Identifying Host Cell Death Pathway Targets for Host-Directed Therapies for Treatment of Mtb and Mtb/HIV Co-Infection (R01 Clinical Trial Not Allowed)

The purpose of this Funding Opportunity Announcement (FOA) is to support mechanistic studies on host cell death pathways and immune responses to Mycobacterium tuberculosis (Mtb) and Mtb/HIV co-infection to identify immune targets for development of host-directed therapies.Funding Opportunity Description Host-directed therapies (including vaccine adjuvants) have the potential to significantly improve treatment and prevention outcomes among people living with HIV with Mycobacterium tuberculosis (Mtb) infection or at risk for Mtb infection. The objectives of this Funding Opportunity Announcement (FOA) are to understand the role cell death mechanisms (CDMs) play in response to Mtb infection, how Mtb subverts cell death pathways, and to identify cellular targets that could be exploited as potential host-directed therapies to treat Mtb and Mtb/HIV co-infections. Cell death mechanisms include 1) non-inflammatory mechanisms (apoptosis) that promote clearance of dying, damaged or infected cells to maintain healthy tissue micro-environments and 2) inflammatory mechanisms (pyroptosis, necrosis, necroptosis) that release pathogens and pro-inflammatory molecules from dead cells leading to tissue damage and chronic disease. Small molecule/drug approaches that promote apoptotic cell death without inducing a damaging inflammatory response have been shown to improve treatment outcomes in animal models, improving Mtb elimination with less associated tissue damage. CDMs also act as second messengers that guide both development of more effective immune reactions and tissue micro-environment changes to ensure tissue repair and homeostasis during infections. In addition, cell death-related mechanisms have a direct inhibitory effect on some intracellular pathogens and are involved in the selective clearance of HIV-1 infected CD4+ T cells. Emerging evidence indicates that stimulation of CDM pathways and damage-associated molecular patterns (DAMPs) by vaccines/adjuvants have a role in the development of immunogenicity. Understanding how Mtb modulates cell death pathways to promote bacterial spread and tissue inflammation while inhibiting the development of an effective immune response is critical to identifying host pathways that could be targets with current or novel interventions. Applications in response to this FOA are strongly encouraged to be cross-disciplinary and are likely to draw investigators from HIV virology, TB disease and pathogenesis, cell biology, oncology, and immune-based therapies. Both AIDS and non-AIDS applications are responsive. Proposed projects are expected to focus on mechanistic studies of host cell death mechanisms involving host-TB interaction, innate and adaptive immunity, and target identification for interventions. Applicants are encouraged to use relevant animal models and human in vitro models to include, but not limited to tissue chips, organoids, spheroids and three-dimensional models. Research projects and studies may include, but are not limited to the following topics listed below: Studies aimed at basic biological mechanisms of how Mtb modulates CDMs to promote infection, inflammation, cell necrosis, types(s) of cell death and tissue damage Characterizing interactions between CDMs and with other cell death-associated events (e.g., DAMP release profiles) in the context of Mtb and Mtb/HIV co-infections Delineating interactions of CDMs with elements of the innate and adaptive immune systems during Mtb infection and the impact on host response effectiveness Studies that identify novel host CDMs and pathways activated during Mtb or Mtb/HIV co-infection Identification and evaluation of CDM-based targets for development of novel host-directed therapies