Soccer is the most popular sport in the world. Soccer players are at high risk for repetitive subconcussive head impact when heading the ball. Whether this leads to long-term alterations of the ...brain’s structure associated with cognitive decline remains unknown. The aim of this study was to evaluate cortical thickness in former professional soccer players using high-resolution structural MR imaging. Fifteen former male professional soccer players (mean age 49.3 SD 5.1 years) underwent high-resolution structural 3 T MR imaging, as well as cognitive testing. Fifteen male, age-matched former professional non-contact sport athletes (mean age 49.6 SD 6.4 years) served as controls. Group analyses of cortical thickness were performed using voxel-based statistics. Soccer players demonstrated greater cortical thinning with increasing age compared to controls in the right inferolateral-parietal, temporal, and occipital cortex. Cortical thinning was associated with lower cognitive performance as well as with estimated exposure to repetitive subconcussive head impact. Neurocognitive evaluation revealed decreased memory performance in the soccer players compared to controls. The association of cortical thinning and decreased cognitive performance, as well as exposure to repetitive subconcussive head impact, further supports the hypothesis that repetitive subconcussive head impact may play a role in early cognitive decline in soccer players. Future studies are needed to elucidate the time course of changes in cortical thickness as well as their association with impaired cognitive function and possible underlying neurodegenerative process.
Soccer is played by more than 250 million people worldwide. Repeatedly heading the ball may place soccer players at high risk for repetitive subconcussive head impacts (RSHI). This study evaluates ...the long-term effects of RSHI on neurochemistry in athletes without a history of clinically diagnosed concussion, but with a high exposure to RSHI. Eleven former professional soccer players (mean age 52.0±6.8 years) and a comparison cohort of 14 age- and gender-matched, former non-contact sport athletes (mean age 46.9±7.9 years) underwent 3T magnetic resonance spectroscopy (MRS) and neurocognitive evaluation. In the soccer players a significant increase was observed in both choline (Cho), a membrane marker, and myo-inositol (ml), a marker of glial activation, compared with control athletes. Additionally, ml and glutathione (GSH) were significantly correlated with lifetime estimate of RSHI within the soccer group. There was no significant difference in neurocognitive tests between groups. Results of this study suggest an association between RSHI in soccer players and MRS markers of neuroinflammation, suggesting that even subconcussive head impacts affect the neurochemistry of the brain and may precede neurocognitive changes. Future studies will need to determine the role of neuroinflammation in RSHI and the effect on neurocognitive function.
Human immunity to Toxoplasma gondii Fisch, Daniel; Clough, Barbara; Frickel, Eva-Maria
PLOS pathogens,
12/2019, Letnik:
15, Številka:
12
Journal Article
Recenzirano
Odprti dostop
...the use of mice as a model can only contribute partially to the study of the human response to Tg-infection. Mechanisms include ubiquitin-driven non-canonical autophagy of the entire PV and growth ...stunting; marking the PV with Ub, LAMP1, and the autophagy adapter proteins NDP52 and p62, followed by acidification of the vacuoles and killing of the parasite; recruitment of GBP1 to Tg vacuoles to disrupt them and expose the parasite within or growth restriction of Tg by GBP1 without translocation to the vacuole; and host cell death in response to opened PVs and leakage of pathogen-associated molecular patterns into the cytosol for detection by PRRs. AIM, absent in melanoma 2; ASC, apoptosis-associated speck-like protein containing a CARD; CASP, caspase; CCL, chemokine (C-C motif) ligand; GBP, guanylate binding protein; IL, interleukin; IFNγ, interferon gamma; LAMP, lysosome-associated membrane