Inhibition of Necroptosis to Prevent Long-term Cardiac Damage During Pneumococcal Pneumonia and Invasive Disease

Abstract

Background Streptococcus pneumoniae infection can result in bacteremia with devastating consequences including heart damage. Necroptosis is a proinflammatory form of cell death instigated by pore-forming toxins such as S. pneumoniae pneumolysin. Necroptosis-inhibiting drugs may lessen organ damage during invasive pneumococcal disease (IPD). Methods In vitro experiments were carried out with human and mouse cardiomyocytes. Long-term cardiac damage was assessed using high-resolution echocardiography in ampicillin-rescued mice 3 months after challenge with S. pneumoniae. Ponatinib, a necroptosis-inhibiting and Food and Drug Administration–approved drug for lymphocytic leukemia treatment, was administered intraperitoneally alongside ampicillin to test its therapeutic efficacy. Histology of heart sections included hematoxylin-eosin staining for overt damage, immunofluorescence for necroptosis, and Sirius red/fast green staining for collagen deposition. Results Cardiomyocyte death and heart damage was due to pneumolysin-mediated necroptosis. IPD leads to long-term cardiac damage, as evidenced by de novo collagen deposition in mouse hearts and a decrease in fractional shortening. Adjunct necroptosis inhibition reduced the number of S. pneumoniae foci observed in hearts of acutely infected mice and serum levels of troponin I. Ponatinib reduced collagen deposition and protected heart function in convalescence. Conclusions Acute and long-term cardiac damage incurred during IPD is due in part to cardiomyocyte necroptosis. Necroptosis inhibitors may be a viable adjunct therapy.

Pandemic Influenza Infection Promotes Streptococcus pneumoniae Infiltration, Necrotic Damage, and Proteomic Remodeling in the Heart

“…For decades, extensive evidence has implicated risk of myocardial infarction in various infectious diseases such as influenza, pneumococcal pneumonia, and bacteremia ( 1 – 3 ). Our group has previously shown that the bacterium Streptococcus pneumoniae (pneumococcus) is capable of myocardial invasion, induction of cardiomyocyte death, and disruption of cardiac contractility and function during acute infection and convalescence ( 4 – 6 ). Cardiac complications have also been observed during influenza epidemics and pandemics.…”

“…Mice were then challenged with S. pneumoniae (strain TIGR4) at a dose of 1 × 10 3 CFU for 2 days before euthanasia. Immunofluorescent staining against S. pneumoniae showed cardiac microlesion ( 4 ) formation only in animals preinfected with IAV ( Fig. 1A ), with a significant increase in the percentage of area of heart with lesions ( Fig.…”

Cardiomyocyte death in sepsis: Mechanisms and regulation (Review)

“…To investigate the importance of necroptosis in cardiomyocyte death and heart injury in sepsis, a number of studies both in vivo and in vitro have been performed ( 53 , 54 ). Beno et al ( 55 ) reported that cardiomyocyte death and heart damage are necroptosis-dependent in a Streptococcus pneumoniae mouse model in which necroptosis inhibition attenuated myocardial injury. The promotive effects of necroptosis on sepsis-associated myocardial damage have been confirmed by cell experiments ( 56 , 57 ).…”

Platelets and Their Role in the Pathogenesis of Cardiovascular Events in Patients With Community-Acquired Pneumonia

“…Very recently, Beno et al using high-resolution echocardiography, observed that administration of ponatinib, a novel multi-tyrosine kinase inhibitor that attenuates necroptosis, to mice with experimentally induced severe pneumococcal disease, resulted in significant attenuation of long-term cardiac damage ( 185 , 186 ). Although these cardio-protective effects of ponatinib were attributed to attenuation of pneumolysin-mediated cardiomyocyte necroptosis, it is also noteworthy that toxin-induced platelet activation and resultant microvascular occlusion represents an additional cause of cardiac necroptosis.…”