Genetically distinct Group B Streptococcus strains induce varying macrophage cytokine responses

Group B Streptococcus (GBS) is an opportunistic bacterial pathogen that can contribute to the induction of preterm birth in colonized pregnant women and to severe neonatal disease. Many questions regarding the mechanisms that drive GBS-associated pathogenesis remain unanswered, and it is not yet clear why virulence has been observed to vary so extensively across GBS strains. Previously, we demonstrated that GBS strains of different sequence types (STs) and capsule (CPS) types induce different cytokine profiles in infected THP-1 macrophage-like cells. Here, we have expanded on these studies by utilizing the same set of genetically diverse GBS isolates to assess ST and CPS-specific differences in upstream cell death and inflammatory signaling pathways. Our results demonstrate that particularly virulent STs and CPS types, such as the ST-17 and CPS III groups, induce enhanced JNK and NFκB pathway activation following GBS infection of macrophages when compared with other ST or CPS groups. Additionally, we found that ST-17, CPS III and CPS V GBS strains induce the greatest levels of macrophage cell death during infection and exhibit a more pronounced ability to be internalized and to survive in macrophages following phagocytosis. These data provide further support for the hypothesis that variable host innate immune responses to GBS, which significantly impact pathogenesis, stem in part from genotypic and phenotypic differences among GBS isolates. These and similar studies may inform the development of improved diagnostic, preventive, or therapeutic strategies targeting invasive GBS infections.

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Preterm Infants Have Deficient Monocyte and Lymphocyte Cytokine Responses to Group B Streptococcus

Infection and Immunity ◽

10.1128/iai.00535-10 ◽

2011 ◽

Vol 79 (4) ◽

pp. 1588-1596 ◽

Cited By ~ 40

Author(s):

Andrew J. Currie ◽

Samantha Curtis ◽

Tobias Strunk ◽

Karen Riley ◽

Khemanganee Liyanage ◽

...

Keyword(s):

Preterm Infants ◽

Late Onset ◽

Group B Streptococcus ◽

Term Infants ◽

Very Preterm Infants ◽

Immunological Responses ◽

Very Preterm ◽

Cytokine Responses ◽

Late Onset Sepsis ◽

Group B

ABSTRACTGroup B streptococcus (GBS) is an important cause of early- and late-onset sepsis in the newborn. Preterm infants have markedly increased susceptibility and worse outcomes, but their immunological responses to GBS are poorly defined. We compared mononuclear cell and whole-blood cytokine responses to heat-killed GBS (HKGBS) of preterm infants (gestational age [GA], 26 to 33 weeks), term infants, and healthy adults. We investigated the kinetics and cell source of induced cytokines and quantified HKGBS phagocytosis. HKGBS-induced tumor necrosis factor (TNF) and interleukin 6 (IL-6) secretion was significantly impaired in preterm infants compared to that in term infants and adults. These cytokines were predominantly monocytic in origin, and production was intrinsically linked to HKGBS phagocytosis. Very preterm infants (GA, <30 weeks) had fewer cytokine-producing monocytes, but nonopsonic phagocytosis ability was comparable to that for term infants and adults. Exogenous complement supplementation increased phagocytosis in all groups, as well as the proportion of preterm monocytes producing IL-6, but for very preterm infants, responses were still deficient. Similar defective preterm monocyte responses were observed in fresh whole cord blood stimulated with live GBS. Lymphocyte-associated cytokines were significantly deficient for both preterm and term infants compared to levels for adults. These findings indicate that a subset of preterm monocytes do not respond to GBS, a defect compounded by generalized weaker lymphocyte responses in newborns. Together these deficient responses may increase the susceptibility of preterm infants to GBS infection.

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