Research Highlights

There are amendments to 10.1038/s41577-021-00511-4 in brief Credit: Malte Mueller/Getty Malte Credit: COVID-19 SARS-CoV-2​ variant evades antibodies whilst maintaining fitness The SARS-CoV-2​ N439K mutation, located in the receptor- ​ MAST CELLS binding motif (RBM) of the spike protein, has emerged multiple times independently and was the first RBM variant to spread significantly. Thomson et al. now demonstrate that the RBM, which is the primary target for neutralizing antibodies, is High-​speed delivery to structurally plastic and that the N439K mutation confers an approximately twofold enhanced binding affinity for human ACE2 (the viral entry receptor), without a loss in replication neutrophils fitness and with similar clinical outcomes to infection with the ancestral virus. They also show that the mutation confers resistance to several neutralizing monoclonal antibodies and Neutrophils are the ‘first responders’ ability to extravasate into inflamed allows for immune escape from some polyclonal sera derived of the circulating immune system, skin in wild-type​ recipient mice, from individuals who recovered from infection. The fact that being recruited rapidly to sites of whereas ‘activated’ wild-type​ the RBM can readily mutate without loss of fitness indicates inflammation by tissue-resident​ neutrophils having high levels of that despite the slow mutation rate of the virus, potentially immune-​evading variants will continue to emerge — which mast cells. Dudeck et al. describe a CD11b expression extravasated ΔTnf has indeed been observed since the completion of this study. mechanism to ensure this high-speed​ normally in MC mice. Together, Original article Thomson, E. C. et al. Circulating SARS-CoV-2​ spike N439K variants response, involving direct delivery of the results indicate a direct effect maintain fitness while evading antibody-mediated​ immunity. Cell https://doi.org/10.1016/ mast cell mediators into the blood. of mast cell-derived​ TNF on the j.cell.2021.01.037 (2021) On the basis of previous extravasation of neutrophils. COVID-19 studies suggesting a role for mast So how is TNF delivered directly cell-derived​ tumour necrosis factor and rapidly from mast cells to Do rogue antibodies make the difference between (TNF) in neutrophil recruitment, the neutrophils? The authors identified mild versus severe COVID-19? authors investigated hapten-induced​ perivascular mast cells that are not To shed light on the immunological mechanisms underlying the skin inflammation in mice lacking only attached to the exterior wall mild/severe distinction in COVID-19 pathology, Combes et al. ΔTnf performed single-cell​ RNA-seq​ analysis on blood samples mast cell-​derived TNF (MC mice). of the blood vessel but also are from patients with mild/moderate or severe COVID-19. The number of neutrophils infil­ embedded within the endothelial In patients with mild/moderate COVID-19, they found trating inflamed skin was markedly cells and have intravascular exten­ populations of immune cells that displayed a coordinated reduced in MCΔTnf mice and the ratio sions making direct contact with pattern of interferon-stimulated​ gene (ISG) expression, but of extravascular to intravascular teth- the bloodstream that are increased these cells were systemically absent in patients with severe ered neutrophils suggested reduced in number and size during inflam­ disease. Surprisingly, patients with severe disease had higher diapedesis. This was confirmed by mation. Furthermore, they showed virus-specific​ antibody titres and lower viral loads than patients with mild/moderate disease. However, they uniquely the decreased number of neutrophils that these perivascular mast cells produced antibodies that appeared to functionally block the attached to vessel walls and their can degranulate directly into the production of ISG-expressing​ cells by engaging FcγRIIβ. This reduced crawling velocity in bloodstream and they were able to Fc receptor antagonizes IFNα receptor (IFNAR) signalling and MCΔTnf mice. observe this happening in real time. thereby disrupts a positive-feedback​ loop that would otherwise The effect of TNF deficiency Mast cell granules isolated in vitro enhance interferon responses. on neutrophil diapedesis did not then injected intravenously into Original article Combes, A. J. et al. Global absence and targeting of protective immune states in severe COVID-19. Nature https://doi.org/10.1038/s41586-021-03234-7 result from changes to endothelial hapten-challenged​ mice increased (2021) cell activation; expression levels the number of skin-infiltrating​ of chemokines and adhesion neutrophils. This ability of mast cells COVID-19 molecules by vascular endothelial to degranulate into the bloodstream, Intracranial inflammatory mediators involved cells were not affected in MCΔTnf and thus prime neutrophils with in SARS-CoV-2​ neurological manifestations? mice. By contrast, hapten-induced​ TNF, was confirmed in two other COVID-19 is frequently associated with a wide spectrum upregulation of CD11b and Ly6G models of skin inflammation. of neurological dysfunction that can persist long after the by neutrophils, which are required Although these results remain acute infection. Remsik et al. analysed cerebrospinal fluid from for blood vessel adhesion and to be verified in humans, they patients with cancer who had neurological manifestations after crawling, did not occur in MCΔTnf suggest that this pathway could be a SARS-​CoV-2 infection. They found an increase in intracranial mice. Mice lacking neutrophil therapeutic target for inflammation- inflammatory mediators such as IL-6, IL-8, IFNγ and MMP10, in the absence of viral neuroinvasion. IFNγ and its downstream expression of the TNF receptor ​associated anaphylactic shock or effectors CXCL9, CXCL10 and CXCL11 were still elevated TNFR1 had similarly reduced cytokine storm syndromes. nearly 2 months after the infection and intracranial levels of hapten-induced​ CD11b expression. Kirsty Minton MMP10 correlated with the degree of neurological dysfunction. Adoptive transfer experiments These findings support the investigation of anti-inflammatory​ were used to show that the reduced Original article Dudeck, J. et al. Directional drugs to treat neurological symptoms following COVID-19. mast cell degranulation of tumor necrosis factor expression of CD11b and Ly6G by into blood vessels primes neutrophil extravasation. Original article Remsik, J. et al. Inflammatory leptomeningeal cytokines mediate Immunity https://doi.org/10.1016/j.immuni.2020. COVID-19 neurologic symptoms in cancer patients. Cancer Cell https://doi.org/10.1016/ neutrophils from hapten-stimulated​ 12.017 (2021) j.ccell.2021.01.007 (2021) MCΔTnf mice resulted in a reduced

136 | MARCH 2021 | volume 21 www.nature.com/nri

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