Saturday, November 23, 2024
11/23/2024
PROJECT SUMMARY Mycobacterium tuberculosis (Mtb), the causative agent of Tuberculosis (TB) is one of the leading causes of death globally by a single infectious agent. There continues to be an urgent and unmet need for new drugs, diagnostics, vaccines, and host-directed therapies for TB. Two critical events that occur early after Mtb aerosol transmission are the confinement of the initial inoculum into alveolar macrophages (AM), the first cells infected in the lung, and the slow establishment of T cell priming and the adaptive immune response. These two features highlight the importance of early recognition by the host in affecting the course of TB disease and the significant role of lung-resident AM in initiating the host immune response. As innate airway sentinels, AM must recognize Mtb bacilli and respond quickly in order to recruit other innate cells to the site of infection, including cells that will transport bacteria to the draining lymph node for T cell priming. We have previously shown that upon infection with Mtb in vivo, AM mount an Nrf2-dependent cell-protective, rather than pro-inflammatory, response that impedes an effective host response and contributes to early Mtb replication. However, the AM response to Mtb also has plasticity. We observed that mycobacterial exposure, either through BCG vaccination or a contained Mtb infection, leads to AM cell-intrinsic and durable remodeling, including up-regulation of Interferon Response Genes and a robust pro-inflammatory response to Mtb, that is associated with an accelerated host response and enhanced bacterial control after Mtb challenge. The objective of this proposal is to evaluate mechanisms that restrain or enhance AM responses to Mtb to better understand the regulation of the early events during infection. In Aim 1, we will categorize AM sensing abilities and defects using both ex vivo and in vivo delivery of Mtb- related Pathogen Associated Molecular Patterns (PAMPs), and screen for novel negative regulators of AM innate sensing using a CRISPR-Cas9 knockout library. In Aim 2, we will determine how Type I and II Interferons regulate AM innate responses using in vitro models and in vivo cell transfer approaches. In Aim 3, we will evaluate how alterations in AM sensing by Type I and II Interferons impact downstream events in Mtb infection by measuring changes to innate cell recruitment, transfer of bacteria to the draining lymph node, T cell priming, and AM antigen presentation in murine aerosol Mtb infection and a macrophage-T cell co-culture system. The studies are motivated by the hypothesis that the hypo-inflammatory response of AM during Mtb infection is a result of the reliance on AM as the initial Mtb sentinel, a function for which they are impaired, and the absence of early systemic signals such as Type I and II Interferons, for which AM are highly sensitive. A better understanding of the regulation of AM during Mtb infection will inform development of new vaccines and host-directed therapies.
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