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114


Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19

Blanco-Melo, Daniel; Nilsson-Payant, Benjamin E; Liu, Wen-Chun; Uhl, Skyler; Hoagland, Daisy; Møller, Rasmus; Jordan, Tristan X; Oishi, Kohei; Panis, Maryline; Sachs, David; Wang, Taia T; Schwartz, Robert E; Lim, Jean K; Albrecht, Randy A; tenOever, Benjamin R
Viral pandemics, such as the one caused by SARS-CoV-2, pose an imminent threat to humanity. Because of its recent emergence, there is a paucity of information regarding viral behavior and host response following SARS-CoV-2 infection. Here we offer an in-depth analysis of the transcriptional response to SARS-CoV-2 compared with other respiratory viruses. Cell and animal models of SARS-CoV-2 infection, in addition to transcriptional and serum profiling of COVID-19 patients, consistently revealed a unique and inappropriate inflammatory response. This response is defined by low levels of type I and III interferons juxtaposed to elevated chemokines and high expression of IL-6. We propose that reduced innate antiviral defenses coupled with exuberant inflammatory cytokine production are the defining and driving features of COVID-19.
PMCID:7227586
PMID: 32416070
ISSN: 1097-4172
CID: 4843472

Leveraging the antiviral type I interferon system as a first line of defense against SARS-CoV-2 pathogenicity

Hoagland, Daisy A; Møller, Rasmus; Uhl, Skyler A; Oishi, Kohei; Frere, Justin; Golynker, Ilona; Horiuchi, Shu; Panis, Maryline; Blanco-Melo, Daniel; Sachs, David; Arkun, Knarik; Lim, Jean K; tenOever, Benjamin R
The emergence and spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in significant global morbidity, mortality, and societal disruption. A better understanding of virus-host interactions may potentiate therapeutic insights toward limiting this infection. Here we investigated the dynamics of the systemic response to SARS-CoV-2 in hamsters by histological analysis and transcriptional profiling. Infection resulted in consistently high levels of virus in the upper and lower respiratory tracts and sporadic occurrence in other distal tissues. A longitudinal cohort revealed a wave of inflammation, including a type I interferon (IFN-I) response, that was evident in all tissues regardless of viral presence but was insufficient to prevent disease progression. Bolstering the antiviral response with intranasal administration of recombinant IFN-I reduced viral disease, prevented transmission, and lowered inflammation in vivo. This study defines the systemic host response to SARS-CoV-2 infection and supports use of intranasal IFN-I as an effective means of early treatment.
PMCID:7846242
PMID: 33577760
ISSN: 1097-4180
CID: 4843602

SARS-CoV-2 infection in hamsters and humans results in lasting and unique systemic perturbations post recovery

Frere, Justin J; Serafini, Randal A; Pryce, Kerri D; Zazhytska, Marianna; Oishi, Kohei; Golynker, Ilona; Panis, Maryline; Zimering, Jeffrey; Horiuchi, Shu; Hoagland, Daisy A; Møller, Rasmus; Ruiz, Anne; Kodra, Albana; Overdevest, Jonathan B; Canoll, Peter D; Borczuk, Alain C; Chandar, Vasuretha; Bram, Yaron; Schwartz, Robert; Lomvardas, Stavros; Zachariou, Venetia; tenOever, Benjamin R
The host response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can result in prolonged pathologies collectively referred to as post-acute sequalae of COVID-19 (PASC) or long COVID. To better understand the mechanism underlying long COVID biology, we compared the short- and long-term systemic responses in the golden hamster following either SARS-CoV-2 or influenza A virus (IAV) infection. Results demonstrated that SARS-CoV-2 exceeded IAV in its capacity to cause permanent injury to the lung and kidney and uniquely impacted the olfactory bulb (OB) and epithelium (OE). Despite a lack of detectable infectious virus, the OB and OE demonstrated myeloid and T cell activation, proinflammatory cytokine production, and an interferon response that correlated with behavioral changes extending a month post viral clearance. These sustained transcriptional changes could also be corroborated from tissue isolated from individuals who recovered from COVID-19. These data highlight a molecular mechanism for persistent COVID-19 symptomology and provide a small animal model to explore future therapeutics.
PMCID:9210449
PMID: 35857629
ISSN: 1946-6242
CID: 5279142

