LANCL2: A Novel Therapeutic Target for Influenza
BLACKSBURG, VA. February 28, 2017—The BioTherapeutics (BTI) team has recently explored the potential of activating lanthionine synthetase C-like 2 (LANCL2) to treat infectious diseases, particularly influenza virus infection. Overall, seasonal flu is one of the most relevant infectious disease-related public health problems since it causes important economic losses up to $166 billion during one influenza pandemic. The work, which characterizes the effects of model LANCL2 ligand NSC61610 in influenza A infection of mice, is published in Frontiers in Immunology.
LANCL2 is an important molecule in the induction of regulatory responses that act to prevent excessive inflammation, among other functions. In line with this, initial experiments identified that mice lacking LANCL2 struggled to recover after the peak of influenza virus infection and experienced higher mortality. Pharmacological activation of LANCL2 by NSC61610 resulted in significantly lower disease severity and a 2-fold increase in survival rates.
These beneficial effects of NSC61610 and LANCL2 were dependent on the production of IL-10 from macrophages and CD8+ T cells late in infection, which are able to drive resolution and repair responses within the lungs. The BTI team has also assessed the efficacy of abscisic acid (ABA), a proposed natural ligand of LANCL2, as a therapeutic for influenza infection in a 2013 publication in the Journal of Nutritional Biochemistry.
“While the mechanism by which LANCL2 ligands modulate immune responses in the gastrointestinal (GI) tract are well understood, less was known about what LANCL2 does in the respiratory tract. We have shown conclusively that not only does LANCL2 activation ameliorate disease activity and lung inflammatory pathology, but it does it through a mechanism involving upregulation of lung IL-10 in influenza-infected mice,” said Raquel Hontecillas, BioTherapeutics CSO and the corresponding author of the paper.
While vaccines have been valuable against the spread of infections, they often require more than 6 months from the emergence of a particular strain to become fully developed. In contrast, the current therapeutic option for those contracting disease, is anti-viral treatment such as Tamiflu. Unlike vaccines, numerous issues arise with anti-viral treatments, such as the need to early administration (before or immediately after first presentation of symptoms), the potential for emergence of resistant strains, and an inability to modulate host responses, which amount to only a 24-hour reduction in disease course on average.
When compared to Tamiflu, pharmacological activation of LANCL2 in the lungs results in increased survival and accelerated recovery from influenza. Further, a common concern of immunoregulatory treatment is that it will result in a greater viral or bacterial load. However, the viral titer from the lungs of NSC61610-treated mice did not significantly differ from untreated groups.
“Anti-virals used to treat influenza such as Tamiflu target the virus rather than the immune response to the virus,” said Josep Bassaganya-Riera, the CEO of BioTherapeutics. “We provide novel evidence that modulating the host response to influenza virus by activating LANCL2 and favoring tolerance can dramatically ameliorate survival, disease and pathology during influenza and possibly outperform Tamiflu, the current standard of care for treating infections with influenza virus.”
Beyond treating influenza infection, the role of LANCL2 has previously been characterized in gastrointestinal and metabolic disease, showing potent capabilities in a variety of diseases and validating efforts to advance the LANCL2 as a therapeutic target for infectious and immune-mediated diseases.
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