tions [16] . While the infection rates for these viruses are similar among different age groups, the morbidity and fatality rates are significantly higher in the aging population [17, 18] . The respiratory system of aging individuals is characterized by alterations of tissue stiffness [19] . Notably, recent micropatterning experiments have shown that cells subjected to substrates of different stiffness stimulated with the same cytokine (TNF-α) exhibit different downstream NF-κB signaling [20] . In a recent commentary, we outlined that the cross-talk between coronavirus infection and cellular aging could play a critical role in the replication of the virus in host cells by differentially intersecting with NF-κB signaling [21] . This suggests that efforts for drug repurposing should analyze SARS-CoV-2 infected host cell expression programs in conjunction with aging-dependent programs. While a number of studies are underway that investigate viral integration/replication and interactions with the host cell [6, 22] , to our knowledge the interplay of SARS-CoV-2 host response and aging has not been explored in the context of drug development and repurposing.
In this paper, we propose a novel computational platform for drug repurposing, which integrates transcriptomic, proteomic and structural data with a principled causal framework, and we apply it in the context of SARS-CoV-2 ( Fig. 1) . Given the age-dependent pathogenicity of SARS-CoV-2, we first identify genes that are differentially regulated by SARS-CoV-2 infection and aging based on bulk RNAseq data from [23, 24] . We then use an autoencoder, a type of artificial neural network used to learn data representations in an unsupervised manner [25, 26] , to embed the CMap data together with the SARS-CoV-2 expression data for signature matching to obtain an ordered list of FDA approved drugs. In particular, we show that overparameterized autoencoders align drug signatures from different cell types and thus allow constructing synthetic interventions [27, 28] by translating the effect of a drug from one cell type to another. We then construct a combined SARS-CoV-2 and aging interactome using a Steiner tree analysis to connect the differentially expressed genes within a protein-protein interaction network [29, 30] . By intersecting the resulting combined SARS-CoV-2 and aging interactome with the targets of the 300 top ranked FDA approved drugs from the previous analysis, we identify serine/threonine and tyrosine kinases as potential drug targets for therapeutic interventions. Causal structure discovery methods applied to the combined SARS-CoV-2 and aging interactome show that the identified protein kinase inhibitors such as axitinib, dasatinib, pazopanib and sunitinib target proteins that are upstream from genes that are differentially expressed in SARS-CoV-2 infection and aging, thereby validating these drugs as being of particular interest for the repurposing against COVID-19. While we apply our computational platform in the context of SARS-CoV-2, our algorithms integrate data modalities that are available for many diseases, thereby making them broadly applicable.
Differential expression analysis identifies genes that intersect the SARS-CoV-2 host response and aging pathways Since age is strongly associated with severe outcomes in patients with COVID-19, we sought to analyze genes differentially expressed in normal versus SARS-CoV-2 infected cells as well as genes differentially expressed in young versus old individuals. Used as model system for lung epithelial cells and the effect of SARS-CoV-2 infection, we obtained from [23] RNA-seq samples from normal and SARS-CoV-2 infected A549 lung alveolar cells as well as A549 cells supplemented with ACE2 (A549-ACE2), a receptor that has been shown to be critical for SARS-CoV-2 cell entry [31] . Fig. 2a shows the expression of A549-ACE2 cells infected with SARS-CoV-2 in comparison to normal A549-ACE2 cells, with many genes upregulated as a result of the infection, as expected. Given the availability of A549 data with/without ACE2 and with/without SARS-CoV-2 infection, we removed genes from this initial list of differentially expressed genes that were just ACE2-specific or just SARS-CoV-2 infection-specific to extract a more refined expression pattern of ACE2-mediated SARS-CoV-2 infection (Methods, Fig. 2b ). The rationale was to remove genes linked to the response of the ACE2 receptor to signals other than SARS-CoV-2 infection or genes involved in the entry of SARS-CoV-2 into the cell through means other than the ACE2 receptor, which has been shown to be the critical mode of entry in humans [31] . Gene ontology (GO) enrichment analysis revealed enrichment in mitotic cell cycle as the top term, further supporting removal of these genes ( Supplementary Fig. S1 ). The remaining 1926 genes are denoted in red in Fig. 2a,b and used for the subsequent analysis. GO enrichment analysis of these genes revealed that they are significantly enriched in the type I interferon signaling pathway and defense response to virus in addition to other GO terms (Fig. 2c) . Next, in order to analyze the link between SARS-CoV-2 infection and aging, we analyzed RNA-seq samples from the lung of different aged individuals collected as part of the Genome Tissue Expression (GTEx) study [24] . Given the stark increase in case fatality rates of COVID-19 after age 70 [17, 18] , we performed a differential expression analysis comparing the youngest group (20) (21) (22) (23) (24) (25) (26) (27) (28) (29) years old) and oldest group (70-79 years old), thereby identifying 1923 genes differentially regulated in aging (Fig. 2d, Supplementary Fig. S2 ). As shown in Fig. 2e , these genes show a significant overlap with the 1926 genes found to be differentially regulated by SARS-CoV-2 (p-value= 0.01999, Fisher's exact test), thereby confirming results obtained using a different analysis in [32] . Interestingly, these 219 genes that we found to intersect the SARS-CoV-2 infection and aging pathways (Fig. 2e ) display concordant changes in gene expression (i.e. the majority of genes is either upregulated or downregulated with SARS-CoV-2 infection and aging) as shown by the log 2 -fold changes in Fig. 2f and Supplementary  Fig. S3a . The association in the directionality of regulation between SARS-CoV-2 infection and aging is statistically significant (p-value < 2.2 × 10 −16 , Fisher's exact test), thereby providing further evidence for the interplay of SARS-CoV-2 host response and aging as hypothesized in [21] . Fig. 2g shows the log 2 -fold changes of the 10 most differentially expressed genes across aging and SARS-CoV-2 infection (based on the sum of their ranks with Supplementary Fig. S3b showing the distribution of the ranks).
Identification of SARS-CoV-2 infection signature in reduced L1000 gene expression space Next, we focused our analysis on identifying the SARS-CoV-2 transcriptional signature, which we then correlated with the transcriptional signatures of FDA approved drugs in CMap to identify drugs that could revert the effect of SARS-CoV-2 infection. While this analysis resulting in an initial ranking of FDA approved drugs did not take the transcriptional signature of aging into account, aging was a critical component in the final selection of FDA approved drugs described below.
