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Article: Antibody-mediated cellular responses are dysregulated in Multisystem Inflammatory Syndrome in Children (MIS-C).

Dick, Jenna K / Sangala, Jules A / Krishna, Venkatramana D / Khaimraj, Aaron / Hamel, Lydia / Erickson, Spencer M / Hicks, Dustin / Soigner, Yvette / Covill, Laura E / Johnson, Alexander / Ehrhardt, Michael J / Ernste, Keenan / Brodin, Petter / Koup, Richard A / Khaitan, Alka / Baehr, Carly / Thielen, Beth K / Henzler, Christine M / Skipper, Caleb /

Miller, Jeffrey S / Bryceson, Yenan T / Wu, Jianming / John, Chandy C / Panoskaltsis-Mortari, Angela / Orioles, Alberto / Steiner, Marie E / Cheeran, Maxim C-J / Pravetoni, Marco / Hart, Geoffrey T

bioRxiv : the preprint server for biology

2024

Abstract: Multisystem Inflammatory Syndrome in Children (MIS-C) is a severe complication of SARS-CoV-2 ... to understand the aberrant immune response in MIS-C is limited. Despite strong antibody production in MIS-C ... responsible for delayed clearance of viral products in MIS-C. In MIS-C, monocytes were hyperfunctional ...

Abstract	Multisystem Inflammatory Syndrome in Children (MIS-C) is a severe complication of SARS-CoV-2 infection characterized by multi-organ involvement and inflammation. Testing of cellular function ex vivo to understand the aberrant immune response in MIS-C is limited. Despite strong antibody production in MIS-C, SARS-CoV-2 nucleic acid testing can remain positive for 4-6 weeks after infection. Therefore, we hypothesized that dysfunctional cell-mediated antibody responses downstream of antibody production may be responsible for delayed clearance of viral products in MIS-C. In MIS-C, monocytes were hyperfunctional for phagocytosis and cytokine production, while natural killer (NK) cells were hypofunctional for both killing and cytokine production. The decreased NK cell cytotoxicity correlated with an NK exhaustion marker signature and systemic IL-6 levels. Potentially providing a therapeutic option, cellular engagers of CD16 and SARS-CoV-2 proteins were found to rescue NK cell function in vitro. Together, our results reveal dysregulation in antibody-mediated cellular responses unique to MIS-C that likely contribute to the immune pathology of this disease.
Language	English
Publishing date	2024-04-18
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.04.16.589585
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Article ; Online: Mitigation of trauma-induced endotheliopathy by activated protein C: A potential therapeutic for postinjury thromboinflammation.

Thielen, Otto / Mitra, Sanchayita / Debot, Margot / Schaid, Terry / Hallas, William / Gallagher, Lauren T / Erickson, Christopher / Cralley, Alexis / Stafford, Preston / Silliman, Christopher / D'Alessandro, Angelo / Hansen, Kirk / Sauaia, Angela / Moore, Ernest / Mosnier, Laurent / Griffin, John / Cohen, Mitchell

The journal of trauma and acute care surgery

2023 Volume 96, Issue 1, Page(s) 116–122

Abstract: Background: Activated Protein C (aPC) plays dual roles after injury, driving both trauma-induced ...

