Discrete viral E2 lysine residues and scavenger receptor MARCO are required for clearance of circulating alphaviruses

The magnitude and duration of vertebrate viremia is a critical determinant of arbovirus transmission, geographic spread, and disease severity. We find that multiple alphaviruses, including chikungunya (CHIKV), Ross River (RRV), and o’nyong ‘nyong (ONNV) viruses, are cleared from the circulation of mice by liver Kupffer cells, impeding viral dissemination. Clearance from the circulation was independent of natural antibodies or complement factor C3, and instead relied on scavenger receptor SR-A6 (MARCO). Remarkably, lysine to arginine substitutions at distinct residues within the E2 glycoproteins of CHIKV and ONNV (E2 K200R) as well as RRV (E2 K251R) allowed for escape from clearance and enhanced viremia and dissemination. Mutational analysis revealed that viral clearance from the circulation is strictly dependent on the presence of lysine at these positions. These findings reveal a previously unrecognized innate immune pathway that controls alphavirus viremia and dissemination in vertebrate hosts, ultimately influencing disease severity and likely transmission efficiency.

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Faculty Opinions recommendation of Direct and indirect induction by 1,25-dihydroxyvitamin D3 of the NOD2/CARD15-defensin beta2 innate immune pathway defective in Crohn disease.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1347975.3123054 ◽

2010 ◽

Author(s):

Jack Satsangi

Keyword(s):

Crohn Disease ◽

Innate Immune ◽

Dihydroxyvitamin D3 ◽

1,25 Dihydroxyvitamin D3 ◽

Immune Pathway ◽

Innate Immune Pathway

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In vitro phosphorylation of human complement factor C3 by protein kinase A and protein kinase C. Effects on the classical and alternative pathways.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(19)39892-8 ◽

1990 ◽

Vol 265 (5) ◽

pp. 2941-2946

Author(s):

P O Forsberg ◽

S C Martin ◽

B Nilsson ◽

P Ekman ◽

U R Nilsson ◽

...

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Protein Kinase A ◽

Complement Factor ◽

Human Complement ◽

Alternative Pathways ◽

Kinase C ◽

Complement Factor C3 ◽

Kinase A

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Deamidation and glycation of a Bacillus licheniformis α-amylase during industrial fermentation can improve detergent wash performance

Amylase ◽

10.1515/amylase-2021-0004 ◽

2021 ◽

Vol 5 (1) ◽

pp. 38-49

Author(s):

Connie Pontoppidan ◽

Svend G. Kaasgaard ◽

Carsten P. Sønksen ◽

Carsten Andersen ◽

Birte Svensson

Keyword(s):

Bacillus Licheniformis ◽

Mutational Analysis ◽

Peptide Mapping ◽

Substrate Binding ◽

Carbohydrate Binding ◽

Surface Binding ◽

Lysine Residues ◽

Tandem Mass Spectrometric ◽

Binding Cleft ◽

Household Detergents

Abstract The industrial thermostable Bacillus licheniformis α-amylase (BLA) has wide applications, including in household detergents, and efforts to improve its performance are continuously ongoing. BLA during the industrial production is deamidated and glycated resulting in multiple forms with different isoelectric points. Forty modified positions were identified by tandem mass spectrometric peptide mapping of BLA forms separated by isoelectric focusing. These modified 12 asparagine, 9 glutamine, 8 arginine and 11 lysine residues are mostly situated on the enzyme surface and several belong to regions involved in stability, activity and carbohydrate binding. Eight residues presumed to interact with starch at the active site and surface binding sites (SBSs) were subjected to mutational analysis. Five mutants mimicking deamidation (N→D, Q→E) at the substrate binding cleft showed moderate to no effect on thermostability and k cat and K M for maltoheptaose and amylose. Notably, the mutations improved laundry wash efficiency in detergents at pH 8.5 and 10.0. Replacing three reducing sugar reactive side chains (K→M, R→L) at a distant substrate binding region and two SBSs enhanced wash performance especially in liquid detergent at pH 8.5, slightly improved enzymatic activity and maintained thermostability. Wash performance was most improved (5-fold) for the N265D mutant near substrate binding subsite +3.

