Bypassing Molecular Evolution by Targeting Toll-like Receptors
October 2014
Vaccines and immunotherapies utilize the host’s immune system to provide protection against a particular pathogen or disease. While various approaches exist, there are common hurdles that all immune-based approaches must overcome. Primarily, they must elicit an “appropriate” immune response, traditionally through an antigen containing a cognate sequence to the pathogen. This task can be particularly challenging for pathogens that are prone to mutate. (This is the primary reason a new flu shot is recommended each year.) One solution is to target the host’s innate immune system to boost its response to invading pathogens. Because this method targets the host instead of the pathogen, the approach also limits the ability of a strain to become resistant to treatment. In a recent paper published in Frontiers in Pharmacology, Alfaro et al. describe a promising safety profile of an aerosolized oligonucleotide and peptide treatment against pneumonia by targeting Toll-like Receptors (TLR).
The lungs are a common site of serious infection due to their exposure to inhaled pathogens. To combat this, the lungs have developed a multilayered defense system of mechanical, humoral and cellular mechanisms. Previously, this group sought to test the functional plasticity of the lungs through the introduction of an aerosolized lysate from Haemophilus influenzae (Clement et al. 2008). They found that the lysate induced a high level of resistance to a lethal dose of streptococcus pneumonia. Importantly, there was no cognate antigen present in the lysate, thus providing a novel therapy that is not contingent on a specific strain of pneumonia. This finding lead to a series of studies examining the mechanisms involved. Through these studies they found that activation of TLR receptors induced an innate immune response that was sufficient to provide resistance against pneumonia. The authors tested a number of TLR ligands and found that the combination of an oligonucleotide targeting the TLR9 homodimer and PAM2CSK4, a diacylated peptide ligand for the TLR 2/6 heterodimer, lead to robust resistance. The synergistic effect that occurred when both receptors were activated was the key (Duggan et al. 2011, Tuvim et al. 2012).
In their recent publication, Alfaro et al. demonstrate the safety of the aerosolized TLR treatment in mice. With an optimal dose of 1 µM of the oligo and 4 µM of PAM2CSK4 previously determined (Evans et al. 2011), the group sets up a series of experiments examining multiple parameters, including histopathologic, physiologic and behavioral measures, at 1/8 - 8X the optimal therapeutic dosage. Through these experiments the authors show that the aerosolized treatment is well tolerated in mice after multiple exposures and can extend to 7 days. Additionally, they determine that innate immune activation through the aerosolized treatment can be determined by checking cytokine levels. This safety profile extends to mice even after myeloablative chemotherapy, an important finding due to the susceptibility immunocompromised individuals have to various lung infections.
With positive results from the safety profile in mice, the authors convincingly demonstrate the feasibility of using an aerosolized TLR treatment as a novel method for the prevention of pneumonia in healthy and immunocompromised individuals. Whether its use in humans will be both efficacious and non-toxic remains to be seen.
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