2018-033 Mouse model to assess immunological responses to Mycobacterium tuberculosis infection in aging humans

Small animal model to accurately mimic the human elderly immune responseEnables development of appropriate therapies and vaccinesPermits testing of specific T cell based mechanisms that may contribute to decreased immune function
  • Small animal model to accurately mimic the human elderly immune response
  • Enables the development of appropriate therapies and vaccines
  • Permits testing of specific T cell-based mechanisms that may contribute to decreased immune function

Abstract

Mycobacterium tuberculosis is again the number one cause of death in the world due to a single infectious agent. In developing countries, up to one-fifth of all tuberculosis (TB) cases occur in individuals over the age of 65 and increasing age is a known and significant risk factor for developing TB. TB in the elderly can arise directly from a new infection, reflecting the documented general increase in susceptibility of the elderly to numerous infections including M. tuberculosis, or reactivate from a previously latent infection. Both forms of disease in the elderly have been associated with altered immune function with increasing age, and frequently attributed to deficits in the adaptive immune response.

However, little experimental information exists to define the specific aspects of this immune dysfunction in the elderly. It is known that there are numerous changes in central immune function (thymus production of T cells), peripheral T cell repertoire and functional parameters, and in the peripheral environment (e.g. increased inflammatory conditions). Any or all of these changes could contribute to the increased risk for active disease in the elderly. However, each of these mechanisms would be best approached therapeutically in different ways.

Unfortunately, there are no small animal models that can accurately mimic the human immune response in the elderly, and thus more appropriate therapies and vaccines for this susceptible age group are not being developed. The mouse model is the most commonly used human surrogate for the study of many aspects of M. tuberculosis infection. However, the mouse does not approximate many aspects of the human immune response to M. tuberculosis infection, and in particular, standard mouse strains do not resemble changes in the aging human immune response. UGA researchers have developed and tested a unique mouse genetic model to identify and test specific T cell-based mechanisms that may contribute to decreased immune function in the elderly human during infection.

Website

https://uga.flintbox.com/technologies/B1F268ECE8884C23AF713C2B901959F3

Advantages

These mouse strains have mutations in the thymic epithelial cell (TEC) specific transcription factor Foxn1 that affect TEC differentiation and thymus function. Foxn1Z allele generates a thymus that produces almost exclusively a specific type of innate-like effector memory T cell; the Foxn1Z allele results in premature onset of aging-related thymic involution.

These mouse models have been successfully used to demonstrate similarities to older humans in enhanced M. tuberculosis infection rates and disease pathology. Our long-term goals are to identify the specific contributions of these immune changes to increased rates of M. tuberculosis infection in the elderly and develop effective treatment strategies.

Potential Applications

Research; Vaccine Development; Therapeutic Drug Discovery