Since gene expression in CMap was quantified using L1000 reduced representation expression profiling [2] , which measures gene expression of 1000 representative genes, we first sought to analyze whether these genes sufficiently capture the transcriptional signature of SARS-CoV-2 infection. For this, we intersected the genes measured both by Blanco et al. [23] and CMap [2] , resulting in 911 genes. We found a statistically significant overlap between the genes identified as differentially expressed by SARS-CoV-2 infection in Fig. 2 and the L1000 genes (p-value=7.94 × 10 −16 , Fisher's exact test), thereby providing a rational for using the CMap database for drug identification in this disease context (Fig. 3a) . We thus proceeded to obtain the signature of SARS-CoV-2 infection in the reduced L1000 gene expression space by projecting the RNA-seq data of A549 cells with and without ACE2-receptor and SARS-CoV-2 infection onto the shared 911 genes. The resulting signatures of SARS-CoV-2 infection and ACE2-receptor are visualized using the first two principal components in Fig. 3b . Interestingly, the signature of SARS-CoV-2 infection (indicated by arrows) was aligned across both A549 and A549-ACE2 cells as well as across different levels of infection (MOI of 0.2 and 2), suggesting that the SARS-CoV-2 transcriptional signature was captured robustly by the L1000 genes, thus providing further rational for using CMap to identify drugs that could reverse the effect of SARS-CoV-2 infection.
Combined autoencoder and synthetic interventions framework to identify drug signatures and rank FDA approved drugs for SARS-CoV-2
Next, we sought to determine transcriptional drug signatures using the CMap database, which includes among other cell lines A549. The data was visualized using Uniform Manifold Approximation and Projection (UMAP) [33] in Supplementary Fig. S4a , showing that the perturbations clustered by cell type and hence the drug signatures were small relative to the differences between cell types. We intersected the perturbations from CMap with a list of FDA approved drugs using Slinky [34] , resulting in 759 drugs of which 605 were available for A549. After removing batch effects using k-means clustering (see Methods and Supplementary Fig. S4b ), we computed initial signatures of these drugs based on the mean before and after drug perturbation in A549 cells. Fig. 3c shows a selection of drug signatures in relation to the signature of SARS-CoV-2 infection visualized using the top two principal components.
Since the effect of a drug can be cell-type specific [35] , this standard approach to computing drug signatures may not allow extrapolating the obtained signatures beyond A549 cells. In order to determine robust drug signatures and consider also FDA approved drugs that have been dosed on cell lines other than A549 in CMap, we employed an autoencoder framework. Autoencoders, a particular class of neural networks where an input is mapped through a latent space to itself, have been widely used for representation learning [25, 26, 36] and more recently also in genomics and single-cell biology [37, 38, 39] . We trained an autoencoder (architecture described in Supplementary Fig. S5 ) to minimize reconstruction error on CMap data and data from Blanco et al. [23] in the L1000 gene expression space. We then computed the disease and drug signatures based on the embedding of the data in the latent space. Interestingly, by comparing the correlations between drug signatures obtained from A549 cells and MCF7 cells (Fig. 3d ) as well as HCC515 cells ( Supplementary Fig. S7 ), cell lines with many perturbations in CMap, it is apparent that the autoencoder aligned the drug signatures across different cell types. While autoencoders and other generative models have been used for computing signatures of perturbations also in other works [39, 40] , these works have used autoencoders in the standard way to obtain a lowerdimensional embedding of the data. Motivated by our recent work which, quite counter-intuitively, described various benefits of using autoencoders to learn a latent representation of the data that is higher -dimensional than the original space [41] , we found that overparameterized autoencoders not only led to better reconstruction of the data than standardly used autoencoders (Supplementary Fig. S6 and architectures described in Supplementary Fig. S5 ), but also to a better alignment of drug signatures between different cell types ( Supplementary Fig. S7 ). Interestingly, overparameterized autoencoders provided about the same alignment of drug signatures as using the top three principal components (Fig.  3e) , while at the same time allowing a near perfect reconstruction of the original gene expression vectors from the embedding. Providing additional validation of the latent space embedding obtained by the overparameterized autoencoder, we found that known ACE2 inhibitors were generally aligned with the reverse signature of ACE2 in A549 cells (e.g. correlations for moexipril, quinapril and perindopril are all 0.88; see Supplementary Dataset 1). We thus used this latent space embedding to rank the drugs based on their correlation with the reverse disease signature in A549 cells (Supplementary Dataset 1). Since overparameterized autoencoders aligned drug signatures across cell types, this embedding also allowed constructing synthetic interventions [27, 28] , i.e., to predict the effect of a drug on A549 cells without measuring it, by linearly transferring the corresponding drug signature in the latent space from a cell type where it has been measured. In this way, we obtained an enlarged list of drug signatures, which we correlated in the latent space with the reverse disease signature to obtain further candidates of FDA approved drugs for SARS-CoV-2 (Supplementary Dataset 1). To compare the correlations obtained with the different embeddings, a list of the top ranked drugs is shown in Fig. 3f . Interestingly, it contains various drugs that were identified also in [6] using a different analysis (clemastine, haloperidol, ribavirin) or are currently in clinical trials (ribavirin, quinapril).
Steiner tree analysis identifies candidate drug targets by constructing combined SARS-CoV-2 and aging interactome Our differential expression analysis revealed relevant genes to investigate in the context of SARS-Cov-2 infection and aging, while the combined autoencoder and synthetic interventions analysis provided candidate FDA approved drugs for reverting the effect of SARS-CoV-2 infection. Next, we integrated these two separate analyses to obtain a final list of FDA approved drugs by constructing a combined SARS-CoV-2 infection and aging protein-protein interactome and intersecting it with the targets of the candidate drugs (Fig. 4a ). For this, we selected the differentially expressed genes identified in Fig. 2f that showed concordant regulation between aging and SARS-CoV-2 infection and intersected them with the nodes of the human protein-protein interaction (PPI) network (IRefIndex Version 14 [42] ), which contains 182,002 interactions between 15,759 human proteins along with a confidence measure for each interaction. This resulted in 162 protein-coding genes, which we call terminals (Supplementary Fig. S8 and Methods). To gain a better understanding of the molecular pathways connecting these terminal genes, we used a Steiner tree algorithm [30, 43] to determine a "minimal" subnetwork or interactome within the PPI network that connects these genes (see Methods). A Steiner tree is minimal in that it is a minimum weight subnetwork that connects the terminals. As edge weights in the PPI network we used 1 minus the confidence in the corresponding interactions so as to favor high-confidence edges. After a careful sensitivity analysis to select the various tuning parameters (Methods and Supplementary  Fig. S9 ), this resulted in an interactome containing 252 nodes and 1,003 edges ( Fig. 4b and Supplementary Fig. S10 ). Interestingly, the interactome contained five genes whose corresponding proteins have been found in [6] to interact with SARS-Cov-2 proteins (EXOSC5, FOXRED2, LOX, RBX1, RIPK1). The 2-nearest-neighborhoods of these proteins are shown in Fig. 4c . Another Steiner tree analysis revealed that two additional SARS-Cov-2 interaction partners (CUL2 and HDAC2) were connected to the identified interactome via few high-confidence edges ( Supplementary Fig. S11 -S13).