Abstract	Background: Activated Protein C (aPC) plays dual roles after injury, driving both trauma-induced coagulopathy (TIC) by cleaving, and thus inactivating, factors Va and VIIIa and depressing fibrinolysis while also mediating an inflammomodulatory milieu via protease activated receptor-1 (PAR-1) cytoprotective signaling. Because of this dual role, it represents and ideal target for study and therapeutics after trauma. A known aPC variant, 3K3A-aPC, has been engineered to preserve cytoprotective activity while retaining minimal anticoagulant activity rendering it potentially ideal as a cytoprotective therapeutic after trauma. We hypothesized that 3K3A-aPC would mitigate the endotheliopathy of trauma by protecting against endothelial permeability. Methods: We used electric cell-substrate impedance sensing to measure permeability changes in real time in primary endothelial cells. These were cultured, grown to confluence, and treated with a 2 μg/mL solution of 3K3A-aPC at 180 minutes, 120 minutes, 60 minutes, 30 minutes prior to stimulation with ex vivo plasma taken from severely injured trauma patients (Injury Severity Score > 15 and BD < -6) (trauma plasma [TP]). Cells treated with thrombin and untreated cells were included in this study as control groups. Permeability changes were recorded in real time via electric cell-substrate impedance sensing for 30 minutes after treatment with TP. We quantified permeability changes in the control and treatment groups as area under the curve (AUC). Rac1/RhoA activity was also compared between these groups. Statistical significance was determined by one-way ANOVA followed by a post hoc analysis using Tukey's multiple comparison's test. Results: Treatment with aPC mitigated endothelial permeability induced by ex vivo trauma plasma at all pre-treatment time points. The AUC of the 30-minute 3K3A-aPC pretreatment group was higher than TP alone (mean diff. 22.12 95% CI [13.75, 30.49], p < 0.0001) (Figure). Moreover, the AUC of the 60-minute, 120-minute, and 180-minute pretreatment groups was also higher than TP alone (mean diff., 16.30; 95% confidence interval [CI], 7.93-24.67; 19.43; 95% CI, 11.06-27.80, and 18.65; 95% CI, 10.28-27.02;, all p < 0.0001, respectively). Rac1/RhoA activity was higher in the aPC pretreatment group when compared with all other groups ( p < 0.01). Conclusion: Pretreatment with 3K3A-aPC, which retains its cytoprotective function but has only ~5% of its anticoagulant function, abrogates the effects of trauma-induced endotheliopathy. This represents a potential therapeutic treatment for dysregulated thromboinflammation for injured patients by minimizing aPC's role in trauma-induced coagulopathy while concurrently amplifying its essential cytoprotective function. Level of evidence: Prognostic and Epidemiological; Level III.
MeSH term(s)	Humans ; Protein C/pharmacology ; Protein C/therapeutic use ; Protein C/metabolism ; Endothelial Cells/metabolism ; Thromboinflammation ; Inflammation/metabolism ; Thrombosis ; Anticoagulants/therapeutic use
Chemical Substances	Protein C ; Anticoagulants
Language	English
Publishing date	2023-09-21
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
ZDB-ID	2651070-4
ISSN	2163-0763 ; 2163-0755
ISSN (online)	2163-0763
ISSN	2163-0755
DOI	10.1097/TA.0000000000004142
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Article ; Online: What Do We C in Children With Scurvy? A Case Series Focused on Musculoskeletal Symptoms.

Gilley, Stephanie P / Ta, Allison / Pryor, William / Roper, Brennan / Erickson, Mark / Fenton, Laura Z / Tchou, Michael J / Cotter, Jillian M / Moore, Jaime M

Hospital pediatrics

2024 Volume 14, Issue 2, Page(s) e98–e103

Abstract: Objectives: Vitamin C deficiency in children commonly presents with musculoskeletal symptoms ... with diagnostic codes for vitamin C deficiency, ascorbic acid deficiency, or scurvy. Medical records were reviewed ... the BMI spectrum, particularly those with neurodevelopmental disorders, can develop vitamin C deficiency ...

Abstract	Objectives: Vitamin C deficiency in children commonly presents with musculoskeletal symptoms such as gait disturbance, refusal to bear weight, and bone or joint pain. We aimed to identify features that could facilitate early diagnosis of scurvy and estimate the cost of care for patients with musculoskeletal symptoms related to scurvy. Methods: We conducted a retrospective chart review of patients at a single site with diagnostic codes for vitamin C deficiency, ascorbic acid deficiency, or scurvy. Medical records were reviewed to identify characteristics including presenting symptoms, medical history, and diagnostic workup. The Pediatric Health Information System was used to estimate diagnostic and hospitalization costs for each patient. Results: We identified 47 patients with a diagnosis of scurvy, 49% of whom had a neurodevelopmental disorder. Sixteen of the 47 had musculoskeletal symptoms and were the focus of the cost analysis. Three of the 16 had moderate or severe malnutrition, and 3 had overweight or obesity. Six patients presented to an emergency department for care, 11 were managed inpatient, and 3 required critical care. Diagnostic workups included MRI, computed tomography, echocardiogram, endoscopy, lumbar puncture, and/or EEG. Across all patients evaluated, the cost of emergency department utilization, imaging studies, diagnostic procedures, and hospitalization totaled $470 144 (median $14 137 per patient). Conclusions: Children across the BMI spectrum, particularly those with neurodevelopmental disorders, can develop vitamin C deficiency. Increased awareness of scurvy and its signs and symptoms, particularly musculoskeletal manifestations, may reduce severe disease, limit adverse effects related to unnecessary tests/treatments, and facilitate high-value care.
MeSH term(s)	Humans ; Child ; Scurvy/complications ; Scurvy/diagnosis ; Ascorbic Acid ; Retrospective Studies ; Ascorbic Acid Deficiency ; Magnetic Resonance Imaging
Chemical Substances	Ascorbic Acid (PQ6CK8PD0R)
Language	English
Publishing date	2024-01-18
Publishing country	United States
Document type	Journal Article
ISSN	2154-1671
ISSN (online)	2154-1671
DOI	10.1542/hpeds.2023-007336
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Article ; Online: Antibody-mediated cellular responses are dysregulated in Multisystem Inflammatory Syndrome in Children (MIS-C)

