Kate Wardenburg
Program: Molecular Microbiology and Microbial Pathogenesis
Current advisor: Christina L. Stallings, PhD
Undergraduate university: Washington University
Research summary
Mycobacterium tuberculosis (Mtb) remains the top infectious cause of death globally, with an estimated 1.6 million deaths in 2021. Inexplicably, 10% of immunocompetent adults develop active disease upon infection, driving efforts to identify host factors that influence susceptibility. We have previously identified that SPTLC2, an enzymatic subunit required for de novo sphingolipid synthesis, is required in innate immune cells during Mtb infection for the repopulation of alveolar macrophages (AMs) from monocytes in a murine model. Mice with deletion of the gene that encodes SPTLC2 in innate immune cells including AMs (Sptlc2fl/fl-Lysm-cre or Sptlc2fl/fl-Cd11c-cre) succumb to Mtb infection much earlier than Sptlc2fl/f control mice. These mice have a significant reduction in AM abundance beginning at 14dpi compared to control. Infection of Sptlc2fl/fl-Lysm-cre or Sptlc2fl/fl-Cd11c-cre mice is also characterized by elevated lung bacterial burden by 56dpi, the development of a striking glossy lung gross pathology, and transcriptional signatures of hypoxia relative to control mice. This phenotypic constellation is reminiscent of pulmonary alveolar proteinosis (PAP). PAP is a disease in which surfactant proteins and lipids, which are normally digested solely by AMs, accumulate in the alveoli, impairing air exchange and eventually causing respiratory failure. Of note, Mtb infection has previously been implicated as a cause of secondary PAP. We detected elevated levels of surfactant protein D in the lungs of Sptlc2fl/fl-Lysm-cre mice by 28dpi, confirming the presence of proteinosis. Interestingly, this precedes the observed increase in bacterial burden. These findings suggest that not only is SPTLC2 required in innate immune cells to maintain AM population, but that loss of SPTLC2 and subsequent inability to replete AMs results in a proteinosis that impairs survival of Mtb infection in mice. Ongoing studies will address by what mechanism sphingolipid perturbation impacts AM repopulation and how this affects development of proteinosis and supports Mtb pathogenicity.
Graduate publications