(433) TLR11/12-mediated regulation of optimal myelopoiesis during Toxoplasma gondii infection

Introduction/Rationale: While host resistance to systemic Type 1 infections depends on the egress of newly generated Ly6Chi inflammatory monocytes from bone marrow, this process remains poorly understood.

Methods: In this study, we performed a kinetic analysis of myeloid progenitors in bone marrow isolated from Toxoplasma gondii-infected wild-type mice alongside mice lacking major toxoplasma pattern recognition receptors TLR11 and TLR12, which display acute mortality and impaired monocyte recruitment to infected tissues.

Results: As early as day 4 post-infection, both wild-type and TLR11/12-/- mice exhibit significant loss of multipotent myeloid precursors (CMP, GMP, and MDP), indicating that these quantitative differences alone cannot explain distinct survival outcomes. However, the population of committed monocyte progenitors (cMoP), which also diminished initially, was subsequently recovered only in wild-type and not TLR11/12-/- mice. Moreover, intracellular staining revealed that cMoP in bone marrow from wild-type mice, concomitant with IFN-γ-induced Ly6A/E expression, also upregulated the transcription factors PU.1 and IRF4, known to positively regulate myelopoiesis. In contrast, the diminishing population of cMoP in bone marrow from TLR11/12-/- animals failed to upregulate PU.1 and IRF4 despite displaying an increased level of Ly6A/E.

Conclusion: Together, these findings indicate that the signaling cascade initiated by TLR11/12 activation plays a dual protective role during T. gondii infection: promoting innate inflammation and sustaining bone marrow myelopoiesis. This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health.