry, and the placental histopathology was evaluated. Clinical data were abstracted. Fisher exact test, Pearson correlations, and linear regression models were used to examine proportions and continuous data between patients with active (<10 days since diagnosis) vs recovered COVID-19 (>10 days since diagnosis) at the time of delivery. Secondary regression models adjusted for labor status as a covariate and evaluated potential correlation between placental innate immune gene expression and other variables. RESULTS: SARS-CoV-2 viral RNA was detected in placental tissues from 5 women with COVID-19 and from no controls (0/24, 0%). Only 1 of 5 cases with detectable SARS-CoV-2 viral RNA in placental tissues was confirmed to express SARS-CoV-2 nucleocapsid and spike proteins in syncytiotrophoblast cells. We detected a considerably lower gene expression of 5 critical innate immune mediators (IFNB, IFIT1, MXA, IL6, IL1B) in the chorionic villi and chorioamniotic membranes from women with active or recovered COVID-19 than controls, which remained significant after adjustment for labor status. There were minimal correlations between placental gene expression and other studied variables including gestational age at diagnosis, time interval between COVID-19 diagnosis and delivery, prepregnancy body mass index, COVID-19 disease severity, or placental pathology. CONCLUSION: A maternal SARS-CoV-2 infection was associated with an impaired placental innate immune response in chorionic villous tissues and chorioamniotic membranes that was not correlated with gestational age at COVID-19 diagnosis, time interval from COVID-19 diagnosis to delivery, maternal obesity, disease severity, or placental pathology.


Assuntos
COVID-19 , Complicações Infecciosas na Gravidez , Nascimento Prematuro , Feminino , Gravidez , Humanos , Recém-Nascido , COVID-19/patologia , Placenta/metabolismo , SARS-CoV-2 , Antivirais/metabolismo , Teste para COVID-19 , Estudos de Casos e Controles , Complicações Infecciosas na Gravidez/diagnóstico , Nascimento Prematuro/metabolismo , Imunidade Inata , RNA Viral/metabolismo , Expressão Gênica , Transmissão Vertical de Doenças Infecciosas
2.
Ann Clin Microbiol Antimicrob ; 21(1): 43, 2022 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-36229877

RESUMO

Group B streptococci (GBS) are bacteria that can cause preterm birth and invasive neonatal disease. Heterogeneous expression of virulence factors enables GBS to exist as both commensal bacteria and to become highly invasive. A molecular epidemiological study comparing GBS bacterial traits, genotype and host characteristics may indicate whether it is possible to predict the risk of perinatal invasive GBS disease and more accurately target intrapartum antibiotic prophylaxis. A total of 229 invasive GBS isolates from Swedish pregnant women or neonates were assessed for virulence and phenotypic traits: hemolysis zone, hemolytic pigment (Granada agar), Streptococcus B Carrot Broth (SBCB) assay, CAMP factor, and hyaluronidase activity. Genes regulating hemolytic pigment synthesis (covR/covS, abx1, stk1, stp1) were sequenced. Of the virulence factors and phenotypes assessed, a Granada pigment or SBCB score ≥ 2 captured more than 90% of EOD isolates with excellent inter-rater reliability. High enzyme activity of hyaluronidase was observed in 16% (36/229) of the invasive GBS isolates and notably, in one case of stillbirth. Hyaluronidase activity was also significantly higher in GBS isolates obtained from pregnant/postpartum individuals versus the stillbirth or neonatal invasive isolates (p < 0.001). Sequencing analysis found that abx1 (g.T106I), stk1 (g.T211N), stp1 (g.K469R) and covS (g.V343M) variants were present significantly more often in the higher (Granada pigment score ≥ 2) versus lower pigmented isolates (p < 0.001, each variant). Among the 203 higher Granada pigment scoring isolates, 22 (10.8%) isolates had 3 of the four sequence variants and 10 (4.9%) had 2 of the four sequence variants. Although heterogeneity in GBS virulence factor expression was observed, the vast majority were more highly pigmented and contained several common sequence variants in genes regulating pigment synthesis. High activity of hyaluronidase may increase risk for stillbirth and invasive disease in pregnant or postpartum individuals. Our findings suggest that testing for GBS pigmentation and hyaluronidase may, albeit imperfectly, identify pregnant people at risk for invasive disease and represent a step towards a personalized medical approach for the administration of intrapartum antibiotic prophylaxis.