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Role of the Inflammasome, IL-1β, and IL-18 in Bacterial Infections

The Scientific World JOURNAL ◽

10.1100/2011/212680 ◽

2011 ◽

Vol 11 ◽

pp. 2037-2050 ◽

Cited By ~ 123

Author(s):

Manoranjan Sahoo ◽

Ivonne Ceballos-Olvera ◽

Laura del Barrio ◽

Fabio Re

Keyword(s):

Bacterial Infections ◽

Innate Immune ◽

Host Responses ◽

Inflammasome Activation ◽

Different Types ◽

Molecular Aspects ◽

Immune Pathway ◽

Innate Immune Pathway ◽

Receptor Family

The inflammasome is an important innate immune pathway that regulates at least two host responses protective against infections: (1) secretion of the proinflammatory cytokines IL-1βand IL-18 and (2) induction of pyroptosis, a form of cell death. Inflammasomes, of which different types have been identified, are multiprotein complexes containing pattern recognition receptors belonging to the Nod-like receptor family or the PYHIN family and the protease caspase-1. The molecular aspects involved in the activation of different inflammasomes by various pathogens are being rapidly elucidated, and their role during infections is being characterized. Production of IL-1βand IL-18 and induction of pyroptosis of the infected cell have been shown to be protective against many infectious agents. Here, we review the recent literature concerning inflammasome activation in the context of bacterial infections and identify important questions to be answered in the future.

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Evidence for non-traditional activation of complement factor C3 during murine liver regeneration

Molecular Immunology ◽

10.1016/j.molimm.2008.03.008 ◽

2008 ◽

Vol 45 (11) ◽

pp. 3125-3132 ◽

Cited By ~ 53

Author(s):

Amelia Clark ◽

Alexander Weymann ◽

Eric Hartman ◽

Yumirle Turmelle ◽

Michael Carroll ◽

...

Keyword(s):

Liver Regeneration ◽

Complement Factor ◽

Murine Liver ◽

Complement Factor C3

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A case of Graves’ disease associated with membranoproliferative glomerulonephritis and leukocytoclastic vasculitis

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2018-0186 ◽

2018 ◽

Vol 31 (10) ◽

pp. 1165-1168 ◽

Cited By ~ 3

Author(s):

Werner Keenswijk ◽

Eva Degraeuwe ◽

Anne Hoorens ◽

Jo Van Dorpe ◽

Johan Vande Walle

Keyword(s):

Renal Function ◽

Membranoproliferative Glomerulonephritis ◽

Leukocytoclastic Vasculitis ◽

White Cell Count ◽

Gastrointestinal Symptoms ◽

Thyroid Stimulating Hormone ◽

Graves Disease ◽

Complement Factor ◽

Gradual Improvement ◽

Complement Factor C3

Abstract Background The association of hyperthyroidism with renal disease is very rare and the importance of timely clinical recognition cannot be overemphasized. Case presentation An 11-year-old girl presented with gastrointestinal symptoms while hypertension, edema and abdominal pain were noticed on clinical examination. Laboratory investigation revealed: hemoglobin 9.4 (11.5–15.5) g/dL, total white cell count 16 (4.5–12)×109/L, platelets 247 (150–450)×109/L, C-reactive protein (CRP) 31.8 (<5) mg/L, blood urea nitrogen (BUN) 126 (13–43) mg/dL, creatinine 0.98 (0.53–0.79) mg/dL, albumin 25 (35–52) g/dL, complement factor C3 0.7 (0.9–1.8) g/L, complement factor C4 0.1 (0.1–0.4) g/L, tri-iodothyronine 6.5 (2.5–5.2) pg/mL, free thyroxine 2.4 (1–1.7) ng/dL, thyroid stimulating hormone (TSH) <0.02 (0.5–4.3) mU/L. Urinalysis showed nephrotic range proteinuria. Renal function deteriorated necessitating hemodialysis (HD). A renal biopsy revealed an immune complex-mediated membranoproliferative glomerulonephritis (MPGN). Elevated thyroid hormones and suppressed TSH levels with elevated thyroperoxidase antibodies and thyroid stimulating immunoglobulins confirmed the diagnosis of Graves’ disease. Corticosteroids were commenced and eventually thiamazole was added with gradual improvement of renal function, cessation of HD and discharge from the hospital. Conclusions Graves’ disease complicated by MPGN is extremely rare, but can cause life-threatening complications.

