Behavior of Neutrophil Granulocytes during Toxoplasma gondii Infection in the Central Nervous System

Abstract

Cerebral toxoplasmosis is characterized by activation of brain resident cells and recruitment of specific immune cell subsets from the periphery to the central nervous system (CNS). Our studies revealed that the rapidly invaded Ly6G+ neutrophil granulocytes are an early non-lymphoid source of interferon-gamma (IFN-γ), the cytokine known to be the major mediator of host resistance to Toxoplasma gondii (T. gondii). Upon selective depletion of Ly6G+ neutrophils, we detected reduced IFN-γ production and increased parasite burden in the CNS. Ablation of Ly6G+ cells resulted in diminished recruitment of Ly6Chi monocytes into the CNS, indicating a pronounced interplay. Additionally, we identified infiltrated Ly6G+ neutrophils to be a heterogeneous population. The Ly6G+CD62-LhiCXCR4+ subset released cathelicidin-related antimicrobial peptide (CRAMP), which can promote monocyte dynamics. On the other hand, the Ly6G+CD62-LloCXCR4+ subset produced IFN-γ to establish early inflammatory response. Collectively, our findings revealed that the recruited Ly6G+CXCR4+ neutrophil granulocytes display a heterogeneity in the CNS with a repertoire of effector functions crucial in parasite control and immune regulation upon experimental cerebral toxoplasmosis.

p75NTR regulates brain mononuclear cell function and neuronal structure in Toxoplasma infection‐induced neuroinflammation

“…Moreover, our results indicate distinct modifications in the synaptic protein composition (Lang et al, ). We previously reported that the chronic infection causes activation of resident microglia and recruitment of mononuclear immune cell subsets to the CNS (Biswas et al, , ; Möhle et al, ). Thus, we hypothesized that activated immune cells possibly interact with neurons upon infection and modify their morphology and function.…”

“…During the chronic phase of infection cysts are predominantly formed in infected neurons enabling the parasites to persist lifelong within the host (Dubey, 1998;Wilson & Hunter, 2004). Chronic infection with T. gondii is followed by a Th1 type inflammatory response and cell recruitment to the brain (Biswas et al, 2017;Blanchard, Dunay, & Schlüter, 2015).…”

Group 1 innate lymphoid cells in Toxoplasma gondii infection

“…Nevertheless, IL‐12 is critical for IFN‐γ production during both, acute and chronic stages of the infection. The contribution of neutrophils to early IFN‐γ production at the site of infection in the periphery and also in the brain only recently became recognized …”

“…The contribution of neutrophils to early IFNγ production at the site of infection in the periphery and also in the brain only recently became recognized. 34,35 Induction of inducible nitric oxide synthase (iNOS) production, indoleamine 2,3-dioxygenase (IDO), reactive oxygen intermediates (ROS) and degradation of nutrients have been implicated in control of T. gondii following IFNγ activation of the infected cells. Inducible nitric oxide synthase (iNOS) mediates a host defence mechanism, and this pathway is dependent of arginine.…”

Robust Control of a Brain-Persisting Parasite through MHC I Presentation by Infected Neurons

“…Mouse studies have highlighted a variety of innate immune mechanisms that can contribute to parasite control in the brain. These include the production of pro-inflammatory mediators by innate mononuclear cells (Biswas et al, 2015;Sa et al, 2015) and neutrophils (Biswas et al, 2017), as well as anti-microbial pathways triggered by interferon gamma (IFNg)/STAT1 in astrocytes (Hidano et al, 2016). Yet, these processes are typically not sufficient to prevent TE pathogenesis.…”