Next, we intersected the interactome with the targets of the candidate drugs identified in the previous analysis. A compound was considered if its signature matched the reverse SARS-CoV-2 signature with at least a correlation of 0.86, resulting in about 300 FDA approved drugs (see Methods). The targets of these drugs were determined using DrugCentral [44, 45] and filtered for high affinity (activity constants lower than 10µM , a common threshold used in the field for K i , K d , IC50 or EC50). Interestingly, the resulting drugs, shown in Fig. 4d , consisted (with few exceptions) of protein kinase inhibitors (e.g. axitinib, dasatinib, pazopanib, sunitinib). To analyze the specificity of our findings to SARS-Cov-2 infection in aged individuals, we repeated the above analysis without using the GTEx data. This resulted in an interactome containing 1,052 edges across 270 nodes, 42 of which (15%) were also present in the interactome taking age into consideration ( Supplementary Fig. S14 ). This pure SARS-CoV-2 interactome contained 6 SARS-Cov-2 interaction partners (ETFA, GNB1, NUP62, RBX1, RIPK1, SNIP1). Drugs targeting proteins in this interactome belonged to several families including serotonin inhibitors (clozapine, cyproheptadine, desipramine, methysergide), histamine H1 blockers (clemastine, cyproheptadine, ketotifen), tyrosine kinase inhibitors (including axitinib, dasatinib, pazopanib, sunitinib) and HDAC inhibitors (vorinostat, belinostat). This analysis shows that taking aging into account acted as a valuable filter for the identification of drugs.
Causal structure discovery methods validate serine/threonine and tyrosine kinases as critical targets in SARS-CoV-2 infection in the elderly.
Finally, in order to suggest putative causal drug mechanisms and validate the predicted drugs for COVID-19, we supplemented the PPI analysis with causal structure discovery. Since the edges in the PPI network and hence in the SARS-CoV-2 and aging interactome are undirected, it is a-priori not clear whether a drug that targets a node in the interactome has any effect on the differentially expressed terminal nodes, since the target may be downstream of these nodes (Fig. 5a) . To understand which genes can be modulated by a drug, it is therefore critical to obtain a causal (directed) network. We obtained single-cell RNA-seq data for A549 cells from [46] and intersected it with the genes present in the combined SARS-CoV-2 and aging interactome. To learn the (causal) regulatory network among these genes, we took advantage of recently developed causal structure discovery algorithms, in particular the greedy sparsest permutation (GSP) algorithm: it performs a greedy search over orderings of the genes to find the sparsest causal network that best fits the data ,and it has been successfully applied to single-cell gene expression data before [11, 12, 47] . To validate the obtained causal model and benchmark the performance of GSP to other prominent causal structure discovery algorithms including PC and GES [48] , we took advantage of the gene knockout and overexpression data available from CMap. A causal model should allow predicting the effect of such interventions. Thus, for each such gene knockout and overexpression experiment in CMap that targeted a gene in the interactome, we inferred the genes whose expression changed as a result of the intervention, when compared to control samples (Methods and Supplementary Fig. S15a ). We then constructed receiver operating characteristic (ROC) curves to evaluate GSP, PC and GES by varying their tuning parameters and counting an edge i → j as a true positive if intervening on gene i resulted in a change in the expression of gene j and a false positive otherwise, thereby showing that GSP exceeded random guessing based on the PPI network (p-value=0.0177, see Methods) and outperformed the other methods ( Supplementary Fig. S15b ).
Having established that the causal network obtained by GSP can be used to predict the effect of an intervention, we turned to analyzing the regulatory effects of the identified candidate drugs on the SARS-CoV-2 and aging interactome in A549 cells. The main connected component of the corresponding causal graph is shown in Fig. 5a (see also Supplementary Fig. S16a ) highlighting the drug targets and the genes that were found to be differentially expressed by SARS-CoV-2 infection and aging. We then traced the possible downstream effects for each identified drug, thereby finding that the protein kinase inhibitors and HDAC inhibitors could target the majority of differentially expressed genes in this connected component (Table S1 ). Similarly, we traced the downstream effects for each gene in the interactome that can be targeted by one of the identified drugs, thereby finding that EGFR, FGFR3, HDAC1, HSP90AA1, IRAK1, PAK1, RIPK1, RIPK2, STK3 all have downstream nodes in the interactome with RIPK1 having the largest number of them (127). To validate these results in a broader context, we obtained single-cell RNA-seq data from [49] and repeated the analysis in AT2 cells, which have been shown to be critically affected by SARS-CoV-2 in humans [31] . The resulting causal network for AT2 cells ( Supplementary  Fig. S16b ) is similar to the one for A549 cells, intersecting it in 55.3% of the edges, with EGFR, HDAC1, HSP90AA1, IRAK1, RIPK1 and RIPK2 all having descendants in the interactome, and targets of protein kinase inhibitors and HDAC inhibitors being particularly central (Table S1 ). To analyze the most critical targets for the crosstalk between SARS-CoV-2 and aging, we repeated the analysis in the interactome obtained without taking aging into account ( Supplementary Fig. S16c ). Interestingly, while HDAC1 and HSP90AA1 continued to have widespread effect, the number of genes downstream of RIPK1 changed drastically to just 1, suggesting that RIPK1 plays a critical role in the SARS-CoV-2 and aging cross-talk. In line with this, while the effect of HDAC inhibitors remained similar in the analysis without ageing, the effect of protein kinase inhibitors changed drastically (Table S1 ). Collectively, our combined analysis points to protein kinase inhibitors, and it in particular highlights RIPK1, a serine/threonine-protein kinase, as one of the main targets against SARS-CoV-2 infections with a highly age-dependent role and the largest number of downstream differentially expressed genes in the combined SARS-CoV-2 and ageing interactome.
