Research Focus

The research in my laboratory is focused around three main areas. The first is regulation of immune function in the setting of stem cell transplantation. The second is inflammatory-induced exacerbations of lung fibrosis. The third is regulation of bacterial clearance post-influenza. In all of these models, we consider how changes in the microbiota may regulate pathogenesis as well.

With regards to our stem cell transplant work, we have programs looking at both innate and adaptive immunity. Our innate immune work centers on understanding how conditioning regimens induce the upregulation of cyclooxygenase-2 (COX-2) and the induction of prostaglandin E₂ (PGE₂). Our current results suggest that conditioning induces secretion of transforming growth factor (TGF)β that causes upregulation of micro RNA (miR)29b. In turn, miR29b targets DNA methyltransferases to induce COX-2 expression in alveolar macrophages. The upregulation of PGE₂ results in alterations in scavenger receptor expression and inhibition of neutrophil extracellular traps to limit the ability of the innate immune cells to fight off infection. Our future plans involve translational work to determine if these same observations characterize human alveolar macrophages and neutrophils post-stem cell transplant. It will also determine whether autophagy defects caused by PGE₂ limit bactericidal functions in innate immune cells. We hope to pursue a clinical study to investigate the efficacy of an EP2 antagonist or indomethacin to limit PGE₂ signaling in patients suffering from antibiotic-resistant bacterial infections post-transplant. In addition, we have plans to study surfactant protein A as an immune collectin that can bind to bacteria and tether them to scavenger receptors that are not lost post-transplant to try and enhance host defense.

The following figure summarizes what we know about the innate immune alterations in alveolar macrophages post-stem cell transplant.

With regards to our adaptive immune work post-transplant, our results suggest antigen presenting cell function is impaired. This impairment relates to defective Notch signaling and altered cytokine responses that result in skewing of effector T cells towards a Th17 as opposed to a Th1 response when confronted with a herpesviral infection. The consequence of the skewing to Th17 responses is that mesenchymal cells are activated to induce a pathologic response in the lung that involves pneumonitis and fibrosis. Our future plans in this area are to fully characterize the antigen presenting cell alterations, to test the ability of antigen presenting cell adoptive transfer to improve host defense and to study IL-17 neutralization strategies as therapies. We also hope to translate this work to humans by doing a prospective study to determine which respiratory viruses predispose to development of later complications, and to characterize Th1/Th17 skewing and antigen presenting cell function in patients.

The figure below summarizes the alterations we know that occur in response to gammaherpesvirus in murine lungs post-BMT

With regards to our lung fibrosis work, we have shown that a circulating inflammatory cell type, fibrocytes, are able to exacerbate fibrotic lung disease. We have determined that their ability to do this relates to the fact that they secrete a matricellular protein, periostin, in response to TGFβ found in the fibrotic lung environment. Our translational work in this area has explored the ability of periostin to serve as a biomarker of disease severity. Most recently, we have shown that the lung microbiome is dysbiotic post-bleomycin injury in mice and that the microbiome is important for mortality. Our current studies are focused on understanding how the microbiome signals innate immunity to drive fibrotic pathogenesis. We are also looking at how the fibrotic milieu in the lung impacts innate immunity. We also have an active study on how myeloid cell production of HB-EGF regulates the development of lung fibrosis.

Finally, we are interested in how influenza infection alters TLR signaling to impair innate immune function. We have projects related to CCR2 and TLR9 and how these molecules impact clearance of bacterial infection post-influenza.