Understanding the molecular pathways driving the acute antiviral and inflammatory response to SARS‐CoV‐2 infection is critical for developing treatments for severe COVID‐19. Here, we find decreasing number of circulating plasmacytoid dendritic cells (pDCs) in COVID‐19 patients early after symptom onset, correlating with disease severity. pDC depletion is transient and coincides with decreased expression of antiviral type I IFNα and of systemic inflammatory cytokines CXCL10 and IL‐6. Using an in vitro stem cell‐based human pDC model, we further demonstrate that pDCs, while not supporting SARS‐CoV‐2 replication, directly sense the virus and in response produce multiple antiviral (interferons: IFNα and IFNλ1) and inflammatory (IL‐6, IL‐8, CXCL10) cytokines that protect epithelial cells from de novo SARS‐CoV‐2 infection. Via targeted deletion of virus‐recognition innate immune pathways, we identify TLR7‐MyD88 signaling as crucial for production of antiviral interferons (IFNs), whereas Toll‐like receptor (TLR)2 is responsible for the inflammatory IL‐6 response. We further show that SARS‐CoV‐2 engages the receptor neuropilin‐1 on pDCs to selectively mitigate the antiviral interferon response, but not the IL‐6 response, suggesting neuropilin‐1 as potential therapeutic target for stimulation of TLR7‐mediated antiviral protection.
This study uses time‐domain induced polarization data for the delineation and characterization of the former landfill site at Eskelund, Denmark. With optimized acquisition parameters combined with a new inversion algorithm, we use the full content of the decay curve and retrieve spectral information from time‐domain IP data. Thirteen IP/DC profiles were collected in the area, supplemented by el‐log drilling for accurate correlation between the geophysics and the lithology. The data were inverted using a laterally constrained 1D inversion considering the full decay curves to retrieve the four Cole‐Cole parameters. For all profiles, the results reveal a highly chargeable unit that shows a very good agreement to the findings from 15 boreholes covering the area, where the extent of the waste deposits was measured. The thickness and depth of surface measurements were furthermore validated by el‐log measurements giving in situ values, for which the Cole‐Cole parameters were computed. The 3D shape of the waste body was pinpointed and well‐defined. The inversion of the IP data also shows a strong correlation with the initial stage of the waste dump and its composition combining an aerial map with acquired results.
Increasingly, electromagnetic induction methods (EMI) are being used within the area of archaeological prospecting for mapping soil structures or for studying paleo-landscapes. Recent hardware developments have made fast data acquisition, combined with precise positioning, possible, thus providing interesting possibilities for archaeological prospecting. However, it is commonly assumed that the instrument operates in what is referred to as Low Induction Number, or LIN. Here, we detail the problems of the approximations while discussing a best practice for EMI measurements, data processing, and inversion for understanding a paleo-landscape at an Iron Age human bone depositional site (Alken Enge) in Denmark. On synthetic as well as field data we show that soil mapping based on EMI instruments can be improved by applying data processing methodologies from adjacent scientific fields. Data from a 10 hectare study site was collected with a line spacing of 1-4 m, resulting in roughly 13,000 processed soundings, which were inverted with a full non-linear algorithm. The models had higher dynamic range in the retrieved resistivity values, as well as sharper contrasts between structural elements than we could obtain by looking at data alone. We show that the pre-excavation EMI mapping facilitated an archaeological prospecting where traditional trenching could be replaced by a few test pits at selected sites, hereby increasing the chance of finding human bones. In a general context we show that (1) dedicated processing of EMI data is necessary to remove coupling from anthropogenic structures (fences, phone cables, paved roads, etc.), and (2) that carrying out a dedicated full non-linear inversion with spatial coherency constraints improves the accuracy of resistivities and structures over using the data as they are or using the Low Induction Number (LIN) approximation.
Among HIV-infected individuals, long-term nonprogressor (LTNP) patients experience slow CD4 T cell decline and almost undetectable viral load for several years after primary acquisition of HIV. Type I IFN has been suggested to play a pathogenic role in HIV pathogenesis, and therefore diminished IFN responses may underlie the LTNP phenotype. In this study, we examined the presence and possible immunological role of multiple homozygous single-nucleotide polymorphisms in the stimulator of IFN genes (STING) encoding gene involved in IFN induction and T cell proliferation in HIV LTNP patients. We identified LTNPs through the Danish HIV Cohort and performed genetic analysis by Sanger sequencing, covering the R71H-G230A-R293Q (HAQ) single-nucleotide polymorphisms in This was followed by investigation of STING mRNA and protein accumulation as well as innate immune responses and proliferation following STING stimulation and infection with replication-competent HIV in human blood-derived cells. We identified G230A-R293Q/G230A-R293Q and HAQ/HAQ homozygous variants in 2 out of 11 LTNP patients. None of the 11 noncontrollers on antiretroviral treatment were homozygous for these variants. We found decreased innate immune responses to DNA and HIV as well as reduced STING-dependent inhibition of CD4 T cell proliferation, particularly in the HAQ/HAQ HIV LTNP patients, compared with the age- and gender-matched noncontrollers on antiretroviral treatment. These findings suggest that homozygous HAQ STING variants contribute to reduced inhibition of CD4 T cell proliferation and a reduced immune response toward DNA and HIV, which might result in reduced levels of constitutive IFN production. Consequently, the HAQ/HAQ genotype may contribute to the slower disease progression characteristic of LTNPs.
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