Morphological changes, nitric oxide production, and phagocytosis are triggered in vitro in microglia by bloodstream forms of Trypanosoma brucei

Abstract

The flagellated parasite Trypanosoma brucei is the causative agent of Human African Trypanosomiasis (HAT). By a mechanism not well understood yet, trypanosomes enter the central nervous system (CNS), invade the brain parenchyma, and cause a fatal encephalopathy if is not treated. Trypanosomes are fast dividing organisms that, without any immune response, would kill the host in a short time. However, infected individuals survive either 6–12 months or more than 3 years for the acute and chronic forms, respectively. Thus, only when the brain defense collapses a lethal encephalopathy will occur. Here, we evaluated interactions between trypanosomes and microglial cells, which are the primary immune effector cells within the CNS. Using co-cultures of primary microglia and parasites, we found clear evidences of trypanosome phagocytosis by microglial cells. Microglia activation was also evident; analysis of its ultrastructure showed changes that have been reported in activated microglia undergoing oxidative stress caused by infections or degenerative diseases. Accordingly, an increase of the nitric oxide production was detected in supernatants of microglia/parasite co-cultures. Altogether, our results demonstrate that microglial cells respond to the presence of the parasite, leading to parasite’s engulfment and elimination.

Mapping the Plasticity of Morphology, Molecular Properties and Function in Mouse Primary Microglia

“…Due to the complexity of the brain’s internal environment, which includes several interacting cell populations and soluble factors, microglia behave very differently in vitro versus in vivo ( Zhang et al, 2020c ). In primary culture, most microglial cells exhibit ameboid morphology without branches, while some have several simple branches ( Giulian and Baker, 1986 ; Figarella et al, 2018 ). In contrast, microglia in the brain have a more complex branching structure, characterized by multiple branches protruding from small somata ( Sankowski et al, 2019 ; Zhang et al, 2020c ).…”

Microglia in neuropathology caused by protozoan parasites

“…These data are consistent with results from co‐cultivation of freshly isolated microglia cells and trypanosomes, where microglia were activated (e.g. NO release) and phagocytically active (Figarella et al ., ). One may speculate that the observed latency of brain infection in humans (late disease stage) could reflect the ability of microglia to destroy parasites that occasionally cross the BBB by an unknown mechanism.…”

“…Experimental data, however, suggest that trypanosomes may indeed cross the BBB earlier in infection but are neutralized by the action of microglia ( Fig. 3) (Figarella et al, 2018). Most important is the parasite's ability to cross the BCB at an early time point, whereby it can cause meningoencephalitis.…”

Role of the inhibitor of serine peptidase 2 (ISP2) of Trypanosoma brucei rhodesiense in parasite virulence and modulation of the inflammatory responses of the host

“…This could result from a lower parasite load in the brain, either due to delayed parasite penetration or to penetration at lower numbers, to a more efficient control of parasite burden in the CNS, or a combination of both. Studies employing co-culture of mouse primary microglia cells and T. b. brucei evidenced parasite phagocytosis and microglia activation, including increased production of nitric oxide (NO) [43]. Furthermore, removal of parasites by microglia-mediated phagocytosis was implicated in parasite clearance from the neuropil.…”