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Genetic architecture of host proteins involved in SARS-CoV-2 infection.
Pietzner M, Wheeler E, Carrasco-Zanini J, Raffler J, Kerrison ND, Oerton E, Auyeung VPW, Luan J, Finan C, Casas JP, Ostroff R, Williams SA, Kastenmüller G, Ralser M, Gamazon ER, Wareham NJ, Hingorani AD, Langenberg C
(2020) Nat Commun 11: 6397
MeSH Terms: ABO Blood-Group System, Aptamers, Peptide, Blood Coagulation, COVID-19, Drug Delivery Systems, Female, Gene Expression Regulation, Host-Derived Cellular Factors, Host-Pathogen Interactions, Humans, Internet, Male, Middle Aged, Proteins, Quantitative Trait Loci, SARS-CoV-2
Show Abstract · Added December 18, 2020
Understanding the genetic architecture of host proteins interacting with SARS-CoV-2 or mediating the maladaptive host response to COVID-19 can help to identify new or repurpose existing drugs targeting those proteins. We present a genetic discovery study of 179 such host proteins among 10,708 individuals using an aptamer-based technique. We identify 220 host DNA sequence variants acting in cis (MAF 0.01-49.9%) and explaining 0.3-70.9% of the variance of 97 of these proteins, including 45 with no previously known protein quantitative trait loci (pQTL) and 38 encoding current drug targets. Systematic characterization of pQTLs across the phenome identified protein-drug-disease links and evidence that putative viral interaction partners such as MARK3 affect immune response. Our results accelerate the evaluation and prioritization of new drug development programmes and repurposing of trials to prevent, treat or reduce adverse outcomes. Rapid sharing and detailed interrogation of results is facilitated through an interactive webserver ( https://omicscience.org/apps/covidpgwas/ ).
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16 MeSH Terms
Cellular mRNA export factor UAP56 recognizes nucleic acid binding site of influenza virus NP protein.
Morris AK, Wang Z, Ivey AL, Xie Y, Hill PS, Schey KL, Ren Y
(2020) Biochem Biophys Res Commun 525: 259-264
MeSH Terms: Binding Sites, DEAD-box RNA Helicases, Genome, Viral, Host-Pathogen Interactions, Humans, Nucleocapsid Proteins, RNA, Messenger, RNA-Binding Proteins, Ribonucleoproteins, Viral Core Proteins, Virus Assembly, Virus Replication
Show Abstract · Added March 3, 2020
Influenza A virus nucleoprotein (NP) is a structural component that encapsulates the viral genome into the form of ribonucleoprotein complexes (vRNPs). Efficient assembly of vRNPs is critical for the virus life cycle. The assembly route from RNA-free NP to the NP-RNA polymer in vRNPs has been suggested to require a cellular factor UAP56, but the mechanism is poorly understood. Here, we characterized the interaction between NP and UAP56 using recombinant proteins and showed that UAP56 features two NP binding sites. In addition to the UAP56 core comprised of two RecA domains, we identified the N-terminal extension (NTE) of UAP56 as a previously unknown NP binding site. In particular, UAP56-NTE recognizes the nucleic acid binding region of NP. This corroborates our observation that binding of UAP56-NTE and RNA to NP is mutually exclusive. Collectively, our results reveal the molecular basis for how UAP56 acts on RNA-free NP, and provide new insights into NP-mediated influenza genome packaging.
Copyright © 2020 Elsevier Inc. All rights reserved.
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12 MeSH Terms
exhibits heterogeneous siderophore production within the vertebrate host.
Perry WJ, Spraggins JM, Sheldon JR, Grunenwald CM, Heinrichs DE, Cassat JE, Skaar EP, Caprioli RM
(2019) Proc Natl Acad Sci U S A 116: 21980-21982
MeSH Terms: Abscess, Animals, Citrates, Host-Pathogen Interactions, Iron, Mice, Ornithine, Siderophores, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Staphylococcal Infections, Staphylococcus aureus
Show Abstract · Added January 22, 2020
Siderophores, iron-scavenging small molecules, are fundamental to bacterial nutrient metal acquisition and enable pathogens to overcome challenges imposed by nutritional immunity. Multimodal imaging mass spectrometry allows visualization of host-pathogen iron competition, by mapping siderophores within infected tissue. We have observed heterogeneous distributions of siderophores across infectious foci, challenging the paradigm that the vertebrate host is a uniformly iron-depleted environment to invading microbes.
Copyright © 2019 the Author(s). Published by PNAS.
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3 Members
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11 MeSH Terms
Rotavirus Species B Encodes a Functional Fusion-Associated Small Transmembrane Protein.
