Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a devastating global pandemic, infecting over 43 million people and claiming over 1 million lives, with these numbers increasing daily. Therefore, there is urgent need to understand the molecular mechanisms governing SARS-CoV-2 pathogenesis, immune evasion, and disease progression. Here, we show that SARS-CoV-2 can block IRF3 and NF-κB activation early during virus infection. We also identify that the SARS-CoV-2 viral proteins NSP1 and NSP13 can block interferon activation via distinct mechanisms. NSP1 antagonizes interferon signaling by suppressing host mRNA translation, while NSP13 downregulates interferon and NF-κB promoter signaling by limiting TBK1 and IRF3 activation, as phospho-TBK1 and phospho-IRF3 protein levels are reduced with increasing levels of NSP13 protein expression. NSP13 can also reduce NF-κB activation by both limiting NF-κB phosphorylation and nuclear translocation. Last, we also show that NSP13 binds to TBK1 and downregulates IFIT1 protein expression. Collectively, these data illustrate that SARS-CoV-2 bypasses multiple innate immune activation pathways through distinct mechanisms.

Highlights d CXCL10 expression is limited to discrete perivascular niches in the inflamed skin d The CXCL10 + niches are hotspots or preferred sites of Th1 tissue entry d The niche is enriched for MHC-II + moDCs and supports prolonged Th1:APC interactions d IFNg enhances niche availability, boosting opportunities for Th1:APC encounter

SUMMARYCorrect positioning of T cells within infected tissues is critical for T cell activation and pathogen control. Upon tissue entry, effector T cells must efficiently locate antigen presenting cells (APC) for peripheral activation. We reveal that tissue entry and initial peripheral activation of Th1 effector T cells are tightly linked to perivascular positioning of chemokine-expressing APCs. Dermal inflammation induced tissue-wide de novo generation of discrete perivascular CXCL10+ cell clusters, enriched for CD11c+MHC-II+ monocyte-derived dendritic cells. These chemokine clusters were ‘hot spots’ for both Th1 extravasation and activation in the inflamed skin. CXCR3-dependent Th1 localization to the cluster micro-environment prolonged T-APC interactions and boosted function. Both the frequency and range of these clusters were enhanced via a Th1-intrinsic, IFNγ-dependent positive feedback loop. Thus, the perivascular CXCL10+ clusters act as initial peripheral activation niches, optimizing controlled activation broadly throughout the tissue by coupling Th1 tissue entry with enhanced opportunities for Th1-APC encounter.

Viruses and hosts must navigate environments in which each tries to outcompete the other for survival or to co-exist within the same spaces. In Lewis Carrol's Through the Looking Glass, the Red Queen tells Alice, ‘Now, here, you see, it takes all the running you can do, to keep in the same place. If you want to get somewhere else, you must run at least twice as fast as that!’ Borrowing from this idea, the Red Queen Hypothesis asserts that organisms, such as viruses, must continuously adapt to environmental pressures to survive. In this commentary, we draw parallels between the Red Queen Hypothesis and the experiences scientists of color navigate to thrive in academic spaces. In both phenomena, adapting to environmental pressures is necessary for survival. We identify the various pressures and bottlenecks faced by historically underrepresented groups in academia, as well as the adaptation strategies they must implement to persist in academia.

Efficient recruitment and correct positioning of T cells within infected peripheral tissues are crucial for pathogen clearance. Using a dual-chemokine reporter (Groom et Al. Immunity, 2012) mouse and intra-vital imaging, we identified a preferred tissue entry and accumulation site for effector Th1 cells, defined by clusters of CXCL9 and CXCL10 expressing hematopoietic cells, enriched with MHC-class-II+ cells, in restricted perivascular spaces within the inflamed dermis. Unbiased computational analysis of motility dynamics of antigen-specific Th1 cells within these clusters, revealed cell confinement characteristics. CXCR3 on Th1 cells and presence of cognate antigen were critical for persistence within clusters and T cell activation. Newly recruited Th1 cells strongly amplified CXCL9 and CXCL10 expression, mainly within skin monocyte-derived dendritic cells, in an antigen- and interferon-gamma-dependent manner, resulting in augmented chemokine clusters. Our data suggest a CXCR3-mediated mechanism of intrinsic amplification loop for optimal Th1 cell recruitment, positioning and activation in restricted antigen presentation sites within the inflamed skin.