The repurposing of drugs for SARS-CoV-2 has been a major challenge given the many pathways involved in host-pathogen interactions and the intricate interplay of SARS-CoV-2 with inflammatory pathways [14, 13, 15, 16] . Interestingly, while both young and old individuals are susceptible to SARS-CoV-2 infection, the virus' pathogenicity is significantly more pronounced in the elderly [17, 18] . Since the mechanical properties of the lung tissue change with aging [19] , this led us to hypothesize an interplay between viral infection/replication and tissue aging [21] , suggesting that this could play an important role in drug discovery programs. While ongoing drug repurposing efforts have analyzed host-pathogen interactions and the associated gene expression programs [6, 23] , they have lacked an integration with aging. More generally, while a number of data-driven and experimental approaches have been proposed for drug identification and repurposing [1] , a platform that systematically integrates different data modalities including transcriptomic, proteomic and structural data into a principled causal framework to predict the effect of different drugs has been missing.
By combining bulk RNA-seq data from GTEx [24] and Blanco et al. [23] , we identified a critical group of genes that were differentially expressed by aging and by SARS-CoV-2 infection. While previous analysis relied primarily on contrasting the expression in cells with and without SARS-CoV-2 infection [32] , we made an attempt to separate the effect of the ACE2 receptor alone and the effect of SARS-CoV-2 in cells without ACE2 receptor to extract a more refined differential expression pattern of ACE2-mediated SARS-CoV-2 infection. While previous computational efforts to repurpose drugs have mainly considered two approaches: (1) identifying drug targets by analyzing disease networks based for example on PPI or transcriptomic data [5, 4, 6] , and (2) identifying drugs by matching their signature (for example obtained from the CMap project [2] ) to the reverse disease signature [3] , we developed a principled causal framework that encompasses these two approaches. First, in order to ensure that the CMap database, which measures expression using 1000 representative genes, would be useful in the context of SARS-CoV-2, we validated that the intersection of these genes with the SARS-CoV-2 differentially expressed genes was significant. Second, to establish drug signatures based on the CMap database, we employed a particular autoencoder framework [41] . Rather unintuitively, we showed that using an overparameterized autoencoder, i.e. by using an autoencoder not to perform dimension reduction as usual but to instead embed the data into a higher-dimensional space, aligned the drug signatures across different cell types. This allowed constructing synthetic interventions, i.e., to predict the effect of a drug on a cell type without measuring it by using other cell types to infer it. Third, to identify drug targets in the pathways intersecting SARS-CoV-2 and aging, we connected the differentially expressed genes in the PPI network using a Steiner tree analysis [30] and intersected the resulting interactome with high-affinity targets of the drugs obtained using the overparameterized autoencoder framework. Finally, while computational drug discovery programs have been largely correlative [1] , we made use of recent causal structure discovery algorithms [11, 47, 48] to validate the identified drug targets and their downstream effects, thereby identifying protein kinase inhibitors such as axitinib, dasatinib, pazopanib, and sunitinib as drugs of particular interest for the repurposing against COVID-19.
Among the various protein kinases, in particular from the family of serine/threonine-protein kinases, identified by our drug repurposing pipeline, RIPK1 was singled out by our causal analysis as being upstream of the largest number of genes that were differentially expressed by SARS-CoV-2 infection and aging, while losing its central role in the corresponding gene regulatory network without taking aging into account. Notably, RIPK1 has been shown to bind to SARS-CoV-2 proteins [6] and has also been found to be in an age-dependent module [32] . RIPK1 belongs to an interesting family of proteins comprising of a kinase domain on the N terminus and a death domain on the C terminus; activation of the kinase domain has been associated with epithelial cell homeostasis, while activation of the death domain leads to triggering necroptotic or apoptotic pathways [50, 51] , the death pathways potentially triggering tissue fibrosis [52] . Interestingly, our differential expression analysis found RIPK1 to be upregulated with SARS-COV-2 infection. We hypothesize that upon SARS-CoV-2 infection in older individuals the death pathways may be favored, thereby leading to fibrosis and increased blood clotting. Consistent with this, recent post-mortem lung tissue biopsies of SARS-CoV-2 human patients revealed a fibrotic epithelium and increased blood clotting [53, 54] .
Collectively, these results highlight the importance of RIPK1 in the interplay between SARS-CoV-2 infection and aging as a potential target for drug repurposing programs. There are various drugs currently approved that non-specifically target RIPK1 (such as pazopanib and sunitinib) as well as under investigation that are highly specific to RIPK1 [55, 56] . Given the distinct pathways elicited by RIPK1, there is a need to develop appropriate cell culture models that can differentiate between young and aging tissues to validate our findings experimentally and allow for highly specific and targeted drug discovery programs. While our work identified particular drugs and drug targets in the context of COVID-19, our computational platform is applicable well beyond SARS-CoV-2, and we believe that the integration of transcriptional, proteomic and structural data with network models into a causal framework is an important addition to current drug discovery pipelines.
The RNA-seq gene expression data related to SARS-CoV-2 infection in A549 and A549-ACE2 cells was obtained from [23] under accession code GSE147507. The RNA-seq data of lung tissues for the aging analysis was downloaded from the GTEx Portal (https://gtexportal.org/home/index.html) along with metadata containing the age of the individual from whom the RNA-seq sample was obtained. The RNA-seq raw read counts were transformed into quantile normalized, log 2 (x + 1) scaled RPKM values, following the normalization performed in [2] .
For differential expression analysis, we focused on genes that were highly expressed, filtering out any genes with log 2 (RPKM +1) < 1 for all considered datasets. In order to determine the ACE2-mediated SARS-CoV-2 genes, we computed three different log 2 -fold changes based on the data from [23] . Namely, we defined as ACE2-mediated SARS-CoV-2 genes all genes that had an absolute log 2 -fold change between A549-ACE2 cells infected with SARS-CoV-2 and A549-ACE2 cells above threshold, excluding genes that had an absolute log 2 -fold change above the same threshold in A549-ACE2 cells versus A549 cells and also excluding genes that had an absolute log 2 -fold change above the same threshold in A549 cells infected with SARS-CoV-2 versus normal A549 cells. In other words, the ACE2-mediated SARS-CoV-2 genes were defined as the genes denoted in red in the Venn diagram in Fig. 2b (with pink, brown and yellow subsets removed). The absolute log 2 -fold change threshold was determined such that the number of ACE2-mediated SARS-CoV-2 genes was 10% of the protein coding genes.
In order to determine the age associated genes, we analyzed lung tissue samples obtained from the GTEx portal (https://gtexportal.org/home/index.html) from individuals of varying ages. We computed the absolute log 2 -fold change between samples of the lung tissue from older (70-79 years old) and younger (20-29 years old) individuals, defining the age associated genes as the top 10% of protein coding genes with highest absolute log 2 -fold change. We also considered defining age-associated genes based on the absolute log 2 -fold change comparing individuals who are 20-29 years old versus 60-79 years old, which yielded similar age-associated genes, with 1339 out of the 1923 genes in common between the two sets as shown in Supplementary Fig. S2b .
