bims-reprim 2021-04-25 papers

Issue of 2021–04–25
three papers selected by
Iva Filipovic, Karolinska Institutet

Immunity. 2021 Apr 19. pii: S1074-7613(21)00133-3. [Epub ahead of print]

The CD94/NKG2A inhibitory receptor educates uterine NK cells to optimize pregnancy outcomes in humans and mice.

Norman Shreeve, Delphine Depierreux, Delia Hawkes, James A Traherne, Ulla Sovio, Oisin Huhn, Jyothi Jayaraman, Amir Horowitz, Hormas Ghadially, John R B Perry, Ashley Moffett, John G Sled, Andrew M Sharkey, Francesco Colucci.

The conserved CD94/NKG2A inhibitory receptor is expressed by nearly all human and ∼50% of mouse uterine natural killer (uNK) cells. Binding human HLA-E and mouse Qa-1, NKG2A drives NK cell education, a process of unknown physiological importance influenced by HLA-B alleles. Here, we show that NKG2A genetic ablation in dams mated with wild-type males caused suboptimal maternal vascular responses in pregnancy, accompanied by perturbed placental gene expression, reduced fetal weight, greater rates of smaller fetuses with asymmetric growth, and abnormal brain development. These are features of the human syndrome pre-eclampsia. In a genome-wide association study of 7,219 pre-eclampsia cases, we found a 7% greater relative risk associated with the maternal HLA-B allele that does not favor NKG2A education. These results show that the maternal HLA-B→HLA-E→NKG2A pathway contributes to healthy pregnancy and may have repercussions on offspring health, thus establishing the physiological relevance for NK cell education. VIDEO ABSTRACT.

Keywords: HLA-B; HLA-E; NK cells; NKG2A; asymmetric fetal growth; inhibitory receptors; placenta; pregnancy; uterine natural killer cells

DOI: https://doi.org/10.1016/j.immuni.2021.03.021

Med (N Y). 2021 Apr 13.

SARS-CoV-2 colonization of maternal and fetal cells of the human placenta promotes alteration of local renin-angiotensin system.

Sonam Verma, Chetanchandra S Joshi, Rachel B Silverstein, Mai He, Ebony B Carter, Indira U Mysorekar.

Background: SARS-CoV-2 infection appears to increase the risk of adverse pregnancy outcomes such as preeclampsia in pregnant women. The mechanism(s) by which this occurs remains unclear.
Methods: We investigated the pathophysiology of SARS-CoV-2 at maternal-fetal interface in pregnant women who tested positive for the virus using RNA in situ hybridization (viral RNA), immunohistochemistry, and hematoxylin and eosin staining. To investigate whether viral infection alters the renin angiotensin system (RAS) in placenta which controls blood pressure, we treated human trophoblasts with recombinant Spike protein or a live modified virus with a vesicular stomatitis viral backbone expressing Spike protein (VSV-S).
Findings: Viral colonization was highest in maternal decidua, fetal trophoblasts, Hofbauer cells, and in placentas delivered prematurely. We localized SARS-CoV-2 to cells expressing Angiotensin-converting enzyme 2 (ACE2), and demonstrate that infected placentas had significantly reduced ACE2. In response to both Spike protein and VSV-S, cellular ACE2 decreased while Angiotensin II receptor type 1 (AT1R) increased with concomitant increase in soluble fms-like tyrosine kinase-1(sFlt1). Viral infection decreased pro-angiogenic factors, AT2R and Placental growth factor, which competitively binds to sFlt1. Sera from infected pregnant women had elevated levels of sFlt1 and Angiotensin II type 1-Receptor Autoantibodies prior to delivery, both signatory markers of preeclampsia.
Conclusions: SARS-CoV-2 colonizes ACE2-expressing maternal and fetal cells in the placenta. Infection in pregnant women correlates with alteration of placental RAS. As RAS regulates blood pressure, SARS-CoV-2 infection may thus increase adverse hemodynamic outcomes such as preeclampsia in pregnant women.
Funding: NIH/NICHD grants R01 HD091218 and 3R01HD091218-04S1 (RADx-UP Supplement).

Keywords: ACE2; AT1R; PIGF; decidua; extravillous trophoblasts; placenta; preeclampsia; pregnancy; sFlt1

DOI: https://doi.org/10.1016/j.medj.2021.04.009

Proc Natl Acad Sci U S A. 2021 Apr 13. pii: e2014464118. [Epub ahead of print]118(15):

Impact of prenatal maternal cytokine exposure on sex differences in brain circuitry regulating stress in offspring 45 years later.

Jill M Goldstein, Justine E Cohen, Klara Mareckova, Laura Holsen, Susan Whitfield-Gabrieli, Stephen E Gilman, Stephen L Buka, Mady Hornig.

Stress is associated with numerous chronic diseases, beginning in fetal development with in utero exposures (prenatal stress) impacting offspring's risk for disorders later in life. In previous studies, we demonstrated adverse maternal in utero immune activity on sex differences in offspring neurodevelopment at age seven and adult risk for major depression and psychoses. Here, we hypothesized that in utero exposure to maternal proinflammatory cytokines has sex-dependent effects on specific brain circuitry regulating stress and immune function in the offspring that are retained across the lifespan. Using a unique prenatal cohort, we tested this hypothesis in 80 adult offspring, equally divided by sex, followed from in utero development to midlife. Functional MRI results showed that exposure to proinflammatory cytokines in utero was significantly associated with sex differences in brain activity and connectivity during response to negative stressful stimuli 45 y later. Lower maternal TNF-α levels were significantly associated with higher hypothalamic activity in both sexes and higher functional connectivity between hypothalamus and anterior cingulate only in men. Higher prenatal levels of IL-6 were significantly associated with higher hippocampal activity in women alone. When examined in relation to the anti-inflammatory effects of IL-10, the ratio TNF-α:IL-10 was associated with sex-dependent effects on hippocampal activity and functional connectivity with the hypothalamus. Collectively, results suggested that adverse levels of maternal in utero proinflammatory cytokines and the balance of pro- to anti-inflammatory cytokines impact brain development of offspring in a sexually dimorphic manner that persists across the lifespan.

Keywords: functional brain imaging; prenatal immune programming; prenatal stress; sex; stress circuitry

DOI: https://doi.org/10.1073/pnas.2014464118