Assuntos
Nascimento Prematuro , Infecções Estreptocócicas , Ágar/metabolismo , Ágar/uso terapêutico , Antibacterianos/uso terapêutico , Feminino , Genótipo , Humanos , Hialuronoglucosaminidase/genética , Hialuronoglucosaminidase/metabolismo , Hialuronoglucosaminidase/uso terapêutico , Recém-Nascido , Fenótipo , Gravidez , Gestantes , Nascimento Prematuro/tratamento farmacológico , Reprodutibilidade dos Testes , Natimorto , Infecções Estreptocócicas/microbiologia , Streptococcus agalactiae , Suécia/epidemiologia , Virulência/genética , Fatores de Virulência/genética , Fatores de Virulência/metabolismo
3.
Front Microbiol ; 13: 820365, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35265059

RESUMO

Group B streptococci (GBS) are Gram-positive ß-hemolytic bacteria that can cause serious and life-threatening infections in neonates manifesting as sepsis, pneumonia, meningitis, osteomyelitis, and/or septic arthritis. Invasive GBS infections in neonates in the first week of life are referred to as early-onset disease (EOD) and thought to be acquired by the fetus through exposure to GBS in utero or to vaginal fluids during birth. Late-onset disease (LOD) refers to invasive GBS infections between 7 and 89 days of life. LOD transmission routes are incompletely understood, but may include breast milk, household contacts, nosocomial, or community sources. Invasive GBS infections and particularly meningitis may result in significant neurodevelopmental injury and long-term disability that persists into childhood and adulthood. Globally, EOD and LOD occur in more than 300,000 neonates and infants annually, resulting in 90,000 infant deaths and leaving more than 10,000 infants with a lifelong disability. In this review, we discuss the clinical impact of invasive GBS neonatal infections and then summarize virulence and host factors that allow the bacteria to exploit the developing neonatal immune system and target organs. Specifically, we consider the mechanisms known to enable GBS invasion into the neonatal lung, blood vessels and brain. Understanding mechanisms of GBS invasion and pathogenesis relevant to infections in the neonate and infant may inform the development of therapeutics to prevent or mitigate injury, as well as improve risk stratification.

4.
Front Cell Infect Microbiol ; 11: 720789, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34540718

RESUMO

Group B streptococcus (GBS) is a gram-positive bacteria that asymptomatically colonizes the vaginal tract. However, during pregnancy maternal GBS colonization greatly predisposes the mother and baby to a wide range of adverse outcomes, including preterm birth (PTB), stillbirth, and neonatal infection. Although many mechanisms involved in GBS pathogenesis are partially elucidated, there is currently no approved GBS vaccine. The development of a safe and effective vaccine that can be administered during or prior to pregnancy remains a principal objective in the field, because current antibiotic-based therapeutic strategies do not eliminate all cases of invasive GBS infections. Herein, we review our understanding of GBS disease pathogenesis at the maternal-fetal interface with a focus on the bacterial virulence factors and host defenses that modulate the outcome of infection. We follow GBS along its path from an asymptomatic colonizer of the vagina to an invasive pathogen at the maternal-fetal interface, noting factors critical for vaginal colonization, ascending infection, and vertical transmission to the fetus. Finally, at each stage of infection we emphasize important host-pathogen interactions, which, if targeted therapeutically, may help to reduce the global burden of GBS.


Assuntos
Complicações Infecciosas na Gravidez , Nascimento Prematuro , Infecções Estreptocócicas , Feminino , Humanos , Recém-Nascido , Transmissão Vertical de Doenças Infecciosas , Gravidez , Streptococcus agalactiae , Vagina
5.
mBio ; 12(1)2021 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-33402537

RESUMO

Invasive bacterial infections during pregnancy are a major risk factor for preterm birth, stillbirth, and fetal injury. Group B streptococci (GBS) are Gram-positive bacteria that asymptomatically colonize the lower genital tract but infect the amniotic fluid and induce preterm birth or stillbirth. Experimental models that closely emulate human pregnancy are pivotal for the development of successful strategies to prevent these adverse pregnancy outcomes. Using a unique nonhuman primate model that mimics human pregnancy and informs temporal events surrounding amniotic cavity invasion and preterm labor, we show that the animals inoculated with hyaluronidase (HylB)-expressing GBS consistently exhibited microbial invasion into the amniotic cavity, fetal bacteremia, and preterm labor. Although delayed cytokine responses were observed at the maternal-fetal interface, increased prostaglandin and matrix metalloproteinase levels in these animals likely mediated preterm labor. HylB-proficient GBS dampened reactive oxygen species production and exhibited increased resistance to neutrophils compared to an isogenic mutant. Together, these findings demonstrate how a bacterial enzyme promotes GBS amniotic cavity invasion and preterm labor in a model that closely resembles human pregnancy.IMPORTANCE Group B streptococci (GBS) are bacteria that commonly reside in the female lower genital tract as asymptomatic members of the microbiota. However, during pregnancy, GBS can infect tissues at the maternal-fetal interface, leading to preterm birth, stillbirth, or fetal injury. Understanding how GBS evade host defenses during pregnancy is key to developing improved preventive therapies for these adverse outcomes. In this study, we used a unique nonhuman primate model to show that an enzyme secreted by GBS, hyaluronidase (HylB) promotes bacterial invasion into the amniotic cavity and fetus. Although delayed immune responses were seen at the maternal-fetal interface, animals infected with hyaluronidase-expressing GBS exhibited premature cervical ripening and preterm labor. These observations reveal that HylB is a crucial GBS virulence factor that promotes bacterial invasion and preterm labor in a pregnancy model that closely emulates human pregnancy. Therefore, hyaluronidase inhibitors may be useful in therapeutic strategies against ascending GBS infection.