Gene ontology analysis was performed on a given gene set using GSEApy, keeping the top 10 gene ontology biological process terms with lowest p-values. All reported terms had p-values ≤ 0.05, after adjusting for multiple hypothesis testing using the Benjamini-Hochberg procedure.
The CMap data measured via L1000 high-throughput reduced representation expression profiling, which quantifies the expression of 1000 landmark genes, was obtained from [2] under accession code GSE92742.
We chose level 2 data, truncated to only the genes that were also measured by [23] , and then performed log 2 (x + 1) scaling and min-max scaling on each of the resulting 911-dimensional expression vectors.
We first describe our training procedures for the autoencoder framework. CMap contains a total of 1,269,922 gene expression vectors and we performed a 90-10 training-test split resulting in 1,142,929 training examples and 126,993 test examples. We selected the best model by applying early stopping with an upper bound on the number of total epochs being 150. Note that this is well past the usual early stopping method of applying a patience strategy with a patience of at most 10 epochs [57] . All hyperparameter settings, optimizer details, and architecture details are presented in Supplementary  Fig. S5c . To summarize, we considered a range of fully connected autoencoders with varying depth, width, and nonlinearity, and we used Adam with a learning rate of 10 −4 for optimization. To compute the drug signatures via the trained autoencoder, we used as embeddings the output of the first hidden layer prior to application of the activation function.
Drug signatures for the A549 cells (and similarly for the MCF7 and HCC515 cells) in CMap were computed by taking the difference between the mean embedding for the A549 samples with drug and the mean embedding for the A549 control (DMSO) samples. To remove batch effects, we performed k-means clustering of the control samples in the embedding space and removed all points falling in the smaller of the two clusters (see Supplementary Fig. S4b ).
Next, we briefly describe the synthetic interventions framework and how the embedding from our trained overparameterized autoencoder is used for this. The traditional application of synthetic interventions [27, 28] in the context of drug repurposing would proceed as follows: when a drug signature is unavailable on a given cell type but is available on other cell types, we would express the cell type as a linear combination of the other cell types and use this linear combination to predict the signature on the cell type for which data is unavailable. Since we demonstrated that over-parameterized autoencoders align drug signatures between different cell types ( Supplementary Fig. S7) , instead of using a linear combination of drug signatures across cell types, we can simply use one of the available drug signatures as the synthetic intervention. In particular, in this work, we used drug signatures on MCF7 cells to construct synthetic interventions for A549 cells. We also considered drug signatures on HCC515 cells; however, there was only one FDA approved drug that was applied to HCC515 cells which was not also applied to A549 cells in CMap. While this analysis did not help to increase the number of considered drugs, we used the data on HCC515 cells in conjunction with the data on A549 and MCF7 cells to validate that the overparameterized autoencoder aligns the signatures of drugs between different cell types ( Fig. 3d and Supplementary Fig. S7 ).
For each cell type and perturbation, we computed a cell-type specific "perturbation signature", which is defined as the difference between the average gene expression of a cell type under that perturbation and under the control perturbation, DMSO. Then, for each perturbation, we computed the cosine similarity a·b |a||b| between the perturbation vectors for all pairs of cell types which received that perturbation in CMap. For example, daunorubicin was applied to 14 cell types in cMap, resulting in 14 2 = 91 cosine similarities associated with daunorubicin. All cosine similarities were plotted (Fig. 3e) .
Human protein-protein interaction (PPI) network A weighted version of the publicly available IRefIndex v14 human PPI network [42] was retrieved from the OmicsIntegrator2 GitHub repository (http://github.com/fraenkel-lab/OmicsIntegrator2). The interactome contains 182,002 interactions between 15,759 proteins. Each interaction e has an associated cost c(e) = 1 − m(e) where the score m(e) is obtained using the MIScore algorithm [58] , which quantifies confidence in the interaction e based on several evidence criteria (e.g. number of publications reporting the interaction and corresponding detection methods).
A high-confidence host-pathogen interaction map of 27 SARS-Cov-2 viral proteins with HEK293T proteins [6] was retrieved from NDEx (http://www.ndexbio.org/#/network/5d97a04a-6fab-11ea-bfdc-0ac135e8bacf), which reports interactions with 332 human proteins.
Data on the targets of drugs was obtained from DrugCentral (http://drugcentral.org/download), an online drug information resource, which includes drug-target interaction data extracted from the literature along with metrics (such as inhibition constant K i , dissociation constant K d , effective concentration EC50, and inhibitory concentration IC50) measuring the affinity of the drug for its target [44, 45] . Drugs in the database are approved by the FDA and may also be approved by other regulatory agencies (such as the EMA). From this database, we filtered out compounds targeting non-human proteins. We also discarded drug-target pairs with affinity metrics (K i , K d , EC50 or IC50) higher than 10µM , a commonly used threshold in the field. Based on this filtering we obtained a data set containing 12,949 high affinity drug-target pairs involving 1,457 unique human protein targets and 2,095 unique compounds. This dataset was further restricted to drugs predicted to reverse the SARS-Cov-2 signature (correlation greater than 0.86 in the overparameterized autoencoder embedding). As a result, the final drug-target data set included information on 2,296 drug-target pairs involving 652 unique human gene targets and 117 unique FDA approved drugs.
The Prize-Collecting Steiner Forest (PCSF) problem is an extension of the classical Steiner tree problem: Given a connected undirected network with non-negative edge weights (costs) and a subset of nodes, the terminals, find a subnetwork of minimum weight that contains all terminals. The resulting subnetwork is always a tree, which in general contains more nodes than the terminals; these are known as Steiner nodes. In the special case when there are only 2 terminals, this boils down to finding the shortest path between these nodes. The Steiner tree problem in general is known to be NP-complete, but various approximations are available. The PCSF problem generalizes this problem by introducing prices for the terminals (in addition to the edge costs already present in the Steiner tree problem) and a dummy node connected to all terminals. The problem is then to find a connected subnetwork that minimizes an objective function involving the cost of selected edges and the prizes of terminals that are missing from the subnetwork as detailed below; we used OmicsIntegrator2 to solve this optimization problem [30] .