Diller JR, Parrington HM, Patton JT, Ogden KM
(2019) J Virol 93:
MeSH Terms: Amino Acid Sequence, Animals, Cell Line, Cytopathogenic Effect, Viral, Giant Cells, Host-Pathogen Interactions, Humans, Membrane Proteins, Protein Binding, Protein Interaction Domains and Motifs, Rotavirus, Rotavirus Infections, Viral Nonstructural Proteins, Viral Proteins
Show Abstract · Added March 3, 2020
Rotavirus is an important cause of diarrheal disease in young mammals. Rotavirus species A (RVA) causes most human rotavirus diarrheal disease and primarily affects infants and young children. Rotavirus species B (RVB) has been associated with sporadic outbreaks of human adult diarrheal disease. RVA and RVB are predicted to encode mostly homologous proteins but differ significantly in the proteins encoded by the NSP1 gene. In the case of RVB, the NSP1 gene encodes two putative protein products of unknown function, NSP1-1 and NSP1-2. We demonstrate that human RVB NSP1-1 mediates syncytium formation in cultured human cells. Based on sequence alignment, NSP1-1 proteins from species B, G, and I contain features consistent with fusion-associated small transmembrane (FAST) proteins, which have previously been identified in other genera of the family. Like some other FAST proteins, RVB NSP1-1 is predicted to have an N-terminal myristoyl modification. Addition of an N-terminal FLAG peptide disrupts NSP1-1-mediated fusion. NSP1-1 from a human RVB mediates fusion of human cells but not hamster cells and, thus, may serve as a species tropism determinant. NSP1-1 also can enhance RVA replication in human cells, both in single-cycle infection studies and during a multicycle time course in the presence of fetal bovine serum, which inhibits rotavirus spread. These findings suggest potential yet untested roles for NSP1-1 in RVB species tropism, immune evasion, and pathogenesis. While species A rotavirus is commonly associated with diarrheal disease in young children, species B rotavirus has caused sporadic outbreaks of adult diarrheal disease. A major genetic difference between species A and B rotaviruses is the NSP1 gene, which encodes two proteins for species B rotavirus. We demonstrate that the smaller of these proteins, NSP1-1, can mediate fusion of cultured human cells. Comparison with viral proteins of similar function provides insight into NSP1-1 domain organization and fusion mechanism. These comparisons suggest that there is a fatty acid modification at the amino terminus of the protein, and our results show that an intact amino terminus is required for NSP1-1-mediated fusion. NSP1-1 from a human virus mediates fusion of human cells, but not hamster cells, and enhances species A rotavirus replication in culture. These findings suggest potential, but currently untested, roles for NSP1-1 in RVB host species tropism, immune evasion, and pathogenesis.
Copyright © 2019 American Society for Microbiology.
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14 MeSH Terms
The novel interaction between Neisseria gonorrhoeae TdfJ and human S100A7 allows gonococci to subvert host zinc restriction.
Maurakis S, Keller K, Maxwell CN, Pereira K, Chazin WJ, Criss AK, Cornelissen CN
(2019) PLoS Pathog 15: e1007937
MeSH Terms: Amino Acid Sequence, Animals, Bacterial Outer Membrane Proteins, Gonorrhea, Host-Pathogen Interactions, Humans, Mice, Neisseria gonorrhoeae, S100 Calcium Binding Protein A7, Zinc
Show Abstract · Added March 11, 2020
Neisseria gonorrhoeae causes the sexually-transmitted infection gonorrhea, a global disease that is difficult to treat and for which there is no vaccine. This pathogen employs an arsenal of conserved outer membrane proteins called TonB-dependent transporters (TdTs) that allow the gonococcus to overcome nutritional immunity, the host strategy of sequestering essential nutrients away from invading bacteria to handicap infectious ability. N. gonorrhoeae produces eight known TdTs, of which four are utilized for acquisition of iron or iron chelates from host-derived proteins or xenosiderophores produced by other bacteria. Of the remaining TdTs, two of them, TdfH and TdfJ, facilitate zinc uptake. TdfH was recently shown to bind Calprotectin, a member of the S100 protein family, and subsequently extract its zinc, which is then internalized by N. gonorrhoeae. Like Calprotectin, other S100s are also capable of binding transition metals such as zinc and copper, and thus have demonstrated growth suppression of numerous other pathogens via metal sequestration. Considering the functional and structural similarities of the TdTs and of the S100s, as well as the upregulation in response to Zn limitation shown by TdfH and TdfJ, we sought to evaluate whether other S100s have the ability to support gonococcal growth by means of zinc acquisition and to frame this growth in the context of the TdTs. We found that both S100A7 and S10012 are utilized by N. gonorrhoeae as a zinc source in a mechanism that depends on the zinc transport system ZnuABC. Moreover, TdfJ binds directly to S100A7, from which it internalizes zinc. This interaction is restricted to the human version of S100A7, and zinc presence in S100A7 is required to fully support gonococcal growth. These studies highlight how gonococci co-opt human nutritional immunity, by presenting a novel interaction between TdfJ and human S100A7 for overcoming host zinc restriction.
