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Review
. 2022 Dec 8:13:1024998.
doi: 10.3389/fimmu.2022.1024998. eCollection 2022.

Parasite infections, neuroinflammation, and potential contributions of gut microbiota

Jérémy Alloo  1 , Ines Leleu  1 , Corinne Grangette  1 , Sylviane Pied  1
Affiliations
Review

Parasite infections, neuroinflammation, and potential contributions of gut microbiota

Jérémy Alloo et al. Front Immunol. .

Abstract

Many parasitic diseases (including cerebral malaria, human African trypanosomiasis, cerebral toxoplasmosis, neurocysticercosis and neuroschistosomiasis) feature acute or chronic brain inflammation processes, which are often associated with deregulation of glial cell activity and disruption of the brain blood barrier's intactness. The inflammatory responses of astrocytes and microglia during parasite infection are strongly influenced by a variety of environmental factors. Although it has recently been shown that the gut microbiota influences the physiology and immunomodulation of the central nervous system in neurodegenerative diseases like Alzheimer's disease and Parkinson's, the putative link in parasite-induced neuroinflammatory diseases has not been well characterized. Likewise, the central nervous system can influence the gut microbiota. In parasite infections, the gut microbiota is strongly perturbed and might influence the severity of the central nervous system inflammation response through changes in the production of bacterial metabolites. Here, we review the roles of astrocytes and microglial cells in the neuropathophysiological processes induced by parasite infections and their possible regulation by the gut microbiota.

Keywords: astrocytes; brain-inflammation; gut microbiota; immunopathophysiology; immunoregulation; microglia; parasitic disease.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Mechanisms of the acute CNS inflammation induced by a protozoan parasite infection. The parasites P. falciparum and T. brucei enter the blood and then infect various cell types, in order to escape the immune system and splenic clearance. During this phase, the parasites activate circulating immune cells; in turn, this induces inflammation and favors the expression of adhesion molecules (ICAM-1 and VCAM-1) by endothelial cells and the activation of glial cells (astrocytes and microglia). This results in a vicious circle because the inflammation makes it easier for parasites to enter and accumulate in the glial parenchyma. The sensing of parasites by the glial cells induces the production of pro-inflammatory cytokines, allows the recruitment of immune cells and creates a pro-inflammatory environment. The brain inflammation disturbs the BBB and helps the parasite to invade the glial parenchyma. The accumulation of parasites exacerbates the activation of astrocytes and microglia cells and leads to a harmful, pro-inflammatory environment.
Figure 2
Figure 2
Host regulation of neuroimmune processes during acute versus chronic parasite infection. (A) During an acute parasite infection (e.g by P. falciparum or T.brucei), parasites cross the BBB and activate astrocytes and microglia, which produce large amounts of pro-inflammatory cytokine/chemokines (e.g CXCL-10) that recruit T lymphocytes. Together, CD8+ and CD4+ T lymphocytes favor a pro-inflammatory environment by releasing molecules like perforin, granzyme, reactive oxygen species and IFN-γ. This release leads to disruption of the BBB, which favors parasite entry, aggravates the brain inflammation, and causes collateral damage to neurons. (B) In contrast, immune tolerance and pro-inflammatory responses are balanced during a chronic parasite infection. The cysts release compounds that inhibit granuloma formation and the activation of resident glial cells. For example, the parasites polarize pro-inflammatory macrophages into anti-inflammatory macrophages, which suppress the production of adhesion molecules and the local TH1 response via TGF-β and IL-10 production. Other cyst-derived compounds polarize CD4+ cells into regulatory T cells (Tregs) by modulating the maturation of dendritic cells and preventing the infiltration and migration of neutrophils, eosinophils and monocytes from the peripheral system into the brain via the production of immunomodulatory cytokines and the blockade of chemokines and adhesion molecules. Through an as-yet unknown mechanism, the parasite also inhibits the activation of microglia and astrocytes. Nevertheless, some of the material released by the cysts elicits an inflammatory reaction (mainly characterized by the secretion of IFN-γ and TNF-α by the activated glial cells and leukocytes). The chemoattractants lead to the recruitment of neutrophils, eosinophils and monocytes, which form a granuloma. Formation of a granuloma limits the collateral damage caused by the TH1 response and enables the parasite to be contained and destroyed. The astrocytes and microglia become activated and the BBB is damaged (C). Progressively, the TH1 response is replaced by a TH2 response and fibrosis occurs where the cyst was located. This fibrosis is associated with neuronal damage (D).
Figure 3
Figure 3
The chronic latent brain inflammation induced by parasite infection. T. solium and S. mansoni are intestinal parasites. Their eggs pass into the blood and then cross the BBB via as-yet unknown mechanisms. T. gondii infects leukocytes and crosses the BBB via a “trojan horse” mechanism or via a paracellular or transcellular route. Once inside the glial parenchyma, the parasites form extracellular cysts (for T. solium and S. mansoni) or intracellular cysts (for T. gondii) in neurons and microglia cells. The cysts can survive for several years and induce a low-level pro-inflammatory response. However, after few years or in an immunocompromised state, the cysts degenerate (for T. solium and S. mansoni) or proliferate (for T. gondii) and strongly activate astrocytes and microglia cells. In turn, this excessive activation creates a pro-inflammatory environment that damages neurons and the BBB.
Figure 4
Figure 4
Modulation of the CNS inflammation response by the GM during a parasite infection. Eubiosis of GM favors the maintenance of the gut barrier’s intactness (122, 123). Moreover, the GM can produce metabolites like SCFAs, tryptophan, tryptophan derivatives, neurotransmitters, and vitamins, which are disseminated through the host’s circulation. These metabolites are known to have an impact on the BBB’s intactness and on CNS cells like astrocytes and microglia. Infection by a parasite induces dysbiosis of the GM directly or indirectly, which perturbs metabolite production, impairs gut barrier intactness and allows the possible translocation of bacteria throughout the organism. Dysbiosis is associated with an impairment of glial cell activity and loss of the BBB’s intactness. Dysbiosis might also favor the excessive pro-inflammatory response of glial cells induced by the parasite and that leads to neuronal damage.
Figure 5
Figure 5
The three-way dialogue between parasites, the gut microbiota, and glial cells. A complex bidirectional dialogue exists between the gut microbiota, the CNS and the parasite. Green boxes and arrows summarize gut microbiota interactions with the CNS and the parasites. Red boxes and arrows represent parasites interactions with the CNS and the gut microbiota. Blue boxes and arrows indicate CNS interactions with the gut microbiota and the parasites.
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