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Cross-species differences form barriers to translational research that ultimately hinder the success of clinical trials, yet knowledge of species differences has yet to be systematically incorporated in the interpretation of animal models. We developed a machine learning model that leverages human and mouse public gene expression data to extrapolate the results of a new mouse experiment to expression changes in the equivalent human condition. We applied FIT to data from mouse models of 28 different human diseases and show it is able to identify 20-50% more human-relevant differentially expressed genes. FIT predicted novel disease-associated genes, an example of which we validated experimentally in Crohn’s patients. FIT highlights signals that may otherwise be missed and reduces false leads with no experimental cost. It is available both as an R package and as a web tool.

Pregnancy is a risk factor for increased severity of SARS-CoV-2 and other respiratory infections. The mechanisms underlying this risk have not been well-established, partly due to a limited understanding of how pregnancy shapes immune responses. To gain insight into the role of pregnancy in modulating immune responses at steady state and upon perturbation, we collected peripheral blood mononuclear cells (PBMC), plasma, and stool from 226 women, including 152 pregnant individuals (n = 96 with SARS-CoV-2 infection and n = 56 healthy controls) and 74 non-pregnant women (n = 55 with SARS-CoV-2 and n = 19 healthy controls). We found that SARS-CoV-2 infection was associated with altered T cell responses in pregnant compared to non-pregnant women. Differences included a lower percentage of memory T cells, a distinct clonal expansion of CD4-expressing CD8 + T cells, and the enhanced expression of T cell exhaustion markers, such as programmed cell death-1 (PD-1) and T cell immunoglobulin and mucin domain-3 (Tim-3), in pregnant women. We identified additional evidence of immune dysfunction in severely and critically ill pregnant women, including a lack of expected elevation in regulatory T cell (Treg) levels, diminished interferon responses, and profound suppression of monocyte function. Consistent with earlier data, we found maternal obesity was also associated with altered immune responses to SARS-CoV-2 infection, including enhanced production of inflammatory cytokines by T cells. Certain gut bacterial species were altered in pregnancy and upon SARS-CoV-2 infection in pregnant individuals compared to non-pregnant women. Shifts in cytokine and chemokine levels were also identified in the sera of pregnant individuals, most notably a robust increase of interleukin-27 (IL-27), a cytokine known to drive T cell exhaustion, in the pregnant uninfected control group compared to all non-pregnant groups. IL-27 levels were also significantly higher in uninfected pregnant controls compared to pregnant SARS-CoV-2-infected individuals. Using two different preclinical mouse models of inflammation-induced fetal demise and respiratory influenza viral infection, we found that enhanced IL-27 protects developing fetuses from maternal inflammation but renders adult female mice vulnerable to viral infection. These combined findings from human and murine studies reveal nuanced pregnancy-associated immune responses, suggesting mechanisms underlying the increased susceptibility of pregnant individuals to viral respiratory infections.

The SARS-CoV-2 pandemic has caused over 1 million deaths globally, mostly due to acute lung injury and acute respiratory distress syndrome, or direct complications resulting in multiple-organ failures. Little is known about the host tissue immune and cellular responses associated with COVID-19 infection, symptoms, and lethality. To address this, we collected tissues from 11 organs during the clinical autopsy of 17 individuals who succumbed to COVID-19, resulting in a tissue bank of approximately 420 specimens. We generated comprehensive cellular maps capturing COVID-19 biology related to patients' demise through single-cell and single-nucleus RNA-Seq of lung, kidney, liver and heart tissues, and further contextualized our findings through spatial RNA profiling of distinct lung regions. We developed a computational framework that incorporates removal of ambient RNA and automated cell type annotation to facilitate comparison with other healthy and diseased tissue atlases. In the lung, we uncovered significantly altered transcriptional programs within the epithelial, immune, and stromal compartments and cell intrinsic changes in multiple cell types relative to lung tissue from healthy controls. We observed evidence of: alveolar type 2 (AT2) differentiation replacing depleted alveolar type 1 (AT1) lung epithelial cells, as previously seen in fibrosis; a concomitant increase in myofibroblasts reflective of defective tissue repair; and, putative TP63 + intrapulmonary basal-like progenitor (IPBLP) cells, similar to cells identified in H1N1 influenza, that may serve as an emergency cellular reserve for severely damaged alveoli. Together, these findings suggest the activation and failure of multiple avenues for regeneration of the epithelium in these terminal lungs. SARS-CoV-2 RNA reads were enriched in lung mononuclear phagocytic cells and endothelial cells, and these cells expressed distinct host response transcriptional programs. We corroborated the compositional and transcriptional changes in lung tissue through spatial analysis of RNA profiles in situ and distinguished unique tissue host responses between regions with and without viral RNA, and in COVID-19 donor tissues relative to healthy lung. Finally, we analyzed genetic regions implicated in COVID-19 GWAS with transcriptomic data to implicate specific cell types and genes associated with disease severity. Overall, our COVID-19 cell atlas is a foundational dataset to better understand the biological impact of SARS-CoV-2 infection across the human body and empowers the identification of new therapeutic interventions and prevention strategies., Competing Interests: Competing Interests P.D., R.F., E.M.M., M.R., E.H.R., L.P., T.He., J.R., J.B., and S.W. are employees and stockholders at Nanostring Technologies Inc. D.Z., is a former employee and stockholder at NanoString Technologies. N.H., holds equity in BioNTech and Related Sciences. T.H.is an employee and stockholder of Prime Medicine as of Oct. 13, 2020. G.H. is an employee of Genentech as of Nov 16, 2020. R.N. is a founder, shareholder, and member of the board at Rhinostics Inc. A.R. is a co-founder and equity holder of Celsius Therapeutics, an equity holder in Immunitas, and was an SAB member of ThermoFisher Scientific, Syros Pharmaceuticals, Neogene Therapeutics and Asimov until July 31, 2020. From August 1, 2020, A.R. is an employee of Genentech. From October 19, 2020, O.R.-R is an employee of Genentech. P.C.S is a co-founder and shareholder of Sherlock Biosciences, and a Board member and shareholder of Danaher Corporation. A.K.S. reports compensation for consulting and/or SAB membership from Honeycomb Biotechnologies, Cellarity, Repertoire Immune Medicines, Ochre Bio, and Dahlia Biosciences. Z.G.J. reports grant support from Gilead Science, Pfizer, compensation for consulting from Olix Pharmaceuticals. Y.V.P. reports grant support from Enanta Pharmaceuticals, CymaBay Therapeutics, Morphic Therapeutic; consulting and/or SAB in Ambys Medicines, Morphic Therapeutics, Enveda Therapeutics, BridgeBio Pharma, as well as being an Editor – American Journal of Physiology-Gastrointestinal and Liver Physiology. GS reports consultant service in Alnylam Pharmaceuticals, Merck, Generon, Glympse Bio, Inc., Mayday Foundation, Novartis Pharmaceuticals, Quest Diagnostics, Surrozen, Terra Firma, Zomagen Bioscience, Pandion Therapeutics, Inc. Durect Corporation; royalty from UpToDate Inc., and Editor service in Hepatology Communications. P.R.T. receives consulting fees from Cellarity Inc., and Surrozen Inc., for work not related to this manuscript.