protein; NDP52, nuclear domain 10 protein 52; NK, natural killer; NLRP, nucleotide-binding oligomerization domain, Leucine rich repeat and Pyrin domain containing; PAMP, pathogen-associated molecular patterns; PRR, pattern recognition receptor; PV, parasitophorous vacuole; Tg, Toxoplasma gondii; Th, T helper cell; TNFα, tumour necrosis factor α; Ub, Ubiquitin. https://doi.org/10.1371/journal.ppat.1008097.g001 Cellular response to Toxoplasma infection The human cellular response to Tg-infection is highly dependent on cell type 18 and the infecting strain of Tg 19. In both cell types, the protein was able to restrict Tg independent of its recruitment 29,30. ...recruited GBP1 seems to uniquely induce host cell death in macrophages.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The guanylate binding protein (GBP) family of interferon-inducible GTPases promotes antimicrobial immunity and cell death. During bacterial infection, multiple mouse Gbps, human GBP2, and GBP5 ...support the activation of caspase-1-containing inflammasome complexes or caspase-4 which trigger pyroptosis. Whether GBPs regulate other forms of cell death is not known. The apicomplexan parasite Toxoplasma gondii causes macrophage death through unidentified mechanisms. Here we report that Toxoplasma-induced death of human macrophages requires GBP1 and its ability to target Toxoplasma parasitophorous vacuoles through its GTPase activity and prenylation. Mechanistically, GBP1 promoted Toxoplasma detection by AIM2, which induced GSDMD-independent, ASC-, and caspase-8-dependent apoptosis. Identical molecular determinants targeted GBP1 to Salmonella-containing vacuoles. GBP1 facilitated caspase-4 recruitment to Salmonella leading to its enhanced activation and pyroptosis. Notably, GBP1 could be bypassed by the delivery of Toxoplasma DNA or bacterial LPS into the cytosol, pointing to its role in liberating microbial molecules. GBP1 thus acts as a gatekeeper of cell death pathways, which respond specifically to infecting microbes. Our findings expand the immune roles of human GBPs in regulating not only pyroptosis, but also apoptosis.
Interferon-inducible guanylate-binding proteins (GBPs) promote cell-intrinsic defense through host cell death. GBPs target pathogens and pathogen-containing vacuoles and promote membrane disruption ...for release of microbial molecules that activate inflammasomes. GBP1 mediates pyroptosis or atypical apoptosis of Salmonella Typhimurium (STm)- or Toxoplasma gondii (Tg)- infected human macrophages, respectively. The pathogen-proximal detection-mechanisms of GBP1 remain poorly understood, as humans lack functional immunity-related GTPases (IRGs) that assist murine Gbps. Here, we establish that GBP1 promotes the lysis of Tg-containing vacuoles and parasite plasma membranes, releasing Tg-DNA. In contrast, we show GBP1 targets cytosolic STm and recruits caspase-4 to the bacterial surface for its activation by lipopolysaccharide (LPS), but does not contribute to bacterial vacuole escape. Caspase-1 cleaves and inactivates GBP1, and a cleavage-deficient GBP1D192E mutant increases caspase-4-driven pyroptosis due to the absence of feedback inhibition. Our studies elucidate microbe-specific roles of GBP1 in infection detection and its triggering of the assembly of divergent caspase signaling platforms.
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•Development of two microscopy assays for microbe/microbe-containing vacuole lysis•Human GBP1 is essential for the lysis of Toxoplasma gondii vacuoles and parasites•Caspase-4 recruitment, but not cytosolic escape of Salmonella, is GBP1 dependent•Caspase-1 cleaves and inactivates GBP1 and suppresses caspase-4-driven pyroptosis
Fisch et al. find that GBP1 targets Toxoplasma vacuolar and parasite membranes for disruption of both membranes. In contrast, appearance of cytosolic Salmonella is GBP1 independent, but caspase-4 recruitment to bacteria and activation is GBP1 dependent. In a negative feedback loop, caspase-1 cleaves GBP1 and suppresses caspase-4-driven pyroptosis during Salmonella infection.
