Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 6 de 6
Filter
1.
Nat Genet ; 54(8): 1078-1089, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1960394

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a range of symptoms in infected individuals, from mild respiratory illness to acute respiratory distress syndrome. A systematic understanding of host factors influencing viral infection is critical to elucidate SARS-CoV-2-host interactions and the progression of Coronavirus disease 2019 (COVID-19). Here, we conducted genome-wide CRISPR knockout and activation screens in human lung epithelial cells with endogenous expression of the SARS-CoV-2 entry factors ACE2 and TMPRSS2. We uncovered proviral and antiviral factors across highly interconnected host pathways, including clathrin transport, inflammatory signaling, cell-cycle regulation, and transcriptional and epigenetic regulation. We further identified mucins, a family of high molecular weight glycoproteins, as a prominent viral restriction network that inhibits SARS-CoV-2 infection in vitro and in murine models. These mucins also inhibit infection of diverse respiratory viruses. This functional landscape of SARS-CoV-2 host factors provides a physiologically relevant starting point for new host-directed therapeutics and highlights airway mucins as a host defense mechanism.


Subject(s)
COVID-19 , Animals , COVID-19/genetics , Clustered Regularly Interspaced Short Palindromic Repeats , Epigenesis, Genetic , Humans , Mice , Mucins/genetics , SARS-CoV-2
2.
Ann N Y Acad Sci ; 1510(1): 79-99, 2022 04.
Article in English | MEDLINE | ID: covidwho-1822055

ABSTRACT

Targeted protein degradation is critical for proper cellular function and development. Protein degradation pathways, such as the ubiquitin proteasomes system, autophagy, and endosome-lysosome pathway, must be tightly regulated to ensure proper elimination of misfolded and aggregated proteins and regulate changing protein levels during cellular differentiation, while ensuring that normal proteins remain unscathed. Protein degradation pathways have also garnered interest as a means to selectively eliminate target proteins that may be difficult to inhibit via other mechanisms. On June 7 and 8, 2021, several experts in protein degradation pathways met virtually for the Keystone eSymposium "Targeting protein degradation: from small molecules to complex organelles." The event brought together researchers working in different protein degradation pathways in an effort to begin to develop a holistic, integrated vision of protein degradation that incorporates all the major pathways to understand how changes in them can lead to disease pathology and, alternatively, how they can be leveraged for novel therapeutics.


Subject(s)
Proteasome Endopeptidase Complex , Ubiquitin , Autophagy/physiology , Humans , Organelles , Proteasome Endopeptidase Complex/metabolism , Proteins/metabolism , Proteolysis , Ubiquitin/metabolism
3.
ACS Chem Biol ; 17(5): 1184-1196, 2022 05 20.
Article in English | MEDLINE | ID: covidwho-1783934

ABSTRACT

Vaccine scaffolds and carrier proteins increase the immunogenicity of subunit vaccines. Here, we developed, characterized, and demonstrated the efficacy of a novel microparticle vaccine scaffold comprised of bacterial peptidoglycan (PGN), isolated as an entire sacculi. The PGN microparticles contain bio-orthogonal chemical handles allowing for site-specific attachment of immunogens. We first evaluated the purification, integrity, and immunogenicity of PGN microparticles derived from a variety of bacterial species. We then optimized PGN microparticle modification conditions; Staphylococcus aureus PGN microparticles containing azido-d-alanine yielded robust conjugation to immunogens. We then demonstrated that this vaccine scaffold elicits comparable immunostimulation to the conventional carrier protein, keyhole limpet hemocyanin (KLH). We further modified the S. aureus PGN microparticle to contain the SARS-CoV-2 receptor-binding domain (RBD)─this conjugate vaccine elicited neutralizing antibody titers comparable to those elicited by the KLH-conjugated RBD. Collectively, these findings suggest that chemically modified bacterial PGN microparticles are a conjugatable and biodegradable microparticle scaffold capable of eliciting a robust immune response toward an antigen of interest.


Subject(s)
COVID-19 , SARS-CoV-2 , COVID-19/prevention & control , Humans , Peptidoglycan , Staphylococcus aureus , Vaccines, Conjugate , Vaccines, Subunit
4.
ACS Cent Sci ; 7(4): 650-657, 2021 Apr 28.
Article in English | MEDLINE | ID: covidwho-1225484

ABSTRACT

Severe cases of coronavirus disease 2019 (COVID-19), caused by infection with SARS-CoV-2, are characterized by a hyperinflammatory immune response that leads to numerous complications. Production of proinflammatory neutrophil extracellular traps (NETs) has been suggested to be a key factor in inducing a hyperinflammatory signaling cascade, allegedly causing both pulmonary tissue damage and peripheral inflammation. Accordingly, therapeutic blockage of neutrophil activation and NETosis, the cell death pathway accompanying NET formation, could limit respiratory damage and death from severe COVID-19. Here, we demonstrate that synthetic glycopolymers that activate signaling of the neutrophil checkpoint receptor Siglec-9 suppress NETosis induced by agonists of viral toll-like receptors (TLRs) and plasma from patients with severe COVID-19. Thus, Siglec-9 agonism is a promising therapeutic strategy to curb neutrophilic hyperinflammation in COVID-19.

5.
Cell ; 184(9): 2394-2411.e16, 2021 04 29.
Article in English | MEDLINE | ID: covidwho-1126769

ABSTRACT

SARS-CoV-2 is the cause of a pandemic with growing global mortality. Using comprehensive identification of RNA-binding proteins by mass spectrometry (ChIRP-MS), we identified 309 host proteins that bind the SARS-CoV-2 RNA during active infection. Integration of this data with ChIRP-MS data from three other RNA viruses defined viral specificity of RNA-host protein interactions. Targeted CRISPR screens revealed that the majority of functional RNA-binding proteins protect the host from virus-induced cell death, and comparative CRISPR screens across seven RNA viruses revealed shared and SARS-specific antiviral factors. Finally, by combining the RNA-centric approach and functional CRISPR screens, we demonstrated a physical and functional connection between SARS-CoV-2 and mitochondria, highlighting this organelle as a general platform for antiviral activity. Altogether, these data provide a comprehensive catalog of functional SARS-CoV-2 RNA-host protein interactions, which may inform studies to understand the host-virus interface and nominate host pathways that could be targeted for therapeutic benefit.


Subject(s)
Host-Pathogen Interactions , RNA, Viral/genetics , SARS-CoV-2/genetics , Animals , COVID-19/virology , CRISPR-Cas Systems/genetics , Cell Line, Tumor , Chlorocebus aethiops , Female , Genome, Viral , Humans , Lung/virology , Male , Mass Spectrometry , Mitochondria/metabolism , Mitochondria/ultrastructure , Proteome/metabolism , RNA-Binding Proteins/metabolism , SARS-CoV-2/ultrastructure , Vero Cells
6.
ACS Central Science ; 6(4):446-447, 2020.
Article in English | SciFinder | ID: covidwho-1016683

ABSTRACT

A review introducing the "In Focus" series of the journal ACS Central Science and its inaugural article, "Research and Development on Therapeutic Agents and Vaccines for COVID-19 and Related Human Coronavirus Diseases" by C. Liu et al. (2020).

SELECTION OF CITATIONS
SEARCH DETAIL