Highlights d SARS-CoV-2-infected RMs mimic signatures of inflammation seen in COVID-19 patients d Baricitinib suppresses production of pro-inflammatory cytokines in lung macrophages d Baricitinib limits recruitment of neutrophils to the lung and NETosis d Baricitinib preserves innate antiviral and SARS-CoV-2specific T cell responses

The COVID-19 pandemic remains a global health crisis, yet, the immunopathological mechanisms driving the development of severe disease remain poorly defined. Here, we utilize a rhesus macaque (RM) model of SARS-CoV-2 infection to delineate perturbations in the innate immune system during acute infection using an integrated systems analysis. We found that SARS-CoV-2 initiated a rapid infiltration (two days post infection) of plasmacytoid dendritic cells into the lower airway, commensurate with IFNA production, natural killer cell activation, and induction of interferon-stimulated genes. At this early interval, we also observed a significant increase of blood CD14-CD16+ monocytes. To dissect the contribution of lung myeloid subsets to airway inflammation, we generated a novel compendium of RM-specific lung macrophage gene expression using a combination of sc-RNA-Seq data and bulk RNA-Seq of purified populations under steady state conditions. Using these tools, we generated a longitudinal sc-RNA-seq dataset of airway cells in SARS-CoV-2-infected RMs. We identified that SARS-CoV-2 infection elicited a rapid recruitment of two subsets of macrophages into the airway: a C206+MRC1- population resembling murine interstitial macrophages, and a TREM2+ population consistent with CCR2+ infiltrating monocytes, into the alveolar space. These subsets were the predominant source of inflammatory cytokines, accounting for ~75% of IL6 and TNF production, and >90% of IL10 production, whereas the contribution of CD206+MRC+ alveolar macrophages was significantly lower. Treatment of SARS-CoV-2 infected RMs with baricitinib (Olumiant®), a novel JAK1/2 inhibitor that recently received Emergency Use Authorization for the treatment of hospitalized COVID-19 patients, was remarkably effective in eliminating the influx of infiltrating, non-alveolar macrophages in the alveolar space, with a concomitant reduction of inflammatory cytokines. This study has delineated the major subsets of lung macrophages driving inflammatory and anti-inflammatory cytokine production within the alveolar space during SARS-CoV-2 infection.

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Conclusion:In patients with a hemodialysis access graft and an asymptomatic central venous stenosis (CVS) of Ͼ50%, treatment of the CVS results in more rapid stenosis progression compared with a nontreatment approach.Summary: The authors evaluated the natural history of Ͼ50% asymptomatic CVSs in hemodialysis patients. Outcome of serial treatment of CVS with percutaneous catheter-based techniques (PTA) was also evaluated. All patients in this study required maintenance procedures for their dialysis access.Between 1998 and 2004, 35 patients (19 men, 16 women), with a mean age of 58.7 years, were found to have asymptomatic CVS of Ͼ50%. CVS was measured by using venograms obtained before and after PTA. Patients with arm swelling, multiple CVSs, or indwelling catheters, were excluded. CVS progression was calculated by comparing degrees of stenoses with serial venographic examinations.The mean severity of CVSs before intervention was 71% (range, 50% to 100%), with 62% of lesions having associated collateral vessels. Twenty eight percent of CVSs were not treated. The mean degree of stenosis in the untreated group was 72% (range, 30% to 100%). Mean progression of stenosis in the untreated group was -0.8% point per day. No untreated CVS progressed to symptoms, stent placement, or developed additional CVS.PTA was used to treat 62 CVS lesions (72%). The mean degree of stenosis in the treated group was 74% (range, 50% to 100%) before and 40% (range, 0% to 75%) after treatment. In the treated group, mean progression of CVS was 0.21% per day after treatment. Six of the 62 treated CVS lesions were monitored, with symptomatic escalation of the CVS as manifested by arm swelling, need for stent placement, or development of additional CVS lesions.Comment: Treatment of an asymptomatic CVS in a dialysis patient is not a good thing. One is reminded of the old adage that it is wise to avoid poking a skunk. A major weakness of this study is that the patients were undergoing maintenance procedures for their dialysis access. We do not know if the CVS contributed to the need for the dialysis access maintenance. It would be interesting to know if there was a higher rate of repeat procedures for maintenance of dialysis access in patients with treated vs untreated CVS.

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Effective therapeutics aimed at mitigating COVID-19 symptoms are urgently needed. SARS-CoV-2 induced hypercytokinemia and systemic inflammation are associated with disease severity. Baricitinib, a clinically approved JAK1/2 inhibitor with potent anti-inflammatory properties is currently being investigated in COVID-19 human clinical trials. Recent reports suggest that baricitinib may also have antiviral activity in limiting viral endocytosis. Here, we investigated the immunologic and virologic efficacy of baricitinib in a rhesus macaque model of SARS-CoV-2 infection. Viral shedding measured from nasal and throat swabs, bronchoalveolar lavages and tissues was not reduced with baricitinib. Type I IFN antiviral responses and SARS-CoV-2 specific T cell responses remained similar between the two groups. Importantly, however, animals treated with baricitinib showed reduced immune activation, decreased infiltration of neutrophils into the lung, reduced NETosis activity, and more limited lung pathology. Moreover, baricitinib treated animals had a rapid and remarkably potent suppression of alveolar macrophage derived production of cytokines and chemokines responsible for inflammation and neutrophil recruitment. These data support a beneficial role for, and elucidate the immunological mechanisms underlying, the use of baricitinib as a frontline treatment for severe inflammation induced by SARS-CoV-2 infection.

Type-I interferons (IFN-I) are critical mediators of innate control of viral infections, but also drive recruitment of inflammatory cells to sites of infection, a key feature of severe COVID-19. Here, and for the first time, IFN-I signaling was modulated in rhesus macaques (RMs) prior to and during acute SARS-CoV-2 infection using a mutated IFNα2 (IFN-modulator; IFNmod), which has previously been shown to reduce the binding and signaling of endogenous IFN-I. In SARS-CoV-2-infected RMs, IFNmod reduced both antiviral and inflammatory ISGs. Notably, IFNmod treatment resulted in a potent reduction in (i) SARS-CoV-2 viral load in Bronchoalveolar lavage (BAL), upper airways, lung, and hilar lymph nodes; (ii) inflammatory cytokines, chemokines, and CD163+MRC1- inflammatory macrophages in BAL; and (iii) expression of Siglec-1, which enhances SARS-CoV-2 infection and predicts disease severity, on circulating monocytes. In the lung, IFNmod also reduced pathogenesis and attenuated pathways of inflammasome activation and stress response during acute SARS-CoV-2 infection. This study, using an intervention targeting both IFN-α and IFN-β pathways, shows that excessive inflammation driven by type 1 IFN critically contributes to SARS-CoV-2 pathogenesis in RMs, and demonstrates the potential of IFNmod to limit viral replication, SARS-CoV-2 induced inflammation, and COVID-19 severity.

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