Human nasal wash RNA-Seq reveals distinct cell-specific innate immune responses in influenza versus SARS-CoV-2

BACKGROUND Influenza A virus (IAV) and SARS-CoV-2 are pandemic viruses causing millions of deaths, yet their clinical manifestations are distinctly different. METHODS With the hypothesis that upper airway immune and epithelial cell responses are also distinct, we performed single-cell RNA sequencing (scRNA-Seq) on nasal wash cells freshly collected from adults with either acute COVID-19 or influenza or from healthy controls. We focused on major cell types and subtypes in a subset of donor samples. Results Nasal wash cells were enriched for macrophages and neutrophils for both individuals with influenza and those with COVID-19 compared with healthy controls. Hillock-like epithelial cells, M2-like macrophages, and age-dependent B cells were enriched in COVID-19 samples. A global decrease in IFN-associated transcripts in neutrophils, macrophages, and epithelial cells was apparent in COVID-19 samples compared with influenza samples. The innate immune response to SARS-CoV-2 appears to be maintained in macrophages, despite evidence for limited epithelial cell immune sensing. Cell-to-cell interaction analyses revealed a decrease in epithelial cell interactions in COVID-19 and highlighted differences in macrophage-macrophage interactions for COVID-19 and influenza. Conclusions Our study demonstrates that scRNA-Seq can define host and viral transcriptional activity at the site of infection and reveal distinct local epithelial and immune cell responses for COVID-19 and influenza that may contribute to their divergent disease courses. Funding Massachusetts Consortium on Pathogen Readiness, the Mathers Foundation, and the Department of Defense (W81XWH2110029) COVID-19 Expansion for AIRe Program

cGAS-STING Pathway Does Not Promote Autoimmunity in Murine Models of SLE

Detection of DNA is an important determinant of host-defense but also a driver of autoinflammatory and autoimmune diseases. Failure to degrade self-DNA in DNAseII or III(TREX1)-deficient mice results in activation of the cGAS-STING pathway. Deficiency of cGAS or STING in these models ameliorates disease manifestations. However, the contribution of the cGAS-STING pathway, relative to endosomal TLRs, in systemic lupus erythematosus (SLE) is controversial. In fact, STING deficiency failed to rescue, and actually exacerbated, disease manifestations in Fas-deficient SLE-prone mice. We have now extended these observations to a chronic model of SLE induced by the i.p. injection of TMPD (pristane). We found that both cGAS- and STING-deficiency not only failed to rescue mice from TMPD-induced SLE, but resulted in increased autoantibody production and higher proteinuria levels compared to cGAS STING sufficient mice. Further, we generated cGAS(KO)Fas(lpr) mice on a pure MRL/Fas(lpr) background using Crispr/Cas9 and found slightly exacerbated, and not attenuated, disease. We hypothesized that the cGAS-STING pathway constrains TLR activation, and thereby limits autoimmune manifestations in these two models. Consistent with this premise, mice lacking cGAS and Unc93B1 or STING and Unc93B1 developed minimal systemic autoimmunity as compared to cGAS or STING single knock out animals. Nevertheless, TMPD-driven lupus in B6 mice was abrogated upon AAV-delivery of DNAse I, implicating a DNA trigger. Overall, this study demonstrated that the cGAS-STING pathway does not promote systemic autoimmunity in murine models of SLE. These data have important implications for cGAS-STING-directed therapies being developed for the treatment of systemic autoimmunity

Endothelial cell expression of a STING gain-of-function mutation initiates pulmonary lymphocytic infiltration

Summary: Patients afflicted with Stimulator of interferon gene (STING) gain-of-function mutations frequently present with debilitating interstitial lung disease (ILD) that is recapitulated in mice expressing the STINGV154M mutation (VM). Prior radiation chimera studies revealed an unexpected and critical role for non-hematopoietic cells in initiating ILD. To identify STING-expressing non-hematopoietic cell types required for the development of ILD, we use a conditional knockin (CKI) model and direct expression of the VM allele to hematopoietic cells, fibroblasts, epithelial cells, or endothelial cells. Only endothelial cell-targeted VM expression results in enhanced recruitment of immune cells to the lung associated with elevated chemokine expression and the formation of bronchus-associated lymphoid tissue, as seen in the parental VM strain. These findings reveal the importance of endothelial cells as instigators of STING-driven lung disease and suggest that therapeutic targeting of STING inhibitors to endothelial cells could potentially mitigate inflammation in the lungs of STING-associated vasculopathy with onset in infancy (SAVI) patients or patients afflicted with other ILD-related disorders

Search for Bc+→π+μ+μ−B_c^+\to\pi^+\mu^+\mu^- decays and measurement of the branching fraction ratio B(Bc+→ψ(2S)π+)/B(Bc+→J/ψπ+){\cal B}(B_c^+\to\psi(2S)\pi^+)/{\cal B}(B_c^+\to J/\psi \pi^+)