To formally introduce the objective function, let G = (V, E, c(·), p(·)) denote the undirected PPI network with protein set V (containing N proteins), interaction set E, edge cost function c(·), set of terminals S ⊂ V (containing N proteins) and attributed prizes p(·). The version of the PCSF problem solved by OmicsIntegrator2 [30] and used in this article consists of finding a connected subnetwork T = (V T , E T ) of the modified graph G * = (V ∪ {r}, E ∪ {{r, s} : s ∈ S}) that minimizes the objective function
The node r is a dummy root node connecting all terminals in the network. The parameter b ∈ R + linearly scales the node prizes (which are non-zero for terminal nodes exclusively), and the modified edge cost function c * (·) can be expressed as follows. For any edge e = {x, y}
where d x denotes the degree of node x in G and g, w ∈ R + are tuning parameters. If the resulting tree contains the root node r, r is removed from the tree, and the output is an ensemble of trees, a forest. The final output, the interactome, is the subnetwork in the PPI network induced by the nodes of this forest.
Results from the differential expression analysis yielded 219 protein-coding genes that were associated with both aging and SARS-Cov-2 infection. Of particular interest among these genes were 181 genes that showed concordant regulation, i.e. they were either upregulated in both SARS-Cov-2 infection and aging or downregulated in both SARS-Cov-2 infection and aging. Intersecting the proteins corresponding to these 181 genes with proteins in the IREF interactome resulted in 162 proteins. These 162 proteins were selected as terminal nodes for the PCSF algorithm and prized according to their absolute log 2 -fold change between SARS-Cov-2-infected A549-ACE2 cells and normal A549-ACE2 cells ( Supplementary  Fig. S8 )
Running the PCSF algorithm in the OmicsIntegrator2 required specifying three tuning parameters: g, w and b. In order to guarantee the robustness of the resulting network with respect to moderate changes in these parameters, we selected the parameters based on a sensitivity analysis. The parameter g modifies the background PPI network by imposing an additive penalty on each edge based on the degrees of the corresponding vertices. It reduces the propensity of the algorithm to select hub nodes connecting many proteins in the interactome. While this feature may be relevant in certain biological applications, it was not necessarily the case in our work since high degree nodes may be of interest for the purpose of drug target identification. In the cost function in Equation (1), the absence of penalty corresponds to g = −∞. However the OmicsIntegrator2 implementation only allows for g ∈ R + . In Supplementary Fig. S9a1 , we reported boxplots of penalized edge costs in the IREF interactome for different values of g. These boxplots suggest that the hub penalty parameter g = 0 yields similar edge costs to the desired setting where g = −∞. For this reason we chose the value g = 0 in all OmicsIntegrator2 runs in this work.
The parameter w corresponds to the cost of edges connecting terminal nodes to the dummy root r. This parameter influences the number of trees in the Steiner forest. If w is chosen too low compared to the typical shortest path cost between two terminals, a trivial solution will connect all terminal nodes via r, leading to fully isolated terminals in the final forest. For high values of w the PCSF algorithm will not include the root r and output a connected network. Based on the histogram of the cost of the shortest path between any two terminals in the IREF interactome reported in Supplementary Fig. S9a2 , we ran a sensitivity analysis for w in the range [0.2, 2].
The parameter b linearly inflates the prizes of terminal nodes in the objective function. Higher values of b result in more terminal nodes in the final PCSF. We analyzed edge costs in the network to determine a suitable range for b so as to include many terminal nodes in the resulting interactome. Supplementary  Fig. S9a1 shows that the maximum edge cost in the network for g = 0 was lower than 1, which meant that making b of order greater than 1 was necessary to ensure that trading off cost of edges added and prizes collected in the solution would rarely require discarding a terminal node. For this reason we ran a sensitivity analysis for b in the range [5, 50] .
Based on the previous considerations we fixed g = 0 and ran a sensitivity analysis as described in Supplementary Fig. S9b 10, 15, 20, 25, 30, 35, 40, 45, 50} . We obtained 100 PCSFs, each corresponding to a particular choice of (w, b). All of them included the entire terminal set S, a desired property resulting from the chosen range of the values of b. To analyze the robustness of the resulting networks to changes in the parameters, we analyzed the matrix M ∈ [0, 1] 100×100 defined by
for every pair of PCSFs i and j corresponding to parameters (w i , b i ) and (w j , b j ), respectively. Supplementary Fig. S9c displays heatmaps of this matrix. We considered three different node sets C, namely the set of all nodes in the input PPI network ( Supplementary Fig. S9c1 ), the subset of terminal nodes (C = S, Supplementary Fig. S9c2 ) and the subset of SARS-Cov-2 interaction partners ( Supplementary  Fig. S9c3 ). Supplementary Fig. S9c1 , S9c2, S9c3 illustrate that choosing any (w, b) ∈ [1.2, 2] × [5, 50] led to the same connected PCSF with 252 nodes and 1,003 edges. This network is robust to moderate parameter changes for w and b. Collectively, this sensitivity analysis motivated the choice of g = 0, w = 1.4 and b = 40 used to obtain the interactome in Fig. 4b , where nodes are grouped by general function. The same interactome is presented in Supplementary Fig. S10 with nodes grouped by general process. Note that since this interactome included all terminals and did not include the root node, it is equivalent to the solution of the classical Steiner tree problem.
For the interactomes obtained in this work, we reported 2-nearest-neighborhoods of genes of interest in Fig. 4c for the interactome of Fig. 4b , in Supplementary Fig. S13 for the interactome of Supplementary  Fig. S12 , and in Supplementary Fig. S14d for the interactome in Supplementary Fig. S14c . Depending on the interactome, genes of interest include SARS-Cov-2 interaction partners (e.g. EXOSC5, FOXRED2, LOX, RBX1, RIPK1) as well as genes of potential therapeutic interest (e.g. HDAC1, EGFR). Neighborhood plots were enriched with information such as SARS-Cov-2 interaction partners and FDA approved, high affinity (based on data from DrugCentral) drugs with high correlation to the reverse SARS-Cov-2 infection signature. To improve legibility of the neighborhood networks, we discarded the highly connected hub node UBC (connected to 62% of proteins in the IREF network). To further improve legibility, we applied an upper threshold on edge cost (i.e., only visualizing high confidence edges) when the neighborhood networks were too densely connected. We generally chose this threshold at 0.53, with the exception of the LOX neighborhood (0.58) and the FOXRED2, ETFA and GNB1 neighborhoods (no thresholding). For each edge e in a given neighborhood, we defined the min-max scaled edge confidence C(e) as
where E denotes the edge set of the corresponding interactome and c(e) denotes the cost of edge e in the PPI network. This confidence metric was used to color edges in the neighborhood plots.