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MeSH Terms
The Innate Immune Protein S100A9 Protects from T-Helper Cell Type 2-mediated Allergic Airway Inflammation.
Palmer LD, Maloney KN, Boyd KL, Goleniewska AK, Toki S, Maxwell CN, Chazin WJ, Peebles RS, Newcomb DC, Skaar EP
(2019) Am J Respir Cell Mol Biol 61: 459-468
MeSH Terms: Adaptive Immunity, Allergens, Alternaria, Alveolitis, Extrinsic Allergic, Animals, Bronchial Hyperreactivity, Bronchoalveolar Lavage Fluid, Calgranulin A, Calgranulin B, Cytokines, Forkhead Transcription Factors, Immunoglobulin E, Inflammation, Leukocyte L1 Antigen Complex, Lung, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Pulmonary Eosinophilia, Specific Pathogen-Free Organisms, T-Lymphocytes, Regulatory, Th2 Cells
Show Abstract · Added April 7, 2019
Calprotectin is a heterodimer of the proteins S100A8 and S100A9, and it is an abundant innate immune protein associated with inflammation. In humans, calprotectin transcription and protein abundance are associated with asthma and disease severity. However, mechanistic studies in experimental asthma models have been inconclusive, identifying both protective and pathogenic effects of calprotectin. To clarify the role of calprotectin in asthma, calprotectin-deficient and wild-type (WT) C57BL/6 mice were compared in a murine model of allergic airway inflammation. Mice were intranasally challenged with extracts of the clinically relevant allergen, (Alt Ext), or PBS every third day over 9 days. On Day 10, BAL fluid and lung tissue homogenates were harvested and allergic airway inflammation was assessed. Alt Ext challenge induced release of S100A8/S100A9 to the alveolar space and increased protein expression in the alveolar epithelium of WT mice. Compared with WT mice, mice displayed significantly enhanced allergic airway inflammation, including production of IL-13, CCL11, CCL24, serum IgE, eosinophil recruitment, and airway resistance and elastance. In response to Alt Ext, mice accumulated significantly more IL-13IL-5CD4 T-helper type 2 cells. mice also accumulated a significantly lower proportion of CD4 T regulatory (Treg) cells in the lung that had significantly lower expression of CD25. Calprotectin enhanced WT Treg cell suppressive activity . Therefore, this study identifies a role for the innate immune protein, S100A9, in protection from CD4 T-helper type 2 cell hyperinflammation in response to Alt Ext. This protection is mediated, at least in part, by CD4 Treg cell function.
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2 Members
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23 MeSH Terms
A Phenome-Wide Association Study Uncovers a Pathological Role of Coagulation Factor X during Infection.
Choby JE, Monteith AJ, Himmel LE, Margaritis P, Shirey-Rice JK, Pruijssers A, Jerome RN, Pulley J, Skaar EP
(2019) Infect Immun 87:
MeSH Terms: Acinetobacter Infections, Acinetobacter baumannii, Animals, Disease Models, Animal, Factor X, Host-Pathogen Interactions, Humans, Mice, Mice, Inbred C57BL, Phenotype, Polymorphism, Genetic
Show Abstract · Added April 7, 2019
Coagulation and inflammation are interconnected, suggesting that coagulation plays a key role in the inflammatory response to pathogens. A phenome-wide association study (PheWAS) was used to identify clinical phenotypes of patients with a polymorphism in coagulation factor X. Patients with this single nucleotide polymorphism (SNP) were more likely to be hospitalized with hemostatic and infection-related disorders, suggesting that factor X contributes to the immune response to infection. To investigate this, we modeled infections by human pathogens in a mouse model of factor X deficiency. Factor X-deficient mice were protected from systemic infection, suggesting that factor X plays a role in the immune response to Factor X deficiency was associated with reduced cytokine and chemokine production and alterations in immune cell population during infection: factor X-deficient mice demonstrated increased abundance of neutrophils, macrophages, and effector T cells. Together, these results suggest that factor X activity is associated with an inefficient immune response and contributes to the pathology of infection.
Copyright © 2019 American Society for Microbiology.
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1 Members
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11 MeSH Terms
S100 Proteins in the Innate Immune Response to Pathogens.
