Immune Response: Mechanisms of Host Protection Against TB

We need new and effective vaccines to control the ongoing TB epidemic, but we lack the deeper understanding of the mechanisms by which the human immune response can kill TB and prevent disease needed to design these life-saving therapeutics.  (I/Dr. Fortune) serves as the Principal Investigator for a 7-year NIH-funded contract called Immune Mechanisms of Protection against Tuberculosis (IMPAcTB), which aims to apply high-dimensional immunological profiling tools to diverse human and animal models of TB infection to gain insights into immune pathways that both promote and protect against TB.

IMPAcTB is comprised of a consortium of 14 groups collaborating across three countries to share blood and lung samples from animal models of TB infection as well as human cohorts who have had TB exposure. These samples are then subjected to a diverse array of high-throughput profiling around the consortium—namely, single cell RNA sequencing, biophysical and functional serological profiling, multiplexed flow/mass cytometry profiling and myeloid functional dissection.  These data are then integrated within a systems immunology framework to identify new immune signals associated with protection in different infection contexts, offering up hypotheses for further validation across our groups.

The Fortune lab’s work under IMPAcTB includes diverse research efforts, including analysis of single cell RNA sequencing datasets to identify vaccine correlates of protection, profiling of lung myeloid responses to TB infection, applying bacterial barcoding tools to trace TB infection and dissemination dynamics during animal infection and dissection of antibody features that mediate host immunomodulation and protection against TB infection.

To date, we have gained deeper insight into immunological structure of the lung in response to both TB infection and vaccination; and these findings have identified avenues of crosstalk between key immunological compartments (T cells, antibody and myeloid cells) that associate with both good and bad infection outcomes. We are validating and pursuing these findings as translational paths towards the future development of effective TB vaccines.