International audienceThe first search for nonresonant $B_c^+\to\pi^+\mu^+\mu^-$ decays is reported. The analysis uses proton-proton collision data collected with the LHCb detector between 2011 and 2018, corresponding to an integrated luminosity of 9 fb$^{-1}$. No evidence for an excess of signal events over background is observed and an upper limit is set on the branching fraction ratio ${\cal B}(B_c^+\to\pi^+\mu^+\mu^-)/{\cal B}(B_c^+\to J/\psi \pi^+) < 2.1\times 10^{-4}$ at $90\%$ confidence level. Additionally, an updated measurement of the ratio of the $B_c^+\to\psi(2S)\pi^+$ and $B_c^+\to J/\psi \pi^+$ branching fractions is reported. The ratio ${\cal B}(B_c^+\to\psi(2S)\pi^+)/{\cal B}(B_c^+\to J/\psi \pi^+)$ is measured to be $0.254\pm 0.018 \pm 0.003 \pm 0.005$, where the first uncertainty is statistical, the second systematic, and the third is due to the uncertainties on the branching fractions of the leptonic $J/\psi$ and $\psi(2S)$ decays. This measurement is the most precise to date and is consistent with previous LHCb results

Helium identification with LHCb

The identification of helium nuclei at LHCb is achieved using a method based on measurements of ionisation losses in the silicon sensors and timing measurements in the Outer Tracker drift tubes. The background from photon conversions is reduced using the RICH detectors and an isolation requirement. The method is developed using $pp$ collision data at $\sqrt{s}=13\,{\rm TeV}$ recorded by the LHCb experiment in the years 2016 to 2018, corresponding to an integrated luminosity of $5.5\,{\rm fb}^{-1}$. A total of around $10^5$ helium and antihelium candidates are identified with negligible background contamination. The helium identification efficiency is estimated to be approximately $50\%$ with a corresponding background rejection rate of up to $\mathcal O(10^{12})$. These results demonstrate the feasibility of a rich programme of measurements of QCD and astrophysics interest involving light nuclei

Study of Bc+→χcπ+B_c^+ \rightarrow \chi_c \pi^+ decays

International audienceA study of $B_c^+ \rightarrow \chi_c \pi^+$ decays is reported using proton-proton collision data, collected with the LHCb detector at centre-of-mass energies of 7, 8, and 13 TeV, corresponding to an integrated luminosity of 9fb$^{-1}$. The decay $B_c^+ \rightarrow \chi_{c2} \pi^+$ is observed for the first time, with a significance exceeding seven standard deviations. The relative branching fraction with respect to the $B_c^+ \rightarrow J/\psi \pi^+$ decay is measured to be $$\frac{\mathcal{B}_{B_c^+ \rightarrow \chi_{c2} \pi^+}} {\mathcal{B}_{B_c^+ \rightarrow J/\psi \pi^+}} = 0.37 \pm 0.06 \pm 0.02 \pm 0.01 ,$$ where the first uncertainty is statistical, the second is systematic, and the third is due to the knowledge of the $\chi_c \rightarrow J/\psi \gamma$ branching fraction. No significant $B_c^+ \rightarrow \chi_{c1} \pi^+$ signal is observed and an upper limit for the relative branching fraction for the $B_c^+ \rightarrow \chi_{c1} \pi^+$ and $B_c^+ \rightarrow \chi_{c2} \pi^+$ decays of $$\frac{\mathcal{B}_{B_c^+ \rightarrow \chi_{c1} \pi^+}} {\mathcal{B}_{B_c^+ \rightarrow \chi_{c2} \pi^+}} < 0.49$$ is set at the 90% confidence level

Observation of Λb0→Λc+Dˉ(∗)0K−\Lambda_{b}^{0} \to \Lambda_{c}^{+} \bar{D}^{(*)0} K^{-} and Λb0→Λc+Ds∗−\Lambda_{b}^{0} \to \Lambda_{c}^{+} D_{s}^{*-} decays

International audienceThe decays $\Lambda_b^0 \to \Lambda_c^+\bar{D}^{(*)0}K^-$ and $\Lambda_b^0 \to \Lambda_c^+ D_s^{*-}$ are observed for the first time, in proton-proton collision data at $\sqrt{s}=13$TeV corresponding to an integrated luminosity of 5.4 fb${}^{-1}$ collected with the LHCb detector. Their ratios of branching fractions with respect to the $\Lambda_b^0\!\to\Lambda_c^+\mathrm{D}_s^-$ mode are measured to be \begin{align*} \begin{split} \frac{\mathcal{B}(\Lambda_b^0 \to \Lambda_c^+\bar{D}^0 K^-)}{\mathcal{B}(\Lambda_b^0 \to \Lambda_c^+ D_s^-)} & = 0.1908 {}_{-0.0034}^{+0.0036} {}_{-0.0018}^{+0.0016} \pm 0.0038 \\ \frac{\mathcal{B}(\Lambda_b^0 \to \Lambda_c^+\bar{D}^{*0} K^-)}{\mathcal{B}(\Lambda_b^0 \to \Lambda_c^+ D_s^-)} & = 0.589 {}_{-0.017}^{+0.018} {}_{-0.018}^{+0.017} \pm 0.012 \\ \frac{\mathcal{B}(\Lambda_b^0 \to \Lambda_c^+ D_s^{*-})}{\mathcal{B}(\Lambda_b^0 \to \Lambda_c^+ D_s^-)} & = 1.668 \pm 0.022 {}_{-0.055}^{+0.061}\ , \end{split} \end{align*} where the first uncertainties are statistical, the second systematic, and the third, for the $\Lambda_b^0 \to \Lambda_c^+ \bar{D}^{(*)0} K^-$ decays, are due to the uncertainties on the branching fractions of the $D_s^- \to K^- K^+ \pi^-$ and $\bar{D}^0 \to K^+\pi^-$ decay modes. The measured branching fractions probe factorization assumptions in effective theories and provide the normalization for future pentaquark searches in $\Lambda_b^0 \to \Lambda_c^+ \bar{D}^{(*)0}K^-$ decay channels