Miller, Jeffrey S / Bryceson, Yenan T / Wu, Jianming / John, Chandy C / Panoskaltsis-Mortari, Angela / Orioles, Alberto / Steiner, Marie E / Cheeran, Maxim C-J / Pravetoni, Marco / Hart, Geoffrey T

bioRxiv

Abstract	Multisystem Inflammatory Syndrome in Children (MIS-C) is a severe complication of SARS-CoV-2 infection characterized by multi-organ involvement and inflammation. Testing of cellular function ex vivo to understand the aberrant immune response in MIS-C is limited. Despite strong antibody production in MIS-C, SARS-CoV-2 nucleic acid testing can remain positive for 4-6 weeks after infection. Therefore, we hypothesized that dysfunctional cell-mediated antibody responses downstream of antibody production may be responsible for delayed clearance of viral products in MIS-C. In MIS-C, monocytes were hyperfunctional for phagocytosis and cytokine production, while natural killer (NK) cells were hypofunctional for both killing and cytokine production. The decreased NK cell cytotoxicity correlated with an NK exhaustion marker signature and systemic IL-6 levels. Potentially providing a therapeutic option, cellular engagers of CD16 and SARS-CoV-2 proteins were found to rescue NK cell function in vitro. Together, our results reveal dysregulation in antibody-mediated cellular responses unique to MIS-C that likely contribute to the immune pathology of this disease.
Keywords	covid19
Language	English
Publishing date	2024-04-18
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2024.04.16.589585
Database	COVID19

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Article ; Online: Antibody-mediated cellular responses are dysregulated in Multisystem Inflammatory Syndrome in Children (MIS-C)

Dick, Jenna K / Sangala, Jules A / Krishna, Venkatramana D / Khaimraj, Aaron / Hamel, Lydia / Erickson, Spencer M / Hicks, Dustin / Soigner, Yvette / Covill, Laura E / Johnson, Alexander / Ehrhardt, Michael J / Ernst, Keenan / Brodin, Petter / Koup, Richard A / Khaitan, Alka / Baehr, Carly / Thielen, Beth K / Henzler, Christine M / Skipper, Caleb /

Miller, Jeffrey S / Bryceson, Yenan T / Wu, Jianming / John, Chandy C / Panoskaltsis-Mortari, Angela / Orioles, Alberto / Steiner, Marie E / Cheeran, Maxim C-J / Pravetoni, Marco / Hart, Geoffrey T

bioRxiv

Abstract	Multisystem Inflammatory Syndrome in Children (MIS-C) is a severe complication of SARS-CoV-2 infection characterized by multi-organ involvement and inflammation. Testing of cellular function ex vivo to understand the aberrant immune response in MIS-C is limited. Despite strong antibody production in MIS-C, SARS-CoV-2 nucleic acid testing can remain positive for 4-6 weeks after infection. Therefore, we hypothesized that dysfunctional cell-mediated antibody responses downstream of antibody production may be responsible for delayed clearance of viral products in MIS-C. In MIS-C, monocytes were hyperfunctional for phagocytosis and cytokine production, while natural killer (NK) cells were hypofunctional for both killing and cytokine production. The decreased NK cell cytotoxicity correlated with an NK exhaustion marker signature and systemic IL-6 levels. Potentially providing a therapeutic option, cellular engagers of CD16 and SARS-CoV-2 proteins were found to rescue NK cell function in vitro. Together, our results reveal dysregulation in antibody-mediated cellular responses unique to MIS-C that likely contribute to the immune pathology of this disease.
Keywords	covid19
Language	English
Publishing date	2024-04-18
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2024.04.16.589585
Database	COVID19

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Article ; Online: Erratum to: Fields EC, Erickson B, Hubbard A, Chino J, Small C, Weiner A, Petereit D, Mayadev JS, Yashar CM, Joyner M. Tipping the Balance: Adding Resources for Cervical Cancer Brachytherapy. Int J Radiat Oncol Biol Phys 2023;117:1138-1142.

