Live imaging of microglia during sleeping sickness reveals early and heterogeneous inflammatory responses
Nestor L Uzcategui1,2,3, Sena Güçer1, Cris Richter1
1Department of Neurophysiology, Institute of Physiology, University of Tuebingen, Tuebingen, Germany.
Introduction:
Invasion of the central nervous system (CNS) is the most serious consequence of Trypanosoma brucei infection, which causes sleeping sickness. Recent experimental data have revealed some more insights into the disease during the meningoencephalitic stage. However, detailed cellular processes befalling the CNS during the disease are poorly understood.
Methods:
To further address this issue, we implanted a cranial window on the cortex of B6.129P2(Cg)-Cx3cr1/J mice, infected them with Trypanosoma brucei expressing RFP via intraperitoneal injection, and monitored microglial cells and parasites longitudinally over 30 days using in vivo 2-photon imaging. We correlated the observed changes with histological analyses to evaluate the recruitment of peripheral immune cells.
Results And Discussion:
We uncovered an early involvement of microglia that precedes invasion of the CNS by the parasite. We accomplished a detailed characterization of the progressive sequence of events that correlates with microglial morphological changes and microgliosis. Our findings unveiled a heterogeneous microglial response in places of initial homeostatic disruption near brain barriers and pointed out an exceptional capability of microglia to hamper parasite proliferation inside the brain. We also found early signs of inflammation in the meninges, which synchronize with the microglial response. Moreover, we observed a massive infiltration of peripheral immune cells into the parenchyma as a signature in the final disease stage. Overall, our study provides new insights into the host-pathogen immune interactions in the meningeal and parenchymal compartments of the neocortex.
Insights
Microglia actively defend the brain against Trypanosoma brucei early in infection, before parasites invade the central nervous system (CNS). This study reveals microglia
Area of Science:
- Neuroimmunology
- Parasitology
- Infectious Diseases
Background:
- Central nervous system (CNS) invasion by Trypanosoma brucei causes severe sleeping sickness.
- Cellular processes during the meningoencephalitic stage of infection remain poorly understood.
Purpose of the Study:
- To investigate the dynamic cellular interactions within the CNS during Trypanosoma brucei infection.
- To elucidate the role of microglia and peripheral immune cells in the early and late stages of infection.
Main Methods:
- Longitudinal in vivo 2-photon imaging of infected mice with cranial windows.
- Monitoring of microglial cells and parasites over 30 days.
- Histological analysis to assess peripheral immune cell recruitment.
Main Results:
- Microglial involvement precedes parasite invasion of the CNS.
- Characterization of microglial morphological changes and microgliosis.
- Demonstration of microglia's capacity to inhibit parasite proliferation.
- Early meningeal inflammation observed, synchronized with microglial response.
- Massive peripheral immune cell infiltration occurs in the late disease stage.
Conclusions:
- Microglia play a crucial early role in combating Trypanosoma brucei infection within the CNS.
- The study reveals distinct host-pathogen interactions in meningeal and parenchymal compartments.
- Findings offer new insights into immune responses during sleeping sickness.