In order to understand which other SARS-CoV-2 protein interaction partners were in the neighborhood of the identified interactome, we also ran the PCSF algorithm on the IREF PPI network using the SARS-Cov-2 and aging terminal list augmented with all known SARS-Cov-2 interaction partners. All SARS-Cov-2 interaction partners (with the exception of EXOSC5, FOXRED2 and LOX which were already present in the original terminal gene list) were given a small prize p. This prize was chosen by sensitivity analysis over a range of possible values from p = 0 (5 SARS-Cov-2 interaction partners initially selected by the method: EXOSC5, FOXRED2, LOX, RBXL1, RIPK1) to p = 0.02, beyond which all 332 known SARS-Cov-2 interaction partners belonged to the computed interactome. Finegrained analysis revealed that choosing p ∈ [4 × 10 −4 , 10 −3 ] leads to interactomes which include a stable set of 7 SARS-Cov-2 interaction partners, the 5 present initially plus CUL2 and HDAC2 ( Supplementary  Fig. S11a ). Supplementary Fig. S11b -S11c display heatmaps of the matrix M ∈ [0, 1] 16×16 defined as
for every pair of PCSFs i and j corresponding to parameters p i and p j , respectively. For the sensitivity analysis, we considered two different node sets C, namely the set of all nodes in the input PPI network ( Supplementary Fig. S11b ) as well as the subset of SARS-Cov-2 interaction partners ( Supplementary  Fig. S11c) . Supplementary Fig. S11b shows that the obtained interactome was stable over the range p ∈ [7 × 10 −4 , 10 −3 ]. Supplementary Fig. S11c shows that all SARS-Cov-2 interaction partners collected in the interactome when p ∈ [7 × 10 −4 , 10 −3 ] were also collected for higher values of p, which is a consequence of the observation from Supplementary Fig. S11b . We used the value p = 8 × 10 −4 for all subsequent analyses and figures, including Supplementary Fig. S12 and Supplementary Fig. S13 .
Single-cell RNA-seq for A549 cells was obtained from GSE81861 [46] , where each entry in the matrix represents the gene expression (FPKM) of gene i in cell j. We preprocessed the data, keeping only genes that had a nonzero gene expression value in more than 10% of the cells, followed by log 2 (x + 1) transformation of the data. Single-cell RNA-seq data for AT2 cells was obtained from http://www.nupulmonary.org/resources associated with [49] . In order to avoid batch effects, we subset the data to include cells only from Donor 7 since that donor had the largest number of AT2 cells collected (4002 cells). We preprocessed the data using the same threshold as for A549 cells for filtering out genes across cells. Since single-cell RNA-seq data for AT2 cells was not yet normalized, we normalized the expression values across genes for each cell by the total RNA count for that cell, followed by log 2 (x + 1) transformation of the data as for A549 cells.
Prior to reporting the results of learning gene regulatory networks on A549 and AT2 cells, we benchmarked several causal structure discovery methods on the task of predicting the effects of interventions using gene knockout and overexpression data collected on A549 cells as part of the CMap project [2] , similar to prior evaluations of causal methods [11, 12] . We estimated the gene regulatory network underlying the identified interactome in A549 cells using the prominent causal structure discovery methods PC, GES and GSP [8, 48, 47] . Since not all edge directions are identifiable from purely observational data, these methods output a causal graph containing both directed and undirected edges. Since the advantage of causal networks is their ability to predict the effects of interventions on downstream genes, we evaluated these methods using interventions collected in CMap. In the following, we first describe how we estimated the effects of interventions based on the CMap data to use as ground truth for evaluating causal structure discovery methods. We focused our evaluation on genes and interventions that are shared between the combined SARS-CoV-2 and aging interactome and CMap knockout and overexpression experiments, resulting in 32 genes and 41 interventions (note that the number of interventions is larger than the number of genes, since in CMap interventions have been performed on genes that are not part of the L1000 landmark genes, but are contained in the interactome). We formed a matrix of genes by interventions, where each (i, j)-entry in the matrix represents the log 2 -fold change in expression of gene i when gene j was intervened on in comparison to the expression of gene i without intervention. We denoted by Q the binary matrix of intervention effects with Q ij = 1 if the sign of the log 2 -fold change for the (i, j) entry was opposite for knockout and overexpression interventions to filter out unsuccessful interventions, the rational being that knockout and overexpression should have opposite downstream effects. Thus Q ij = 1 denotes that perturbing gene j effects gene i and hence that gene i is downstream of gene j (Supplementary Fig. S15a ). Taking this matrix of interventional effects, Q, as the ground truth, we estimated the causal graph using the PC, GES and GSP algorithms and determined the corresponding ROC curve, counting and edge from j → i as a true positive if Q ij = 1 and a false positive otherwise (Supplementary Fig. S15b ). In order to statistically evaluate whether the different algorithms performed better than random guessing, we sampled causal graphs (from an Erdös-Renyi model, where the edges were directed based on a uniformly sampled permutation) with different edge probabilities from the PPI network and calculated the corresponding number of true and false positives. For each false positive level, we created a distribution over true positives based on the sampled random causal graphs and calculated the p-value for the number of true positives obtained from the PC, GES and GSP algorithms. We combined the p-values across different numbers of false positives using Fisher's method and used this combined p-value for evaluating whether the PC, GES and GSP algorithms were significantly different from random guessing.
In order to learn the gene regulatory networks governing A549 and AT2 cells, we used the recent structure discovery method GSP [47, 11, 12] on single-cell RNA-seq data from A549 cells as well as AT2 cells with the PPI network on 252 nodes as a prior. We used GSP since based on the previous analysis it outperformed the PC and GES algorithms in terms of ROC analysis on predicting the effect of gene knockout and overexpression experiments in A549 cells (p-value = 0.0177 for GSP, p-value = 0.0694 for GSP and p-value = 0.5867 for GES); in addition, GSP is also preferable from a theoretical standpoint, since it is consistent under strictly weaker assumptions than the PC and GES algorithms [47] . To obtain an estimate of the causal graph that is robust across hyperparameters and data subsampling, we used stability selection [59] . In short, stability selection estimates the probability of selection of each edge by running GSP on subsamples of the data. Aggregating selection probabilities across algorithm hyperparameters (in this case the α-level for conditional independence testing), edges with high selection probability (0.3 for A549 cells and 0.4 for AT2 cells) were retained. The threshold for AT2 cells was chosen so as to approximately match the number of edges in the A549 network.