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Brevinin-2 Drug Family—New Applied Peptide Candidates Against Methicillin-Resistant Staphylococcus aureus and Their Effects on Lys-7 Expression of Innate Immune Pathway DAF-2/DAF-16 in Caenorhabditis elegans

Applied Sciences ◽

10.3390/app8122627 ◽

2018 ◽

Vol 8 (12) ◽

pp. 2627

Author(s):

Hui Xie ◽

Yonghua Zhan ◽

Xueli Chen ◽

Qi Zeng ◽

Dan Chen ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Survival Rate ◽

Caenorhabditis Elegans ◽

Antimicrobial Peptides ◽

Real Time ◽

Innate Immune ◽

C Elegans ◽

New Drug ◽

Immune Pathway ◽

Innate Immune Pathway

The issue of Staphylococcus aureus (MRSA) developing a resistance to drugs such as methicillin has long been the focus for new drug development. In recent years, antimicrobial peptides, such as small molecular peptides with broad-spectrum antibacterial activity and special antibacterial mechanism, have shown a strong medicinal potential. In particular, the Brevinin-2 family has been shown to have a significant inhibitory effect against gram-positive bacteria (G+). In this study, we researched the influence of MRSA on the behavior and survival rate of nematodes. We established an assay of Caenorhabditis elegans–MRSA antimicrobial peptides to screen for new potent anti-infective peptides against MRSA. From the Brevinin-2 family, 13 peptides that had shown strong effects on G+ were screened for their ability to prolong the lifespan of infected worms. Real-time Polymerase Chain Reaction (PCR) tests were used to evaluate the effect on the innate immune pathway dauer formation defective (DAF)-2/DAF-16 of C. elegans. The assay successfully screened and filtered out four of the 13 peptides that significantly improved the survival rate of MRSA-infected worms. The result of real-time PCR indicated that the mRNA and protein expression levels of lys-7 were consistently upregulated by being treated with four of the Brevinin-2 family. The Brevinin-2 family peptides, including Brevinin-2, Brevinin-2-OA3, Brevinin-2ISb, and Brevinin-2TSa, also played an active role in the DAF-2/DAF-16 pathway in C. elegans. We successfully demonstrated the utility of anti-infective peptides that prolong the survival rate of the MRSA-infected host and discovered the relationship between antibacterial peptides and the innate immune system of C. elegans. We demonstrated the antimicrobial effects of Brevinin-2 family peptides, indicating their potential for use as new drug candidates against MRSA infections.

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Human Cytomegalovirus UL138 Protein Inhibits the STING Pathway and Reduces Interferon Beta mRNA Accumulation during Lytic and Latent Infections

mBio ◽

10.1128/mbio.02267-21 ◽

2021 ◽

Author(s):

Emily R. Albright ◽

Clayton K. Mickelson ◽

Robert F. Kalejta

Keyword(s):

Innate Immunity ◽

Interferon Beta ◽

Viral Latency ◽

Arms Race ◽

Innate Immune ◽

Mrna Accumulation ◽

Immune Pathway ◽

Sting Pathway ◽

Innate Immune Pathway

While a cellular restriction versus viral countermeasure arms race between innate immunity and viral latency is expected, few examples have been documented. Our identification of the first HCMV latency protein that inactivates the cGAS/STING/TBK1 innate immune pathway opens the door to understanding how innate immunity, or its neutralization, impacts long-term persistence by HCMV and other latent viruses.

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