Fields, Emma C / Erickson, Beth / Hubbard, Anne / Chino, Junzo / Small, Christina / Weiner, Ashley / Petereit, Daniel / Mayadev, Jyoti S / Yashar, Catheryn M / Joyner, Melissa

International journal of radiation oncology, biology, physics

2024 Volume 118, Issue 3, Page(s) 869

Language	English
Publishing date	2024-02-08
Publishing country	United States
Document type	Published Erratum
ZDB-ID	197614-x
ISSN	1879-355X ; 0360-3016
ISSN (online)	1879-355X
ISSN	0360-3016
DOI	10.1016/j.ijrobp.2023.11.041
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Article: Resuscitation With Vitamin C, Hydrocortisone, and Thiamin in Children With Septic Shock: A Multicenter Randomized Pilot Study.

Schlapbach, Luregn J / Raman, Sainath / Buckley, David / George, Shane / King, Megan / Ridolfi, Roberta / Harley, Amanda / Cree, Michele / Long, Debbie / Erickson, Simon / Singh, Puneet / Festa, Marino / Gibbons, Kristen / Bellomo, Rinaldo

Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies

2024 Volume 25, Issue 2, Page(s) 159–170

Abstract: Objectives: Adjunctive therapy with vitamin C, hydrocortisone, and thiamin has been evaluated ... the feasibility of vitamin C, hydrocortisone, and thiamin in PICU patients with septic shock; and to explore ... adjunctive treatment with high-dose vitamin C, hydrocortisone, and thiamin versus standard care was feasible ...

Abstract	Objectives: Adjunctive therapy with vitamin C, hydrocortisone, and thiamin has been evaluated in adults, but randomized controlled trial (RCT) data in children are lacking. We aimed to test the feasibility of vitamin C, hydrocortisone, and thiamin in PICU patients with septic shock; and to explore whether the intervention is associated with increased survival free of organ dysfunction. Design: Open-label parallel, pilot RCT multicenter study. The primary endpoint was feasibility. Clinical endpoints included survival free of organ dysfunction censored at 28 days and nine secondary outcomes, shock reversal, and two proxy measures of intervention efficacy. Setting: Six PICUs in Australia and New Zealand. Patients: Children of age between 28 days and 18 years requiring vasoactive drugs for septic shock between August 2019 and March 2021. Interventions: Patients were assigned 1:1 to receive 1 mg/kg hydrocortisone every 6 hours (q6h), 30 mg/kg ascorbic acid q6h, and 4 mg/kg thiamin every 12 hours (n = 27), or standard septic shock management (n = 33). Measurements and main results: Sixty of 77 (78%) eligible patients consented with 91% of approached parents providing consent. The median time from randomization to intervention was 44 (interquartile range [IQR] 29-120) min. Seventy of seventy-seven (28%) patients had received IV steroids before randomization. Median survival alive and free of organ dysfunction was 20.0 (0.0-26.0) days in the intervention and 21.0 (0.0-25.0) days in the standard care group. Median PICU length of stay was 5.3 (2.5-11.3) days in the intervention group versus 6.9 (3.0-11.5) days in the control group. Shock reversal occurred at a median of 35.2 (14.6-101.2) hours in the intervention group versus 47.3 (22.4-106.8) hours in the standard care group (median difference -12 hr; 95% CI, -56.8 to 32.7 hr). Conclusions: In children requiring vasopressors for septic shock, a protocol comparing adjunctive treatment with high-dose vitamin C, hydrocortisone, and thiamin versus standard care was feasible. These findings assist in making modifications to the trial protocol to enable a better-designed larger RCT.
MeSH term(s)	Child ; Humans ; Infant, Newborn ; Ascorbic Acid/therapeutic use ; Hydrocortisone/therapeutic use ; Multiple Organ Failure ; Pilot Projects ; Shock ; Shock, Septic/therapy ; Thiamine/therapeutic use ; Infant ; Child, Preschool ; Adolescent
Chemical Substances	Ascorbic Acid (PQ6CK8PD0R) ; Hydrocortisone (WI4X0X7BPJ) ; Thiamine (X66NSO3N35)
Language	English
Publishing date	2024-01-19
Publishing country	United States
Document type	Randomized Controlled Trial ; Multicenter Study ; Journal Article
ZDB-ID	2052349-X
ISSN	1947-3893 ; 1529-7535
ISSN (online)	1947-3893
ISSN	1529-7535
DOI	10.1097/PCC.0000000000003346
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Zs.MO 472: Show issues

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Article ; Online: Hepatitis C virus infects and perturbs liver stem cells.

mBio

2023 , Page(s) e0131823

Abstract: Hepatitis C virus (HCV) is the leading cause of death from liver disease. How HCV infection causes ...

