Gr-1+ Cells Other Than Ly6G+ Neutrophils Limit Virus Replication and Promote Myocardial Inflammation and Fibrosis Following Coxsackievirus B3 Infection of Mice

Abstract

Coxsackievirus B3 (CVB3) is the primary cause of viral myocarditis. An early and abundant neutrophil accumulation in the myocardium is a hallmark of early CVB3 infection. Yet the relative contribution of neutrophils to host susceptibility to CVB3 myocarditis remains largely unknown. Herein, peripheral neutrophil depletion was implemented in a BALB/c mouse model of acute CVB3 myocarditis using the specific 1A-8 (anti-Ly6G) or a RB6-8C5 (anti-Gr-1) mAb covering a wide range. Anti-Ly6G treatment led to systemic neutropenia throughout the disease, but did not alter virus replication, disease susceptibility and histopathological changes in the heart and pancreas of mice. In contrast, depletion of both neutrophils and monocytes/macrophages by anti-Gr-1 mAb prior to and after infection significantly promoted susceptibility of mice to CVB3 infection which was associated with exacerbated cardiac and pancreatic viral load. However, depletion of Gr1+ cells significantly suppressed acute myocarditis and pancreatic acini destruction at day 7 post infection via reducing Ly6Chigh monocyte population in the circulation. Additionally, cardiac interstitial fibrosis was not affected by neutrophil depletion, whereas Gr-1+ cells other than neutrophils increased cardiac fibrosis at day 21 p.i. by increasing cardiac expression of profibrotic cytokine TNF-α and TGF-β. Thus, Neutrophil function is most likely not essential for CVB3 control and peripheral neutrophils play dispensable role in the pathogenesis of acute myocarditis and pancreatitis during CVB3 infection. Whereas Gr-1+ cells other than neutrophils play a major role in limiting viral replication while promoting myocardial and pancreatic inflammatory injury and fibrosis.

Antibody-guided in vivo imaging of Aspergillus fumigatus lung infections during antifungal azole treatment

“…In our neutropenic mouse model of IPA, neutrophil deficiency, more specifically loss of Gr-1 + cells, resulted in infection of the entire lung volume within a matter of hours of challenge with spore inoculum, whereas, in the presence of neutrophils, the pathogen was rapidly controlled. This demonstrates further the critical role of Gr-1 + neutrophils in preventing infectious pathogens 43 , and provides an additional, and highly effective, means of depleting neutrophils, to those used by Amich and co-workers in LSFM of A. fumigatus lung infections 44 . Surprisingly, in healthy animals, neutrophil-mediated control of lung infection took longer than expected, as invasion was apparent in LSFM 6 h after initial deposition of A. fumigatus spores.…”

Myocarditis and inflammatory cardiomyopathy: current evidence and future directions

“…Neutrophils are among the first lines of defence against infection. In a mouse model of CVB3 myocarditis, an early (2.5 days) and abundant mobilization and influx of neutrophils into the heart and the pancreas occur after CVB3 infection 91 . This mobilization occurs earlier than that of any other infiltrated innate immune cells.…”

Proteasomal Protein Degradation: Adaptation of Cellular Proteolysis With Impact on Virus—and Cytokine-Mediated Damage of Heart Tissue During Myocarditis

“…The i-proteasome influences the abundance of these cells in blood and spleen, but it controls the activation status of neutrophils as well ( 72 , 121 ). Nevertheless, neutrophils have no disease modifying impact on CVB3-induced myocarditis ( 72 , 122 , 123 ). During myocarditis, particularly monocytes/macrophages—that emigrate the bone marrow, then sequester and differentiate in the spleen—infiltrate the infected mouse heart ( 23 , 99 ).…”