All data used in this work is publicly available from the sources mentioned. We relied on open source code for the analysis (including OmicsIntegrator2, the R package pcalg, as well as the python packages causaldag, GSEApy, networkx, numpy, pandas, PyTorch, scikit-learn, scipy). A comprehensive GitHub repository containing all data and code will be made available upon publication of the manuscript. is associated with more severe outcomes in older individuals, suggesting that gene expression programs associated with SARS-CoV-2 and aging must be analyzed in tandem. A potential hypothesis regarding the crosstalk between SARS-CoV-2 and aging relies on changes in tissue stiffness in older individuals, outlined in [21] . (b) In order to identify potential drug candidates for COVID-19, we integrated RNA-seq data from SARS-CoV-2 infected cells (obtained from [23] ) and RNA-seq data from the lung tissue of young and old individuals (collected as part of the GTEx project [24] ) with protein-protein interaction data (from [42] ), drug-target data (from DrugCentral [45] ) and the large-scale transcriptional drug screen CMap [2] . (c) Based on this data, we develop a novel drug repurposing pipeline, which consists of first, mining relevant drugs by matching their signatures with the disease signature in the latent embedding obtained by an overparameterized autoencoder and sharing data across cell types to obtain missing drug signatures via synthetic interventions. Second, we identify a disease interactome within the proteinprotein interaction network by identifying a minimal subnetwork that connects the genes differentially expressed by SARS-CoV-2 infection and aging using a Steiner tree analysis. Third, we validate the drugs identified in the first step that have targets in the interactome by identifying the potential drug mechanism using causal structure discovery. The general procedure takes as input a list of genes of interest (terminal nodes) with prizes indicating their respective importance, a protein-protein interaction (PPI) network with edge cost/confidence information (e.g. from IRefIndex v14 [42] ), and a list of drugs of interest along with their protein targets and available affinity constants (e.g. from DrugCentral [44, 45] ). In this study we consider 181 terminal nodes (of which 162 are present in the IREF network) corresponding to genes differentially expressed in SARS-CoV-2 infection and aging from Figure 2 that are either up-regulated in both SARS-Cov-2 infection and aging or down-regulated in both SARS-Cov-2 infection and aging. The prize of a terminal node equals the absolute value of its log 2 -fold change in SARS-Cov-2-infected A549-ACE2 cells versus normal A549-ACE2 cells based on the data from [23] . Terminals and PPI data are processed using OmicsIntegrator2 [30] to output the disease interactome, i.e., the subnetwork induced by a Steiner tree, with drug targets indicated by green diamonds and terminal nodes colored according to their prizes. (b) Interactome obtained using this procedure. Genes are grouped by general function and marked with a cross if known to interact with SARS-Cov-2 proteins based on data from [6] . (c) 2-Nearest-Neighborhoods of nodes of interest (denoted by a red hexagon) in the interactome. A threshold was applied on the edge confidence to improve readability. Proteins known to interact with SARS-Cov-2 are denoted by blue squares, drug targets are denoted as green diamonds, terminal nodes are colored according to their log 2 -fold change in SARS-Cov-2-infected A549-ACE2 cells versus normal A549-ACE2 cells, Steiner nodes appear in grey. (d) Table of drug targets and corresponding drugs in the interactome. Selected drugs are FDA approved, high affinity (at least one of the activity constants K i , K d , IC50 or EC50 is below 10µM ), and match the SARS-Cov-2 signature well (correlation > 0.86). The affinity column displays − log 10 (activity). Protein name corresponding to each gene is included. FOXC2  GNRH1  SNAP25  N4BP3  HIVEP2  TCTE3  RAPGEF4  IL20RB  CREB5  LPAR6  GRHL1  OASL  HIST1H1D  OVGP1  HIST1H1E  SUMO4  COLEC11  HAS2  CHIC2  ZFC3H1  SMAD3  ZNF217  ELL  HIST1H4E  ARL4D  LOX  IFI44L  C5orf56  C19orf66  ZSWIM4  PML  CRY1  YY1AP1  INHBA  SP100  ETV6  SPRED3  IRF2  ZSWIM6  HIST3H2BB  SETD5  XAF1  DLL1  MTMR11  KRTAP5-1  LARP6  KAT6A  PHF21A  PLSCR1  RIPK2  TRIM38  WHAMM  GATAD2B  PDE4B  XRN1  ISG20  WDR26  CEP85L  ZNF8  MCTP1  GTPBP1  CDK17  TSPYL4  SCG2  RBM33  USP12  THAP2  HOXB3  PROX1  AURKC  CCDC71L  BTN2A2  BRSK1  MKLN1  TSC22D2  CHN1  RASA2  TERF2IP  CTTNBP2NL  TRAF6  PHC3  RBM5  SAV1  SFMBT2  RNF24  SEC31B  HECA  SMPDL3B  PYCR1  GOT1  TLCD1  TM7SF2  NSDHL  HADH  TRUB2  IPO4  PLS1  DPP3  SLC25A11  GPD1L  FOXRED2  EXOSC5  MMP15  MPDU1  QDPR  TMEM164  DOLK  FAH  PCCB  DCDC2  FARSA  APEH  SRPRB  GLB1  GBA  ARSD  ADK  CYB561D2  METTL13  TMEM238  NUDT14  CDH1  AIFM1  MEGF9  ALDH1B1  PXMP4  AGA  ACAT1  MMP24  C19orf48  MSH2  NLRP2  MIPEP  MSRB1  FADS1  PTPN13  GSR  CLN6  TNFSF15  GGT1  NIPSNAP1  POP1  FECH  TMEM56  PARP1  ATIC  MRPL37  SLC39A11  MYO5C  DTD2  SAC3D1  CCDC71  FH  SDSL  FGFBP1  FGFR3  SMIM4  PAICS  TIMM13  EBNA1BP2  MRPS16  ALG1  SLC27A4  CLN3  MANSC1  NLN  MRPL27  HMBS  OSGIN1  ORMDL2  SLC7A7  GSTZ1  MMAB  MRPS33  SLC31A1  EPS8L2  OCIAD2  PPA2  HSD17B8  THNSL1  TCTA  PDGFD  TM4SF18  HRASLS2  HBQ1  KLF5  LTB  FOXA2  ZNF165  NEDD4L  UTP3  PIGA  EGR2  FA2H  DNM1  RBP4  F8  TRNP1  TUBB1  B3GNT7  UAP1L1  SNCG  MAD2L1BP  PRSS23  ATP8B1  SLC22A17  CNTNAP1  PITPNM1  LTV1  PIGW  EXOC3L2  LGALSL  MED18  ADCY3  COPZ2  PDE4D  CSTF1  CACNA2D1  FAM84B   A549-ACE2 