Abstract	Hepatitis C virus (HCV) is the leading cause of death from liver disease. How HCV infection causes lasting liver damage and increases cancer risk remains unclear. Here, we identify bipotent liver stem cells as novel targets for HCV infection, and their erroneous differentiation as the potential cause of impaired liver regeneration and cancer development. We show 3D organoids generated from liver stem cells from actively HCV-infected individuals carry replicating virus and maintain low-grade infection over months. Organoids can be infected with a primary HCV isolate. Virus-inclusive single-cell RNA sequencing uncovered transcriptional reprogramming in HCV
Language	English
Publishing date	2023-11-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	2557172-2
ISSN	2150-7511 ; 2161-2129
ISSN (online)	2150-7511
ISSN	2161-2129
DOI	10.1128/mbio.01318-23
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Article ; Online: Transport of the Proinflammatory Chemokines C-C Motif Chemokine Ligand 2 (MCP-1) and C-C Motif Chemokine Ligand 5 (RANTES) across the Intact Mouse Blood-Brain Barrier Is Inhibited by Heparin and Eprodisate and Increased with Systemic Inflammation.

Quaranta, Daniel V / Weaver, Riley R / Baumann, Kristen K / Fujimoto, Takashi / Williams, Lindsey M / Kim, Hyung Chan / Logsdon, Aric F / Omer, Mohamed / Reed, May J / Banks, William A / Erickson, Michelle A

The Journal of pharmacology and experimental therapeutics

2022 Volume 384, Issue 1, Page(s) 205–223

Abstract: ... chemokines. C-C motif chemokine receptor 2 (CCL2) (MCP-1) and C-C motif chemokine receptor 5 (CCL5) (RANTES ...

Abstract	One important function of the vascular blood-brain barrier (BBB) is to facilitate neuroimmune communication. The BBB fulfills this function, in part, through its ability to transport cytokines and chemokines. C-C motif chemokine receptor 2 (CCL2) (MCP-1) and C-C motif chemokine receptor 5 (CCL5) (RANTES) are proinflammatory chemokines that mediate neuroimmune responses to acute insults and aspects of brain injury and neurodegenerative diseases; however, a blood-to-brain transport system has not been evaluated for either chemokine in vivo. Therefore, we determined whether CCL2 and CCL5 in blood can cross the intact BBB and enter the brain. Using CD-1 mice, we found that
MeSH term(s)	Mice ; Animals ; Blood-Brain Barrier/metabolism ; Heparin/pharmacology ; Ligands ; Chemokines/metabolism ; Inflammation/drug therapy ; Receptors, Chemokine ; Heparitin Sulfate
Chemical Substances	Iodine-125 (GVO776611R) ; eprodisate (6QFP76V7S7) ; Heparin (9005-49-6) ; Ligands ; Chemokines ; Receptors, Chemokine ; Heparitin Sulfate (9050-30-0)
Language	English
Publishing date	2022-10-30
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, Non-U.S. Gov't
ZDB-ID	3106-9
ISSN	1521-0103 ; 0022-3565
ISSN (online)	1521-0103
ISSN	0022-3565
DOI	10.1124/jpet.122.001380
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Article ; Online: Modelling T-cell immunity against hepatitis C virus with liver organoids in a microfluidic coculture system.

Natarajan, Vaishaali / Simoneau, Camille R / Erickson, Ann L / Meyers, Nathan L / Baron, Jody L / Cooper, Stewart / McDevitt, Todd C / Ott, Melanie

Open biology

2022 Volume 12, Issue 3, Page(s) 210320

Abstract: Hepatitis C virus (HCV) remains a global public health challenge with an estimated 71 million ...

Abstract	Hepatitis C virus (HCV) remains a global public health challenge with an estimated 71 million people chronically infected, with surges in new cases and no effective vaccine. New methods are needed to study the human immune response to HCV since
MeSH term(s)	CD8-Positive T-Lymphocytes/immunology ; Coculture Techniques ; Hepacivirus ; Hepatitis C/immunology ; Humans ; Microfluidics ; Organoids ; Viral Nonstructural Proteins/immunology
Chemical Substances	Viral Nonstructural Proteins
Language	English
Publishing date	2022-03-02
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2630944-0
ISSN	2046-2441 ; 2046-2441
ISSN (online)	2046-2441
ISSN	2046-2441
DOI	10.1098/rsob.210320
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