T regulatory cells that express the transcription factor Foxp3 (Foxp3+
Treg) promote tissue homeostasis in several settings. We now report that
symbiotic members of the human gut microbiota induce a distinct Treg population
in the mouse colon, which constrains immuno-inflammatory responses. This
induction, which we find to map to a broad, but specific, array of individual
bacterial species, requires the transcription factor Rorγ, paradoxically
in that Rorγ is thought to antagonize FoxP3 and promote T helper 17
(Th17) cell differentiation. Rorγ's transcriptional footprint differs in
colonic Tregs and Th17 cells, controlling important effector molecules.
Rorγ, and the Tregs that express it, contribute substantially to
regulating colonic Th1/Th17 inflammation. Thus, the marked context-specificity
of Rorγ results in very different outcomes even in closely related
cell-types.
Background
Pregnant women are at increased risk for severe outcomes from coronavirus disease 2019 (COVID-19), but the pathophysiology underlying this increased morbidity and its potential effect on the developing fetus is not well understood.
Methods
We assessed placental histology, ACE2 expression, and viral and immune dynamics at the term placenta in pregnant women with and without respiratory severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
Findings
The majority (13 of 15) of placentas analyzed had no detectable viral RNA. ACE2 was detected by immunohistochemistry in syncytiotrophoblast cells of the normal placenta during early pregnancy but was rarely seen in healthy placentas at full term, suggesting that low ACE2 expression may protect the term placenta from viral infection. Using immortalized cell lines and primary isolated placental cells, we found that cytotrophoblasts, the trophoblast stem cells and precursors to syncytiotrophoblasts, rather than syncytiotrophoblasts or Hofbauer cells, are most vulnerable to SARS-CoV-2 infection
in vitro
. To better understand potential immune mechanisms shielding placental cells from infection
in vivo
, we performed bulk and single-cell transcriptomics analyses and found that the maternal-fetal interface of SARS-CoV-2-infected women exhibited robust immune responses, including increased activation of natural killer (NK) and T cells, increased expression of interferon-related genes, as well as markers associated with pregnancy complications such as preeclampsia.
Conclusions
SARS-CoV-2 infection in late pregnancy is associated with immune activation at the maternal-fetal interface even in the absence of detectable local viral invasion.
Funding
NIH (T32GM007205, F30HD093350, K23MH118999, R01AI157488, U01DA040588) and Fast Grant funding support from Emergent Ventures at the Mercatus Center.
Background: Astrocytomas are the most common type of primary central nervous system tumors. They are frequently associated with genetic mutations that deregulate cell cycle and render these tumors resistant to apoptosis. STAT3, signal transducer and activator of transcription 3, participates in several human cancers by inducing cell proliferation and inhibiting apoptosis and is frequently activated in astrocytomas.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.