Ph.D. Graduate Student Michigan Medicine, University of Michigan Ann Arbor, Michigan, United States
Disclosure(s):
Christian Davalos Gutierrez: No financial relationships to disclose
Introduction/Rationale: C. neoformans (C.n), a major fungal pathogen, infects the lungs and can disseminate to the brain leading to life threatening meningoencephalitis. Due to limited antifungals, there is a need to identify novel drug targets. Tps1 is required for the biosynthesis of Trehalose, a fungal-specific sugar that has been identified as a promising target for drug development. Mice infected with tps1-KO (tps1Δ) C.n exhibit increased survival, an immediate decrease in lung fungal burden, and clearance by day 7. Infection kinetics suggest innate or resident immunity factors drive this response. Surfactant protein (SP) D is a collectin endogenously expressed in the alveolar space, and its role in several pulmonary infections has been well characterized. Therefore, we hypothesized SP-D could contribute to tps1Δ clearance.
Methods: We infected C57BL/6 (WT) or SP-D -/- mice with either tps1Δ or H99 C.n Mice were sacrificed at 2 days post infection (dpi) and lung fungal burdens and immune cell populations were investigated by flow cytometry analysis.
Results: Tps1Δ infected mice had reduced fungal burdens compared to H99-infected mice, consistent with previous work. Interestingly, pulmonary fungal burdens were not affected by the loss of SP-D on 2dpi. Our results indicate that SP-D moderately decreased CD45+ immune cell recruitment to the lung in H99-infected mice whereas tps1Δ -infected mice saw no change. Additionally, alveolar macrophages from SP-D-/- H99-infected mice saw an increase in CD86 and CD206 expression compared to H99-infected WT mice, whereas tps1Δ -infected mice saw no difference in macrophage activation regardless of the presence or absence of SP-D.
Conclusion: These results support that WT C.n exploits SP-D for its benefit by promoting a non-protective immune response. This exploitation appears to require trehalose, as it is lost in tps1Δ infections, suggesting a novel effect linked to Tps1-targeting. Further molecular and cellular pathways underpinning these interactions are under investigation.
