Abstract
Broad-based, host-targeted therapeutics have the potential to ameliorate viral infections without inducing antiviral resistance. We identified lanthionine synthetase C-like 2 (LANCL2) as a new therapeutic target for immunoinflammatory diseases. To examine the therapeutic efficacy of oral NSC61610 administration on influenza, we infected C57BL/6 mice with influenza A H1N1pdm virus and evaluated influenza-related mortality, lung inflammatory profiles, and pulmonary histopathology. Oral treatment with NSC61610 ameliorates influenza virus infection by down-modulating pulmonary inflammation through the downregulation of TNF-α and MCP-1 and reduction in the infiltration of neutrophils. NSC61610 treatment increases IL10-producing CD8+ T cells and macrophages in the lungs during the resolution phase of disease. The loss of LANCL2 or neutralization of IL-10 in mice infected with influenza virus abrogates the ability of NSC61610 to accelerate recovery and induce IL-10-mediated regulatory responses. These studies validate that oral treatment with NSC61610 ameliorates morbidity and mortality and accelerates recovery during influenza virus infection through a mechanism mediated by activation of LANCL2 and subsequent induction of IL-10 responses by CD8+ T cells and macrophages in the lungs.
Highlights
Seasonal influenza causes an estimated 200,000 hospitalizations and 25,000–35,000 deaths annually in the United States, afflicting mainly people older than 65 years of age [1]
We have recently investigated the potential role of abscisic acid (ABA), as a ligand of lanthionine synthetase C-like 2 (LANCL2) leading to elevation of intracellular cAMP and activation of protein kinase A (PKA) [11]
The LANCL2 pathway has emerged as a therapeutic target for inflammatory, chronic, and immune-mediated diseases [15]
Summary
Seasonal influenza causes an estimated 200,000 hospitalizations and 25,000–35,000 deaths annually in the United States, afflicting mainly people older than 65 years of age [1]. Aside from the seasonal flu, pandemic influenza originating from emerging strains can significantly change the disease dynamics. Influenza pandemics cause considerable disease, with associated mortality ranging from approximately 50 million deaths during the 1918 pandemic to 1 to 4 million deaths in 1957 and approximately 1 million deaths in 1968. In 2009, a novel H1N1 virus emerged and spread rapidly in humans, causing severe disease in susceptible populations and high numbers of respiratory- and cardiovascular-related deaths [2]. Seasonal flu is one of the most relevant infectious diseaserelated public health problems since it causes important economic losses ranging from 71 to 166 billion dollars during one influenza pandemic [3]. Current approaches for the prevention and treatment of influenza infections include vaccination and early administration of antiviral drugs [4].
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