Search

Background: Currently, there are no therapies targeting specific pathogenic pathways in myocarditis. IL (interleukin)-1 blockade has shown promise in preclinical studies and case reports. We hypothesized that blockade of IL1RAP (IL-1 receptor accessory protein), a shared subunit of the IL-1, IL-33, and IL-36 receptors, could be more efficient than IL-1 blockade alone., Methods: We induced coxsackievirus B3 (CVB3)-mediated or experimental autoimmune myocarditis (EAM) in BALB/c mice, followed by treatment with an Fc (fragment crystallizable)-modified mIgG2a mouse anti-mouse IL1RAP monoclonal antibody (mCAN10). Myocarditis severity and immune infiltration were assessed by histology and flow cytometry. Cardiac function was measured by echocardiography. We used spatial transcriptomics (Visium 10× Genomics) to compare the gene expression landscape in the hearts of mCAN10-treated versus control mice., Results: IL1RAP blockade reduced CVB3 and EAM severity. In EAM, the treatment prevented deterioration of cardiac function, measured on day 42 post-disease induction (left ventricular ejection fraction: 56.5% versus 51.0% in isotype controls [ P =0.002] and versus 51.4% in mice treated with anti-IL-1β antibodies alone [ P =0.003]; n=10-11 mice per group). In the CVB3 model, mCAN10 did not impede viral clearance from the heart and significantly lowered the numbers of CD4 + (cluster of differentiation 4) T cells ( P =0.025), inflammatory Ly6C + CCR2 + (lymphocyte antigen 6 complex, locus C/C-C motif chemokine receptor 2) monocytes ( P =0.038), neutrophils ( P =0.001) and eosinophils ( P <0.001) infiltrating the myocardium. The spatial transcriptomic analysis revealed reduced canonical IL-1 signaling and chemokine expression in cardiac immune foci in CVB3-infected mice treated with IL1RAP blockade., Conclusions: Blocking IL1RAP reduces acute CVB3 myocarditis and EAM severity and preserves cardiac function in EAM. We conclude that IL1RAP blockade is a potential therapeutic strategy in viral and autoimmune myocarditis.

Cardiac myosin-specific (MyHC) T cells drive the disease pathogenesis of immune checkpoint inhibitor-associated myocarditis (ICI-myocarditis). To determine whether MyHC T cells are tissue-resident memory T (T RM ) cells, we characterized cardiac T RM cells in naive mice and established that they have a distinct phenotypic and transcriptional profile that can be defined by their upregulation of CD69, PD-1, and CXCR6. We then investigated the effects of cardiac injury through a modified experimental autoimmune myocarditis mouse model and an ischemia-reperfusion injury mouse model and determined that cardiac inflammation induces the recruitment of autoreactive MyHC T RM cells, which coexpress PD-1 and CD69. To investigate whether the recruited MyHC T RM cells could increase susceptibility to ICI-myocarditis, we developed a two-hit ICI-myocarditis mouse model where cardiac injury was induced, mice were allowed to recover, and then were treated with anti-PD-1 antibodies. We determined that mice who recover from cardiac injury are more susceptible to ICI-myocarditis development. We found that murine and human T RM cells share a similar location in the heart and aggregate along the perimyocardium. We phenotyped cells obtained from pericardial fluid from patients diagnosed with dilated cardiomyopathy and ischemic cardiomyopathy and established that pericardial T cells are predominantly CD69 + T RM cells that up-regulate PD-1. Finally, we determined that human pericardial macrophages produce IL-15, which supports and maintains pericardial T RM cells., Competing Interests: Competing interests statement:Dr. Čiháková has research grants with CSL Behring and Cantargia. Neither grant conflicts with this project.

Hypereosinophilic syndrome is a progressive disease with extensive eosinophilia that results in organ damage. Cardiac pathologies are the main reason for its high mortality rate. A better understanding of the mechanisms of eosinophil-mediated tissue damage would benefit therapeutic development. Here, we describe the cardiac pathologies that developed in a mouse model of hypereosinophilic syndrome. These IL-5 transgenic mice exhibited decreased left ventricular function at a young age which worsened with age. Mechanistically, we demonstrated infiltration of activated eosinophils into the heart tissue that led to an inflammatory environment. Gene expression signatures showed tissue damage as well as repair and remodeling processes. Cardiomyocytes from IL-5Tg mice exhibited significantly reduced contractility relative to wild type (WT) controls. This impairment may result from the inflammatory stress experienced by the cardiomyocytes and suggest that dysregulation of contractility and Ca 2+ reuptake in cardiomyocytes contributes to cardiac dysfunction at the whole organ level in hypereosinophilic mice., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)

Broadly neutralizing antibodies targeting a highly conserved region in the hemagglutinin (HA) stem protect against influenza infection. Here, we investigate the protective efficacy of a protein (HB36.6) computationally designed to bind with high affinity to the same region in the HA stem. We show that intranasal delivery of HB36.6 affords protection in mice lethally challenged with diverse strains of influenza independent of Fc-mediated effector functions or a host antiviral immune response. This designed protein prevents infection when given as a single dose of 6.0 mg/kg up to 48 hours before viral challenge and significantly reduces disease when administered as a daily therapeutic after challenge. A single dose of 10.0 mg/kg HB36.6 administered 1-day post-challenge resulted in substantially better protection than 10 doses of oseltamivir administered twice daily for 5 days. Thus, binding of HB36.6 to the influenza HA stem region alone, independent of a host response, is sufficient to reduce viral infection and replication in vivo. These studies demonstrate the potential of computationally designed binding proteins as a new class of antivirals for influenza.

Direct injection from a capillary supercritical fluid chromatography system was used as an inlet technique for chemical ionization (CI) and low energy collision-induced dissociation (CID) mass spectrometry of a series of low volatility nonionic surfactant mixtures. Characteristic fragment ions produced by CID for various classes of nonionic surfactant molecules were found to depend greatly on the structure of the surfactant hydrophobe. This was the case even when the charge on the molecule appeared localized away from the hydrophobe. Numerous decomposition pathways are suggested by the fragment ions produced. The use of direct supercritical fluid injection as an inlet technique does not appear to influence adversely the ability to produce cm mass spectra. Direct supercritical fluid introduction allows CI to be compared with other ionization mechanisms more commonly used for multifunctional, low volatility samples.