Non-cell-autonomous disruption of nuclear architecture as a potential cause of COVID-19-induced anosmia

Zazhytska, Marianna; Kodra, Albana; Hoagland, Daisy A; Frere, Justin; Fullard, John F; Shayya, Hani; McArthur, Natalie G; Moeller, Rasmus; Uhl, Skyler; Omer, Arina D; Gottesman, Max E; Firestein, Stuart; Gong, Qizhi; Canoll, Peter D; Goldman, James E; Roussos, Panos; tenOever, Benjamin R; Lomvardas, Stavros
SARS-CoV-2 infects less than 1% of cells in the human body, yet it can cause severe damage in a variety of organs. Thus, deciphering the non-cell-autonomous effects of SARS-CoV-2 infection is imperative for understanding the cellular and molecular disruption it elicits. Neurological and cognitive defects are among the least understood symptoms of COVID-19 patients, with olfactory dysfunction being their most common sensory deficit. Here, we show that both in humans and hamsters, SARS-CoV-2 infection causes widespread downregulation of olfactory receptors (ORs) and of their signaling components. This non-cell-autonomous effect is preceded by a dramatic reorganization of the neuronal nuclear architecture, which results in dissipation of genomic compartments harboring OR genes. Our data provide a potential mechanism by which SARS-CoV-2 infection alters the cellular morphology and the transcriptome of cells it cannot infect, offering insight to its systemic effects in olfaction and beyond.
PMID: 35180380
ISSN: 1097-4172
CID: 5217972

RNase III nucleases from diverse kingdoms serve as antiviral effectors

Aguado, Lauren C; Schmid, Sonja; May, Jared; Sabin, Leah R; Panis, Maryline; Blanco-Melo, Daniel; Shim, Jaehee V; Sachs, David; Cherry, Sara; Simon, Anne E; Levraud, Jean-Pierre; tenOever, Benjamin R
In contrast to the DNA-based viruses in prokaryotes, the emergence of eukaryotes provided the necessary compartmentalization and membranous environment for RNA viruses to flourish, creating the need for an RNA-targeting antiviral system. Present day eukaryotes employ at least two main defence strategies that emerged as a result of this viral shift, namely antiviral RNA interference and the interferon system. Here we demonstrate that Drosha and related RNase III ribonucleases from all three domains of life also elicit a unique RNA-targeting antiviral activity. Systemic evolution of ligands by exponential enrichment of this class of proteins illustrates the recognition of unbranched RNA stem loops. Biochemical analyses reveal that, in this context, Drosha functions as an antiviral clamp, conferring steric hindrance on the RNA-dependent RNA polymerases of diverse positive-stranded RNA viruses. We present evidence for cytoplasmic translocation of RNase III nucleases in response to virus in diverse eukaryotes including plants, arthropods, fish, and mammals. These data implicate RNase III recognition of viral RNA as an antiviral defence that is independent of, and possibly predates, other known eukaryotic antiviral systems.
PMCID:5846625
PMID: 28658212
ISSN: 1476-4687
CID: 4843362