Kozlyuk N, Monteith AJ, Garcia V, Damo SM, Skaar EP, Chazin WJ
(2019) Methods Mol Biol 1929: 275-290
MeSH Terms: Calcium, Host-Pathogen Interactions, Humans, Immunity, Innate, Inflammation, Manganese, Models, Molecular, Protein Conformation, S100 Proteins, Toll-Like Receptor 4
Show Abstract · Added March 26, 2019
S100 proteins are distinct dimeric EF-hand Ca-binding proteins that can bind Zn, Mn, and other transition metals with high affinity at two sites in the dimer interface. Certain S100 proteins, including S100A7, S100A12, S100A8, and S100A9, play key roles in the innate immune response to pathogens. These proteins function via a "nutritional immunity" mechanism by depleting essential transition metals in the infection that are required for the invading organism to grow and thrive. They also act as damage-associated molecular pattern ligands, which activate pattern recognition receptors (e.g., Toll-like receptor 4, RAGE) that mediate inflammation. Here we present protocols for these S100 proteins for high-level production of recombinant protein, measurement of binding affinities using isothermal titration calorimetry, and an assay of antimicrobial activity.
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2 Members
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10 MeSH Terms
Colonocyte metabolism shapes the gut microbiota.
Litvak Y, Byndloss MX, Bäumler AJ
(2018) Science 362:
MeSH Terms: Cell Polarity, Colitis, Ulcerative, Colon, Dysbiosis, Gastrointestinal Microbiome, Host-Pathogen Interactions, Humans, Intestinal Mucosa, Oxygen Consumption
Show Abstract · Added March 30, 2020
An imbalance in the colonic microbiota might underlie many human diseases, but the mechanisms that maintain homeostasis remain elusive. Recent insights suggest that colonocyte metabolism functions as a control switch, mediating a shift between homeostatic and dysbiotic communities. During homeostasis, colonocyte metabolism is directed toward oxidative phosphorylation, resulting in high epithelial oxygen consumption. The consequent epithelial hypoxia helps to maintain a microbial community dominated by obligate anaerobic bacteria, which provide benefit by converting fiber into fermentation products absorbed by the host. Conditions that alter the metabolism of the colonic epithelium increase epithelial oxygenation, thereby driving an expansion of facultative anaerobic bacteria, a hallmark of dysbiosis in the colon. Enteric pathogens subvert colonocyte metabolism to escape niche protection conferred by the gut microbiota. The reverse strategy, a metabolic reprogramming to restore colonocyte hypoxia, represents a promising new therapeutic approach for rebalancing the colonic microbiota in a broad spectrum of human diseases.
Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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MeSH Terms
Molecular Basis for the Evolution of Species-Specific Hemoglobin Capture by Staphylococcus aureus.
Choby JE, Buechi HB, Farrand AJ, Skaar EP, Barber MF
(2018) mBio 9:
MeSH Terms: Animals, Cation Transport Proteins, Evolution, Molecular, Hemoglobins, Host-Pathogen Interactions, Iron, Mutation, Primates, Protein Binding, Species Specificity, Staphylococcus aureus
Show Abstract · Added April 7, 2019
Metals are a limiting resource for pathogenic bacteria and must be scavenged from host proteins. Hemoglobin provides the most abundant source of iron in the human body and is required by several pathogens to cause invasive disease. However, the consequences of hemoglobin evolution for bacterial nutrient acquisition remain unclear. Here we show that the α- and β-globin genes exhibit strikingly parallel signatures of adaptive evolution across simian primates. Rapidly evolving sites in hemoglobin correspond to binding interfaces of IsdB, a bacterial hemoglobin receptor harbored by pathogenic Using an evolution-guided experimental approach, we demonstrate that the divergence between primates and staphylococcal isolates governs hemoglobin recognition and bacterial growth. The reintroduction of putative adaptive mutations in α- or β-globin proteins was sufficient to impair binding, providing a mechanism for the evolution of disease resistance. These findings suggest that bacterial hemoprotein capture has driven repeated evolutionary conflicts with hemoglobin during primate descent. During infection, bacteria must steal metals, including iron, from the host tissue. Therefore, pathogenic bacteria have evolved metal acquisition systems to overcome the elaborate processes mammals use to withhold metal from pathogens. uses IsdB, a hemoglobin receptor, to thieve iron-containing heme from hemoglobin within human blood. We find evidence that primate hemoglobin has undergone rapid evolution at protein surfaces contacted by IsdB. Additionally, variation in the hemoglobin sequences among primates, or variation in IsdB of related staphylococci, reduces bacterial hemoglobin capture. Together, these data suggest that has evolved to recognize human hemoglobin in the face of rapid evolution at the IsdB binding interface, consistent with repeated evolutionary conflicts in the battle for iron during host-pathogen interactions.
Copyright © 2018 Choby et al.
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11 MeSH Terms