Siderophore Antigens and Adjuvants for Treatment and Vaccination Against Mycobacterium Tuberculosis
Available for Licensing
US Utility Patent: US 8268330
At A Glance
Researchers at Colorado State have developed a method to treat active and latent Mycobacterium Tuberculosis infection by disruption of the pathogen’s HIF activation pathway, dependent on scavenging host iron. Furthermore, these methods have application in vaccines.
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Iron is a micronutrient required by essentially all living organisms, since it is structurally incorporated into a wide variety of proteins that are crucial for normal metabolic processes, including cell respiration, growth and DNA. Macrophages throughout the body play an important role in iron metabolism through the ability to store and release iron at times of excess and deficiency, respectively. Through protein binding, iron is rendered non-toxic and the in vivo availability to infectious pathogens is limited. Non-protein bound or free iron is extremely toxic causing cytotoxicity through the formation of reactive oxygen species and so is transported and stored by the host iron-binding proteins transferrin, ferritin, and lactoferrin respectively.
M. tuberculosis, like other pathogenic bacteria have evolved complex mechanisms to scavenge host iron, even intra-cellularly from macrophages which are considered the first line of defense following infection. Since iron toxicity is detrimental to both host macrophages and the tubercle bacillus, yet each has a strict nutritional requirement for iron, it stands to reason that the successful accumulation and sequestration of iron would be an important determinant in the outcome of M. tuberculosis infection.
Studies suggest that activation of HIF-1 occurs by a pathway independent of local tissue oxygen. This hypoxia-independent activation of HIF-1 leads to what is referred to here as perceived hypoxia. The activation and elevation of HIF-1 during perceived hypoxia thus occurs during acute and subacute stages of Mtb infection, prior to any extensive tissue damage. The importance of HIF-1 activation at this stage is that it is occurring before the development of actual hypoxia, which can lead to the eventual hallmark of TB, dystrophic calcification.
Alternative pathways of HIF-1α activation include induction by cytokines, nitric oxide, growth factors, cobalt chloride, or by bacterial iron chelators called siderophores. Specifically, Mtb produces mycobactin and carboxymycobactin as its siderophores. The siderophores produced by Mtb can scavenge iron away from host cells, reducing the labile cytoplasmic iron pool, which leads to activation of HIF-1.
- Improvement of current TB vaccinations, treatments, and any combination therapy
- Potential in other bacterial vaccinations and treatments, having similar pathogenesis
Basaraba, Randall J, et al. “Increased Expression of Host Iron-Binding Proteins Precedes Iron Accumulation and Calcification of Primary Lung Lesions in Experimental Tuberculosis in the Guinea Pig.” Tuberculosis (Edinburgh, Scotland), U.S. National Library of Medicine, Jan. 2008, www.ncbi.nlm.nih.gov/pmc/articles/PMC2271031/.
Last updated: April 2020