CAP: Preclinical Development of a TB Therapy Targeting Host Eicosanoid Pathway

National Institute Of Allergy And Infectious Diseases

Investigators

Abstract

Since receiving CAP funding in February our research has been focused on the analysis of the innate immune control to Mycobacterium tuberculosis (Mtb) and how lipid mediators influence the outcome of infection. More specifically we are investigating how modulation of the eicosanoid balance can serve as an adjunct immunotherapy for uncontrolled Mtb infection. In prior research (see report AI001044004 LPD) we established that the IL-1family cytokines, IL-1alpha and IL-1beta are critically required for host resistance against Mtb. Indeed, mice lacking either IL-1alpha or IL-1beta are highly susceptible to low dose aerosol infection and succumb to infection within 5 weeks. In addition, lungs of infected IL-1R-/- mice display large necrotizing lesions. Induction of macrophage necrosis is a hallmark of virulent Mtb strains and has been associated with induction of 5-lipooxygenase (5-LO) dependent products such as lipoxinA4. Necrotic macrophage cell death provides a niche for extracellular bacterial replication, which results in enhanced dissemination. In contrast, apoptotic cell death leads to containment of the bacteria in infected macrophages and is associated with less virulent Mtb strains. This paradigm is supported by the fact that mice deficient in 5-LO have lower bacterial loads at 4 weeks post infection compared to wild-type controls, while mice lacking mPGES display increased pulmonary bacteria counts. IL-1 is a potent inducer of cyclooxygenase2 (COX-2) an enzyme that competes with 5-LO for the substrate arachidonic acid and has been associated with counter-regulating necrotic cell death by inducing apoptosis in Mtb infected macrophages. We therefore hypothesized that IL-1 prevents necrotic cell death through induction of COX-2 dependent prostaglandins. In accordance with this hypothesis, we found that manipulation of the eicosanoid balance via administration of PGE2 together with a 5-LO inhibitor resulted in delayed susceptibility of IL-1 deficient animals and improved lung pathology. Moreover, in a murine experimental model of progressive tuberculosis designed to mimic active human disease, we have determined that the above treatment strategy resulted in 100% protection against infection induced weight loss and mortality. Substantial further progress has been greatly hampered by the extended shut-down of the ABSL3 animal facility in Bldg 33 where this works needs to be performed. Nonetheless, preliminary data obtained from a collaborative clinical study suggest that TB severity is associated with a similar eicosanoid imbalance as predicted from our murine studies. Taken together the present project aims to investigate the relationship between cytokines, cell death and eicosanoids and how this relationship can be exploited as a novel immuno-therapy in adjunction to antibiotic treatment.