TLR4 is a transmembrane protein that belongs to the toll-like receptor family member of the pattern recognition receptor (PRR) family. Firstly, activation of Toll-like receptor 4 (TLR4) promotes the intracellular signaling pathway NF-κB and inflammatory cytokine production. It recognizes bacterial lipopolysaccharide (LPS), thereby activating the innate immune system against microbial infections. Specifically, Ebola virus (EBOV) is the cause of a pandemic. It is associated with bacterial sepsis. Bacterial sepsis leads to immune dysfunction, lymphopenia, and systemic inflammation. Furthermore, bacterial sepsis is associated with the production of bacterial lipopolysaccharide (LPS). It activates TLR4. In contrast, TLR4-/- mice were resistant to lethal influenza virus infection. It is conceivable that TLR4 antagonists have some inhibitory effect on EBOV. Here we present a TLR4 antagonist, Eritoran, that promotes survival in infected EBOV mice.
Eritoran prevents influenza virus infection via decreasing granulocytosis and increasing neutrophils.
In EBOV infection mouse model, mouse infected with EBOV experienced 100% mortality within 7 days. But Eritoran increases the survival rate of mice (70%) and restores the body weight of infected mice on the eighth day of treatment. But short-term treatment with Eritoran (0-3 days), or re-treatment 48 hours after infection, can not improve TLR4-/- mouse survival.
As for research of endogenous mechanism, mouse infected with EBOV develop granulocytosis. Eritoran inhibits granulocytosis in infected mice. It also increases the percentage of muscle neutrophils, specifically CD11b+ Ly6G/Ly6C+ neutrophils. Eritoran also reduces IFN-γ-secreting CD8+ and CD4+ T cells and IL-17A-secreting CD4+ T cells.
All in all, Eritoran is a TLR4 antagonist capable of fighting infection. It increases lymphocytes and reduces levels of endogenous inflammatory markers in mouse models.