scholarly journals Chronic viral infections persistently alter marrow stroma and impair hematopoietic stem cell fitness

2021 ◽  
Vol 218 (12) ◽  
Author(s):  
Stephan Isringhausen ◽  
YeVin Mun ◽  
Larisa Kovtonyuk ◽  
Nike J. Kräutler ◽  
Ute Suessbier ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Viral Infections ◽  
Inflammatory Responses ◽  
Lymphocytic Choriomeningitis ◽  
Type I ◽  
Hematopoietic Stem ◽  
Competitive Fitness ◽  
Chronic Viral Infections ◽  
Functional Analyses

Chronic viral infections are associated with hematopoietic suppression, bone marrow (BM) failure, and hematopoietic stem cell (HSC) exhaustion. However, how persistent viral challenge and inflammatory responses target BM tissues and perturb hematopoietic competence remains poorly understood. Here, we combine functional analyses with advanced 3D microscopy to demonstrate that chronic infection with lymphocytic choriomeningitis virus leads to (1) long-lasting decimation of the BM stromal network of mesenchymal CXCL12-abundant reticular cells, (2) proinflammatory transcriptional remodeling of remaining components of this key niche subset, and (3) durable functional defects and decreased competitive fitness in HSCs. Mechanistically, BM immunopathology is elicited by virus-specific, activated CD8 T cells, which accumulate in the BM via interferon-dependent mechanisms. Combined antibody-mediated inhibition of type I and II IFN pathways completely preempts degeneration of CARc and protects HSCs from chronic dysfunction. Hence, viral infections and ensuing immune reactions durably impact BM homeostasis by persistently decreasing the competitive fitness of HSCs and disrupting essential stromal-derived, hematopoietic-supporting cues.

scholarly journals CD8 T cells induce destruction of bone marrow stromal niches and hematopoietic stem cell dysfunction in chronic viral infections

2020 ◽  
Author(s):  
Stephan Isringhausen ◽  
Larisa Kovtonyuk ◽  
Ute Suessbier ◽  
Nike J. Kraeutler ◽  
Alvaro Gomariz ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Cd8 T Cells ◽  
Viral Infections ◽  
Inflammatory Responses ◽  
Type I ◽  
Hematopoietic Stem ◽  
Chronic Viral Infections

AbstractChronic viral infections are associated with hematopoietic suppression and bone marrow (BM) failure, which have been linked to hematopoietic stem cell (HSC) exhaustion. However, how persistent viral infectious challenge and ensuing inflammatory responses target BM tissues and perturb hematopoietic homeostasis remains poorly understood. Here, we combine extensive functional analyses with advanced 3D microscopy to demonstrate that chronic infection with lymphocytic choriomeningitis virus clone 13 results in the long-term impairment of HSC function, concomitant with a persistent destruction of the HSC-supportive stromal networks of mesenchymal CXCL12-abundant reticular cells. During infections, long lasting injuries and aberrant transcriptional programs of the stromal infrastructure diminish the capacity of the BM microenvironment to adequately support HSC maintenance. Mechanistically, BM immunopathology is elicited by virus-specific, activated CD8 T cells, which accumulate in the BM via interferon-dependent mechanisms. Combined inhibition of type I and II IFN pathways completely preempts viral-mediated degeneration of CARc networks and protects HSCs from persistent dysfunction. Hence, viral infections and ensuing immune reactions chronically interfere with BM function by disrupting essential stromal-derived, hematopoietic-supporting cues.

scholarly journals Pharmacokinetics and Safety of Intravenous Cidofovir for Life-Threatening Viral Infections in Pediatric Hematopoietic Stem Cell Transplant Recipients

2015 ◽  
Vol 59 (7) ◽  
pp. 3718-3725 ◽  
Author(s):  
Amy E. Caruso Brown ◽  
Mindy N. Cohen ◽  
Suhong Tong ◽  
Rebecca S. Braverman ◽  
James F. Rooney ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Half Life ◽  
Viral Infections ◽  
Multiorgan Failure ◽  
Kidney Injury ◽  
Cell Transplant ◽  
Open Label ◽  
Hematopoietic Stem ◽  
Life Threatening

ABSTRACTChildren undergoing hematopoietic stem cell transplantation (HSCT) are at risk for life-threatening viral infections. Cidofovir is often used as a first-line agent for adenovirus infections, despite the absence of randomized controlled trials with HSCT patients, and as a second-line agent for resistant herpesvirus infections. The frequency and severity of adverse effects, particularly nephrotoxicity, in pediatric HSCT recipients are unclear, and pharmacokinetics (PK) of cidofovir in children have not previously been reported. This study was an open-label, nonrandomized, single-dose pilot study to determine the safety and PK of cidofovir in pediatric HSCT recipients with symptomatic adenovirus, nucleoside-resistant cytomegalovirus (CMV) or herpes simplex virus (HSV), and/or human papovavirus infections. Subsequent dosing and frequency were determined by clinical response and side effects, as assessed by the treating physician. Blood and urine samples were obtained from patients for PK studies and assessment of toxicity and virologic response. Twelve patients were enrolled (median age, 9 years; 33.5 days posttransplantation). Four of seven patients with adenovirus infection were successfully treated and eventually cleared their infections. Four of twelve patients died of disseminated viral disease and multiorgan failure. Two of twelve patients had evidence of acute kidney injury after the first dose, and one of these patients developed chronic kidney disease; two other patients developed late nephrotoxicity. The mean drug half-life was 9.5 h. There was no correlation between nephrotoxicity and plasma maximum concentration, clearance, or half-life. PK were similar to those reported for adults, although the drug half-life was significantly longer than that for adults. Cidofovir was well tolerated in the majority of patients. However, effective therapeutic strategies are urgently needed to support patients until immune reconstitution is achieved.

scholarly journals BRD4 directs hematopoietic stem cell development and modulates macrophage inflammatory responses

2019 ◽  
Vol 38 (7) ◽  
Author(s):  
Anup Dey ◽  
Wenjing Yang ◽  
Anne Gegonne ◽  
Akira Nishiyama ◽  
Richard Pan ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Inflammatory Responses ◽  
Cell Development ◽  
Hematopoietic Stem
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