Assuntos
Hialuronoglucosaminidase/metabolismo , Neutrófilos/imunologia , Trabalho de Parto Prematuro/imunologia , Infecções Estreptocócicas/imunologia , Streptococcus agalactiae/metabolismo , Líquido Amniótico/microbiologia , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Hialuronoglucosaminidase/genética , Inflamação , Pulmão/microbiologia , Pulmão/patologia , Macaca nemestrina , Neutrófilos/microbiologia , Gravidez , Nascimento Prematuro , Primatas , Infecções Estreptocócicas/metabolismo , Infecções Estreptocócicas/microbiologia , Streptococcus agalactiae/enzimologia , Streptococcus agalactiae/genética , Streptococcus agalactiae/imunologia
6.
Front Immunol ; 11: 770, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32425945

RESUMO

Leukocyte activation within the chorioamniotic membranes is strongly associated with inflammation and preterm labor (PTL). We hypothesized that prophylaxis with a broad-spectrum chemokine inhibitor (BSCI) would downregulate the inflammatory microenvironment induced by Group B Streptococcus (GBS, Streptococcus agalactiae) to suppress PTL and microbial invasion of the amniotic cavity (MIAC). To correlate BSCI administration with PTL and MIAC, we used a unique chronically catheterized non-human primate model of Group B Streptococcus (GBS)-induced PTL. In the early third trimester (128-138 days gestation; ~29-32 weeks human pregnancy), animals received choriodecidual inoculations of either: (1) saline (N = 6), (2) GBS, 1-5 × 108 colony forming units (CFU)/ml; N = 5), or (3) pre-treatment and daily infusions of a BSCI (10 mg/kg intravenous and intra-amniotic) with GBS (1-5 × 108 CFU/ml; N = 4). We measured amniotic cavity pressure (uterine contraction strength) and sampled amniotic fluid (AF) and maternal blood serially and cord blood at delivery. Cesarean section was performed 3 days post-inoculation or earlier for PTL. Data analysis used Fisher's exact test, Wilcoxon rank sum and one-way ANOVA with Bonferroni correction. Saline inoculation did not induce PTL or infectious sequelae. In contrast, GBS inoculation typically induced PTL (4/5, 80%), MIAC and fetal bacteremia (3/5; 60%). Remarkably, PTL did not occur in the BSCI+GBS group (0/4, 0%; p = 0.02 vs. GBS), despite MIAC and fetal bacteremia in all cases (4/4; 100%). Compared to the GBS group, BSCI prophylaxis was associated with significantly lower cytokine levels including lower IL-8 in amniotic fluid (p = 0.03), TNF-α in fetal plasma (p < 0.05), IFN-α and IL-7 in the fetal lung (p = 0.02) and IL-18, IL-2, and IL-7 in the fetal brain (p = 0.03). Neutrophilic chorioamnionitis was common in the BSCI and GBS groups, but was more severe in the BSCI+GBS group with greater myeloperoxidase staining (granulocyte marker) in the amnion and chorion (p < 0.05 vs. GBS). Collectively, these observations indicate that blocking the chemokine response to infection powerfully suppressed uterine contractility, PTL and the cytokine response, but did not prevent MIAC and fetal pneumonia. Development of PTL immunotherapies should occur in tandem with evaluation for AF microbes and consideration for antibiotic therapy.


Assuntos
Líquido Amniótico/microbiologia , Quimiocinas/antagonistas & inibidores , Trabalho de Parto Prematuro/prevenção & controle , Streptococcus agalactiae/patogenicidade , Animais , Animais Recém-Nascidos , Cesárea , Citocinas/análise , Feminino , Macrófagos/fisiologia , Morbidade , Neutrófilos/efeitos dos fármacos , Neutrófilos/fisiologia , Gravidez , Primatas , Infecções Estreptocócicas/complicações
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