Abstract
Melioidosis, an infection caused by Gram-negative Burkholderia pseudomallei (Bp), has high clinical recurrence and mortality rates associated with pneumonia and sepsis. With the limitations in current therapeutic options and the lack of available human vaccines, development of novel countermeasures against Bp infection is vital. In this study, we evaluated the efficacy of an aminoalkyl glucosaminide 4-phosphate (AGP), a synthetic toll like receptor 4 agonist (CRX-527), in conferring protection against melioidosis in a murine model. Survival data showed 66% of mice treated with AGP prior to lethal intranasal Bp challenge survived and presented no signs of illness over a 3 months period. In contrast, all control mice succumbed to infection within 4 days. Kinetic study on organ bacterial burden demonstrated mice treated with AGP had dramatically reduced bacterial loads in both the lungs and spleens as compared to control mice. Notably, all but one AGP-treated mouse had no Bp growth in the blood as compared to overwhelming bacteraemia found in all control mice. The protective effect of CRX-527 was associated with a transient increase in pulmonary cytokine/ chemokine levels, which boosted the host’s innate immunity. This enabled rapid clearance of the pulmonary and systemic bacterial burden and prevented the development of sepsis. This study demonstrated the potential use of TLR4 agonist as a prophylactic immunotherapy in preventing melioidosis.
Highlights
Burkholderia pseudomallei (Bp), the causative agent of Melioidosis, is a Gram-negative environmental saprophyte endemic in South-East Asia and northern Australia [1]
Inhalation has been recognized as an important route of infection in melioidosis Bp can be transmitted through other routes such as percutaneous inoculation and ingestion [5]
Our initial experiment was aimed at determining the optimum dose of CRX-527 administered via intranasal/intrapulmonary route 48 hours prior to lethal Bp intranasal challenge (28x 10-day LD50)
Summary
Burkholderia pseudomallei (Bp), the causative agent of Melioidosis, is a Gram-negative environmental saprophyte endemic in South-East Asia and northern Australia [1]. Melioidosis can virtually affect any organ and is potentially fatal, with a mortality rate of up to 50% in endemic regions such as Thailand [6, 7]. It can present with a wide range of clinical manifestation, which is thought to be determined by the host’s immune response [4,8]. Manipulating the host’s immune system pre/post-infection with the use of granulocyte colony stimulating factor (G-CSF) or interferongamma (IFN- ) has been proposed [10,11,12] as treatments for melioidosis, clinical benefits of such therapy are limited and need to be re-evaluated. Efforts have recently been directed at developing novel immunotherapeutic strategies to prevent or treat melioidosis
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