Determination of short- and long-distance contributions in B0→K∗0μ+μ−B^{0}\to K^{*0}\mu^+\mu^- decays

International audienceAn amplitude analysis of the $B^0 \to K^{*0} \mu^+\mu^-$ decay is presented. The analysis is based on data collected by the LHCb experiment from proton-proton collisions at $\sqrt{s} = 7,\,8$ and $13$ TeV, corresponding to an integrated luminosity of $4.7$ fb$^{-1}$. For the first time, Wilson coefficients and non-local hadronic contributions are accessed directly from the unbinned data, where the latter are parameterised as a function of $q^2$ with a polynomial expansion. Wilson coefficients and non-local hadronic parameters are determined under two alternative hypotheses: the first relies on experimental information alone, while the second one includes information from theoretical predictions for the non-local contributions. Both models obtain similar results for the parameters of interest. The overall level of compatibility with the Standard Model is evaluated to be between 1.8 and 1.9 standard deviations when looking at the $\mathcal{C}_9$ Wilson coefficient alone, and between 1.3 and 1.4 standard deviations when considering the full set of $\mathcal{C}_9, \, \mathcal{C}_{10}, \, \mathcal{C}_9^\prime$ and $\mathcal{C}_{10}^\prime$ Wilson coefficients. The ranges reflect the theoretical assumptions made in the analysis

A measurement of ΔΓs\Delta \Gamma_{s}

Using a dataset corresponding to 9 fb$^{−1}$ of integrated luminosity collected with the LHCb detector between 2011 and 2018 in proton-proton collisions, the decay-time distributions of the decay modes ${B}_s^0\to J/{\psi \eta}^{\prime }$ and ${B}_s^0\to J/\psi {\pi}^{+}{\pi}^{-}$ are studied. The decay-width difference between the light and heavy mass eigenstates of the ${B}_s^0$ meson is measured to be ∆Γ$_{s}$ = 0.087 ± 0.012 ± 0.009 ps$^{−1}$, where the first uncertainty is statistical and the second systematic.[graphic not available: see fulltext]Using a dataset corresponding to $9~\mathrm{fb}^{-1}$ of integrated luminosity collected with the LHCb detector between 2011 and 2018 in proton-proton collisions, the decay-time distributions of the decay modes $B_s^0 \rightarrow J/\psi \eta'$ and $B_s^0 \rightarrow J/\psi \pi^{+} \pi^{-}$ are studied. The decay-width difference between the light and heavy mass eigenstates of the $B_s^0$ meson is measured to be $\Delta \Gamma_s = 0.087 \pm 0.012 \pm 0.009 \, \mathrm{ps}^{-1}$, where the first uncertainty is statistical and the second systematic

Search for the Bs0→μ+μ−γB_s^0 \rightarrow \mu^+\mu^-\gamma decay

International audienceA search for the fully reconstructed $B_s^0 \rightarrow \mu^+\mu^-\gamma$ decay is performed at the LHCb experiment using proton-proton collisions at $\sqrt{s}=13$ TeV corresponding to an integrated luminosity of $5.4\,\mathrm{fb^{-1}}$. No significant signal is found and upper limits on the branching fraction in intervals of the dimuon mass are set \begin{align} {\cal B}(B_s^0 \rightarrow \mu^+\mu^-\gamma) < 4.2\times10^{-8},~&m(\mu\mu)\in[2m_\mu,~1.70]\,\mathrm{GeV/c^2} ,\nonumber {\cal B}(B_s^0 \rightarrow \mu^+\mu^-\gamma) < 7.7\times10^{-8},~&m(\mu\mu)\in[1.70,~2.88]\,\mathrm{GeV/c^2},\nonumber {\cal B}(B_s^0 \rightarrow \mu^+\mu^-\gamma) < 4.2\times10^{-8},~&m(\mu\mu)\in[3.92 ,~m_{B_s^0}]\,\mathrm{GeV/c^2},\nonumber \end{align} at 95% confidence level. Additionally, upper limits are set on the branching fraction in the $[2m_\mu,~1.70]\,\mathrm{GeV/c^2}$ dimuon mass region excluding the contribution from the intermediate $\phi(1020)$ meson, and in the region combining all dimuon-mass intervals