Identification of Required Host Factors for SARS-CoV-2 Infection in Human Cells

Daniloski, Zharko; Jordan, Tristan X; Wessels, Hans-Hermann; Hoagland, Daisy A; Kasela, Silva; Legut, Mateusz; Maniatis, Silas; Mimitou, Eleni P; Lu, Lu; Geller, Evan; Danziger, Oded; Rosenberg, Brad R; Phatnani, Hemali; Smibert, Peter; Lappalainen, Tuuli; tenOever, Benjamin R; Sanjana, Neville E
To better understand host-virus genetic dependencies and find potential therapeutic targets for COVID-19, we performed a genome-scale CRISPR loss-of-function screen to identify host factors required for SARS-CoV-2 viral infection of human alveolar epithelial cells. Top-ranked genes cluster into distinct pathways, including the vacuolar ATPase proton pump, Retromer, and Commander complexes. We validate these gene targets using several orthogonal methods such as CRISPR knockout, RNA interference knockdown, and small-molecule inhibitors. Using single-cell RNA-sequencing, we identify shared transcriptional changes in cholesterol biosynthesis upon loss of top-ranked genes. In addition, given the key role of the ACE2 receptor in the early stages of viral entry, we show that loss of RAB7A reduces viral entry by sequestering the ACE2 receptor inside cells. Overall, this work provides a genome-scale, quantitative resource of the impact of the loss of each host gene on fitness/response to viral infection.
PMCID:7584921
PMID: 33147445
ISSN: 1097-4172
CID: 4664202

TOP1 inhibition therapy protects against SARS-CoV-2-induced lethal inflammation

Ho, Jessica Sook Yuin; Mok, Bobo Wing-Yee; Campisi, Laura; Jordan, Tristan; Yildiz, Soner; Parameswaran, Sreeja; Wayman, Joseph A; Gaudreault, Natasha N; Meekins, David A; Indran, Sabarish V; Morozov, Igor; Trujillo, Jessie D; Fstkchyan, Yesai S; Rathnasinghe, Raveen; Zhu, Zeyu; Zheng, Simin; Zhao, Nan; White, Kris; Ray-Jones, Helen; Malysheva, Valeriya; Thiecke, Michiel J; Lau, Siu-Ying; Liu, Honglian; Zhang, Anna Junxia; Lee, Andrew Chak-Yiu; Liu, Wen-Chun; Jangra, Sonia; Escalera, Alba; Aydillo, Teresa; Melo, Betsaida Salom; Guccione, Ernesto; Sebra, Robert; Shum, Elaine; Bakker, Jan; Kaufman, David A; Moreira, Andre L; Carossino, Mariano; Balasuriya, Udeni B R; Byun, Minji; Albrecht, Randy A; Schotsaert, Michael; Garcia-Sastre, Adolfo; Chanda, Sumit K; Miraldi, Emily R; Jeyasekharan, Anand D; TenOever, Benjamin R; Spivakov, Mikhail; Weirauch, Matthew T; Heinz, Sven; Chen, Honglin; Benner, Christopher; Richt, Juergen A; Marazzi, Ivan
The ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently affecting millions of lives worldwide. Large retrospective studies indicate that an elevated level of inflammatory cytokines and pro-inflammatory factors are associated with both increased disease severity and mortality. Here, using multidimensional epigenetic, transcriptional, in vitro, and in vivo analyses, we report that topoisomerase 1 (TOP1) inhibition suppresses lethal inflammation induced by SARS-CoV-2. Therapeutic treatment with two doses of topotecan (TPT), an FDA-approved TOP1 inhibitor, suppresses infection-induced inflammation in hamsters. TPT treatment as late as 4 days post-infection reduces morbidity and rescues mortality in a transgenic mouse model. These results support the potential of TOP1 inhibition as an effective host-directed therapy against severe SARS-CoV-2 infection. TPT and its derivatives are inexpensive clinical-grade inhibitors available in most countries. Clinical trials are needed to evaluate the efficacy of repurposing TOP1 inhibitors for severe coronavirus disease 2019 (COVID-19) in humans.
PMID: 33836156
ISSN: 1097-4172
CID: 4840702

SARS-CoV-2 and Influenza A Virus Induce Longitudinal Transcriptomic Changes in Hamster Spinal Cord Tissue

Serafini, Randal A; Frere, Justin J; tenOever, Benjamin; Zachariou, Venetia
PMID: 37389976
ISSN: 1528-1159
CID: 5540612

