Multisystem inflammatory syndrome in children (MIS-C) presents with fever, inflammation and pathology of multiple organs in individuals under 21 years of age in the weeks following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Although an autoimmune pathogenesis has been proposed, the genes, pathways and cell types causal to this new disease remain unknown. Here we perform RNA sequencing of blood from patients with MIS-C and controls to find disease-associated genes clustered in a co-expression module annotated to CD56dimCD57+ natural killer (NK) cells and exhausted CD8+ T cells. A similar transcriptome signature is replicated in an independent cohort of Kawasaki disease (KD), the related condition after which MIS-C was initially named. Probing a probabilistic causal network previously constructed from over 1,000 blood transcriptomes both validates the structure of this module and reveals nine key regulators, including TBX21, a central coordinator of exhausted CD8+ T cell differentiation. Together, this unbiased, transcriptome-wide survey implicates downregulation of NK cells and cytotoxic T cell exhaustion in the pathogenesis of MIS-C.

No abstract

Post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are debilitating, clinically heterogeneous and of unknown molecular etiology. A transcriptome-wide investigation was performed in 165 acutely infected hospitalized individuals who were followed clinically into the post-acute period. Distinct gene expression signatures of post-acute sequelae were already present in whole blood during acute infection, with innate and adaptive immune cells implicated in different symptoms. Two clusters of sequelae exhibited divergent plasma-cell-associated gene expression patterns. In one cluster, sequelae associated with higher expression of immunoglobulin-related genes in an anti-spike antibody titer-dependent manner. In the other, sequelae associated independently of these titers with lower expression of immunoglobulin-related genes, indicating lower non-specific antibody production in individuals with these sequelae. This relationship between lower total immunoglobulins and sequelae was validated in an external cohort. Altogether, multiple etiologies of post-acute sequelae were already detectable during SARS-CoV-2 infection, directly linking these sequelae with the acute host response to the virus and providing early insights into their development.

No abstract

Cancer cell dissemination can occur during very early stages of breast cancer, but the mechanisms controlling this process are unclear. Here we show that a previously reported early MMTV-HER2+/P-p38lo/TWISThi/E-cadherinlo cancer cell subpopulation depends on macrophages for early dissemination. Depletion of macrophages before overt tumor detection drastically reduced early dissemination and diminished the late metastatic burden. CD206+/Tie2+ macrophages were attracted into early lesions in part by CCL2 produced by early HER2+ cancer cells and myeloid cells. Upregulation of Wnt-1 by macrophages could be stimulated by CCL2 and correlated with loss of E-cadherin in HER2+ early cancer cells. Both MMTV-PyMT and MMTV-HER2 early lesions showed macrophage-containing tumor microenvironments of metastasis (TMEM) structures, and PyMT early cancer cells also showed a reduction in early lesion E-cadherin junctions. Intraepithelial macrophages and loss of E-cadherin junctions was also found more frequently in high-grade human DCIS than in low-grade and normal breast tissue, but no association was found with HER2 status. We reveal a previously unrecognized mechanism by which macrophages play a causal role in early dissemination, impacting long-term metastasis development. Citation Format: Nina Linde, Maria Casanova-Acebes, Maria Soledad Sosa, Arthur Mortha, Adeeb Rahman, Eduardo F. Farias, Kathryn Harper, Ethan Tardio, Ivan Reyes-Torres, Joan G. Jones, John S. Condeelis, Miriam Merad, Julio A. Aguirre-Ghiso. Macrophages orchestrate early dissemination and metastasis [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr IA16.

The following text is now added to the beginning of the fourth paragraph of the 'Statistical analysis' subsection of the Methods section: "A normalization factor can be added to account for the uncertainty in the symptom onset dates of the index cases. Assuming a uniform distribution, the likelihood would only differ by a multiplicative constant and give the same estimates. " Also, the time frame in the final sentence of that paragraph ("from day 1 to 7") was incorrect. The correct time frame is "from days 5, 8 and 11. " Finally, Fig. 1c and Extended Data Fig. 1 have been replaced accordingly, and the legend to Extended Data Fig. 1 ("to start from 1 days (top left) to 7 days (bottom right) before symptom onset") is now rephrased ("to start from 5 days (top), 8 days (middle) and 11 days (bottom) before symptom onset") to match the revised figure. The errors have been corrected in the HTML and PDF versions of the article. The original code has also been replaced with updated code in Supplementary Software 1.

No abstract