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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. Synopsis: Plasmacytoid dendritic cells (pDCs) sense SARS‐CoV‐2 via two distinct innate immune pathways. The endosomal TLR7 pathway is activated upon sensing of viral RNA and this leads to type I IFN production. The TLR2 pathway is triggered by sensing of the viral envelope protein, inducing IL‐6 production. Interestingly, SARS‐CoV‐2 is able to specifically antagonize the TLR7‐IFN pathway via a CD304‐mediated signaling cascade. Sensing of SARS‐CoV‐2 RNA by pDCs triggers a signaling cascade involving TLR7‐MyD88‐IRAK4‐TRAF6 to induce CXCL10 and, via IRF7 phosphorylation and translocation, type I and III Interferons. In parallel, SARS‐CoV‐2 envelope (E) glycoprotein is sensed by the extracellular TLR2/6 heterodimer facilitating production of IL‐6.The secreted type I and III IFNs initiate autocrine and paracrine signals that induce the expression of IFN stimulated genes (ISGs), thereby facilitating an antiviral response that protects local epithelial cells against SARS‐CoV‐2 infection.SARS‐CoV‐2 can counteract the protective IFN effects by inducing CD304 signaling, potentially interfering with IRF7 nuclear translocation, thereby inhibiting type I IFNα production and thus reducing the antiviral response generated by pDCs. [ABSTRACT FROM AUTHOR]

The aim of the presented study was to investigate the impact on the radiation budget of biomass burning smoke plume transported from Alaska to high Arctic region (Ny-Alesund, Svalbard) in early July 2015. This high aerosol load event is considered exceptional in the last 25 years with mean aerosol optical depth increased by the factor of 10 in comparison to the average summer background values. We utilised in-situ data with hygroscopic growth equations as well as remote sensing measurements as inputs to radiative transfer models with an objective to estimate biases associated with (i) hygroscopicity, (ii) variability of ω profiles and (iii) plane-parallel closure of the modelled atmosphere. A chemical weather model with satellite-derived biomass burning emissions was used to interpret the transport and transformations pathways. Provided MODTRAN simulations resulted in the mean aerosol direct radiative forcing on the level of -78.9 W m-2 and -47.0 W m-2 at the surface and the top of the atmosphere respectively for the mean value of aerosol optical depth equal to 0.64 at 550 nm. It corresponded to the average clear-sky direct radiative forcing of -43.3 W m-2 estimated by radiometers and model simulations. Furthermore, model-derived aerosol direct radiative forcing efficiency reached on average -126 W m-2 / τ550 and -71 W m-2 / τ550 at the surface and at the top of the atmosphere. Estimated heating rate up to 1.8 K day-1 inside the BB plume implied vertical mixing with the turbulent kinetic energy of 0.3 m2 s-2. Ultimately, uncertainty connected with the plane-parallel atmosphere approximation altered results by about 2 W m-2. [ABSTRACT FROM AUTHOR]

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 TMEM173 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 TMEM173. 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 TMEM173 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 TMEM173 genotype may contribute to the slower disease progression characteristic of LTNPs. [ABSTRACT FROM AUTHOR]