Mouse genome rewriting and tailoring of three important disease loci

Zhang, Weimin; Golynker, Ilona; Brosh, Ran; Fajardo, Alvaro; Zhu, Yinan; Wudzinska, Aleksandra M; Ordoñez, Raquel; Ribeiro-Dos-Santos, André M; Carrau, Lucia; Damani-Yokota, Payal; Yeung, Stephen T; Khairallah, Camille; Vela Gartner, Antonio; Chalhoub, Noor; Huang, Emily; Ashe, Hannah J; Khanna, Kamal M; Maurano, Matthew T; Kim, Sang Yong; tenOever, Benjamin R; Boeke, Jef D
Genetically engineered mouse models (GEMMs) help us to understand human pathologies and develop new therapies, yet faithfully recapitulating human diseases in mice is challenging. Advances in genomics have highlighted the importance of non-coding regulatory genome sequences, which control spatiotemporal gene expression patterns and splicing in many human diseases1,2. Including regulatory extensive genomic regions, which requires large-scale genome engineering, should enhance the quality of disease modelling. Existing methods set limits on the size and efficiency of DNA delivery, hampering the routine creation of highly informative models that we call genomically rewritten and tailored GEMMs (GREAT-GEMMs). Here we describe 'mammalian switching antibiotic resistance markers progressively for integration' (mSwAP-In), a method for efficient genome rewriting in mouse embryonic stem cells. We demonstrate the use of mSwAP-In for iterative genome rewriting of up to 115 kb of a tailored Trp53 locus, as well as for humanization of mice using 116 kb and 180 kb human ACE2 loci. The ACE2 model recapitulated human ACE2 expression patterns and splicing, and notably, presented milder symptoms when challenged with SARS-CoV-2 compared with the existing K18-hACE2 model, thus representing a more human-like model of infection. Finally, we demonstrated serial genome writing by humanizing mouse Tmprss2 biallelically in the ACE2 GREAT-GEMM, highlighting the versatility of mSwAP-In in genome writing.
PMCID:10632133
PMID: 37914927
ISSN: 1476-4687
CID: 5606842

SARS-CoV-2 hijacks p38β/MAPK11 to promote virus replication

Higgins, Christina A; Nilsson-Payant, Benjamin E; Bonaventure, Boris; Kurland, Andrew P; Ye, Chengjin; Yaron, Tomer M; Johnson, Jared L; Adhikary, Prithy; Golynker, Ilona; Panis, Maryline; Danziger, Oded; Rosenberg, Brad R; Cantley, Lewis C; Martínez-Sobrido, Luis; tenOever, Benjamin; Johnson, Jeffrey R
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the coronavirus disease 2019 (COVID-19) pandemic, drastically modifies infected cells to optimize virus replication. One such modification is the activation of the host p38 mitogen-activated protein kinase (MAPK) pathway, which plays a major role in inflammatory cytokine production, a hallmark of severe COVID-19. We previously demonstrated that inhibition of p38/MAPK activity in SARS-CoV-2-infected cells reduced both cytokine production and viral replication. Here, we combined quantitative genetic screening, genomics, proteomics, and phosphoproteomics to better understand mechanisms underlying the dependence of SARS-CoV-2 on the p38 pathway. We found that p38β is a critical host factor for SARS-CoV-2 replication in multiple relevant cell lines and that it functions at a step after viral mRNA expression. We identified putative host and viral p38β substrates in the context of SARS-CoV-2 infection and found that most host substrates have intrinsic antiviral activities. Taken together, this study reveals a unique proviral function for p38β and supports exploring p38β inhibitor development as a strategy toward creating a new class of COVID-19 therapies. IMPORTANCE SARS-CoV-2 is the causative agent of the COVID-19 pandemic that has claimed millions of lives since its emergence in 2019. SARS-CoV-2 infection of human cells requires the activity of several cellular pathways for successful replication. One such pathway, the p38 MAPK pathway, is required for virus replication and disease pathogenesis. Here, we applied systems biology approaches to understand how MAPK pathways benefit SARS-CoV-2 replication to inform the development of novel COVID-19 drug therapies.
PMID: 37345956
ISSN: 2150-7511
CID: 5542842