The guanylate binding protein (GBP) family of interferon‐inducible GTPases promotes antimicrobial immunity and cell death. During bacterial infection, multiple mouse Gbps, human GBP2, and GBP5 ...support the activation of caspase‐1‐containing inflammasome complexes or caspase‐4 which trigger pyroptosis. Whether GBPs regulate other forms of cell death is not known. The apicomplexan parasite Toxoplasma gondii causes macrophage death through unidentified mechanisms. Here we report that Toxoplasma‐induced death of human macrophages requires GBP1 and its ability to target Toxoplasma parasitophorous vacuoles through its GTPase activity and prenylation. Mechanistically, GBP1 promoted Toxoplasma detection by AIM2, which induced GSDMD‐independent, ASC‐, and caspase‐8‐dependent apoptosis. Identical molecular determinants targeted GBP1 to Salmonella‐containing vacuoles. GBP1 facilitated caspase‐4 recruitment to Salmonella leading to its enhanced activation and pyroptosis. Notably, GBP1 could be bypassed by the delivery of Toxoplasma DNA or bacterial LPS into the cytosol, pointing to its role in liberating microbial molecules. GBP1 thus acts as a gatekeeper of cell death pathways, which respond specifically to infecting microbes. Our findings expand the immune roles of human GBPs in regulating not only pyroptosis, but also apoptosis.
Synopsis
GBP1 targets Toxoplasma and Salmonella in macrophages and regulates host cell death. GBP1 promotes Toxoplasma DNA detection by AIM2‐ASC‐caspase‐8 leading to apoptosis and targeting of Salmonella by caspase‐4 leading to pyroptosis.
IFNγ‐induced GBP1 translocates to Toxoplasma gondii‐ and Salmonella Typhimurium‐containing vacuoles in a lipidation and GTPase dependent manner.
GBP1 induces AIM2‐, ASC‐ and caspase‐8‐dependent atypical apoptosis in Toxoplasma gondii‐infected macrophages.
Toxoplasma gondii induces degradation of NLRP1, NLRP3, NLRC4 and pro‐caspase‐1, switching cell death type from pyroptosis to apoptosis.
GBP1 is essential for targeting of Salmonella by caspase‐4, its activation and increased pyroptosis.
Differential host cell death pathway activation upon infection with either Toxoplasma or Salmonella pathogens is mediated by a common guanylate‐binding protein‐family detector.
For image-based infection biology, accurate unbiased quantification of host-pathogen interactions is essential, yet often performed manually or using limited enumeration employing simple image ...analysis algorithms based on image segmentation. Host protein recruitment to pathogens is often refractory to accurate automated assessment due to its heterogeneous nature. An intuitive intelligent image analysis program to assess host protein recruitment within general cellular pathogen defense is lacking. We present HRMAn (Host Response to Microbe Analysis), an open-source image analysis platform based on machine learning algorithms and deep learning. We show that HRMAn has the capacity to learn phenotypes from the data, without relying on researcher-based assumptions. Using
and
Typhimurium we demonstrate HRMAn's capacity to recognize, classify and quantify pathogen killing, replication and cellular defense responses. HRMAn thus presents the only intelligent solution operating at human capacity suitable for both single image and high content image analysis.
This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).
ABSTRACT
Human guanylate binding proteins (GBPs) are key players of interferon–gamma (IFNγ)-induced cell intrinsic defense mechanisms targeting intracellular pathogens. In this study, we combine the ...well-established Toxoplasmagondii infection model with three in vitro macrophage culture systems to delineate the contribution of individual GBP family members to control this apicomplexan parasite. Use of high-throughput imaging assays and genome engineering allowed us to define a role for GBP1, 2 and 5 in parasite infection control. While GBP1 performs a pathogen-proximal, parasiticidal and growth-restricting function through accumulation at the parasitophorous vacuole of intracellular Toxoplasma, GBP2 and GBP5 perform a pathogen-distal, growth-restricting role. We further find that mutants of the GTPase or isoprenylation site of GBP1/2/5 affect their normal function in Toxoplasma control by leading to mis-localization of the proteins.
In human macrophages, guanylate binging protein 1, 2 and 5 (GBP1/2/5) control the growth of the parasite Toxoplasma gondii, with solely GBP1 targeting the parasite vacuole for elimination.
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