Immunopathology and Trypanosoma congolense parasite sequestration cause acute cerebral trypanosomiasis
- Universidade de Lisboa, Portugal
Abstract
Trypanosoma congolense causes a syndrome of variable severity in animals in Africa. Cerebral trypanosomiasis is a severe form, but the mechanism underlying this severity remains unknown. We developed a mouse model of acute cerebral trypanosomiasis and characterized the cellular, behavioral and physiological consequences of this infection. We show large parasite sequestration in the brain vasculature for long periods of time (up to 8 hours) and extensive neuropathology that associate with ICAM1-mediated recruitment and accumulation of T cells in the brain parenchyma. Antibody-mediated ICAM1 blocking and lymphocyte absence reduce parasite sequestration in the brain and prevent the onset of cerebral trypanosomiasis. Here, we establish a mouse model of acute cerebral trypanosomiasis and we propose a mechanism whereby parasite sequestration, host ICAM1, and CD4+ T cells play a pivotal role.
Data availability
Sequencing reads are available from NCBI under BioProject accession number: PRJNA777781.
Article and author information
Author details
Sara Silva Pereira
Funding
European Research Council (771714,679368)
- Cláudio A Franco
- Luisa Figueiredo
Human Frontier Science Program (LT000047/2019-L)
- Mariana De Niz
European Molecular Biology Organization (ALTF 1048-2016)
- Mariana De Niz
HORIZON EUROPE Marie Sklodowska-Curie Actions (839960)
- Sara Silva Pereira
Fundaçäo para a Ciéncia e a Tecnologia (CEECIND/03322/2018,CEECIND/00697/2018,CEECIND/04251/2017)
- Karine Serre
- Cláudio A Franco
- Luisa Figueiredo
Fondation Leducq (17CVD03)
- Cláudio A Franco
Fundaçäo para a Ciéncia e a Tecnologia (IF/00412/2012,EXPL/BEX-BCM/2258/2013,PRECISE-LISBOA-01-0145-FEDER-016394,PTDC/MED-PAT/31639/2017)
- Cláudio A Franco
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Olivier Silvie, Sorbonne Université, UPMC Univ Paris 06, INSERM, CNRS, France
Ethics
Animal experimentation: This study was conducted in accordance with EU regulations and ethical approval was obtained from the Animal Ethics Committee of Instituto de Medicina Molecular (AWB_2016_07_LF_Tropism). All surgeries were performed under anaesthesia, and every effort was made to minimize suffering.
Version history
- Preprint posted: November 5, 2021 (view preprint)
- Received: January 28, 2022
- Accepted: July 4, 2022
- Accepted Manuscript published: July 5, 2022 (version 1)
- Version of Record published: July 18, 2022 (version 2)
Copyright
© 2022, Silva Pereira et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Immunopathology and Trypanosoma congolense parasite sequestration cause acute cerebral trypanosomiasis
eLife 11:e77440.
https://doi.org/10.7554/eLife.77440
Further reading
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- Medicine
- Microbiology and Infectious Disease
Background:
End-stage renal disease (ESRD) patients experience immune compromise characterized by complex alterations of both innate and adaptive immunity, and results in higher susceptibility to infection and lower response to vaccination. This immune compromise, coupled with greater risk of exposure to infectious disease at hemodialysis (HD) centers, underscores the need for examination of the immune response to the COVID-19 mRNA-based vaccines.
Methods:
The immune response to the COVID-19 BNT162b2 mRNA vaccine was assessed in 20 HD patients and cohort-matched controls. RNA sequencing of peripheral blood mononuclear cells was performed longitudinally before and after each vaccination dose for a total of six time points per subject. Anti-spike antibody levels were quantified prior to the first vaccination dose (V1D0) and 7 d after the second dose (V2D7) using anti-spike IgG titers and antibody neutralization assays. Anti-spike IgG titers were additionally quantified 6 mo after initial vaccination. Clinical history and lab values in HD patients were obtained to identify predictors of vaccination response.
Results:
Transcriptomic analyses demonstrated differing time courses of immune responses, with prolonged myeloid cell activity in HD at 1 wk after the first vaccination dose. HD also demonstrated decreased metabolic activity and decreased antigen presentation compared to controls after the second vaccination dose. Anti-spike IgG titers and neutralizing function were substantially elevated in both controls and HD at V2D7, with a small but significant reduction in titers in HD groups (p<0.05). Anti-spike IgG remained elevated above baseline at 6 mo in both subject groups. Anti-spike IgG titers at V2D7 were highly predictive of 6-month titer levels. Transcriptomic biomarkers after the second vaccination dose and clinical biomarkers including ferritin levels were found to be predictive of antibody development.
Conclusions:
Overall, we demonstrate differing time courses of immune responses to the BTN162b2 mRNA COVID-19 vaccination in maintenance HD subjects comparable to healthy controls and identify transcriptomic and clinical predictors of anti-spike IgG titers in HD. Analyzing vaccination as an in vivo perturbation, our results warrant further characterization of the immune dysregulation of ESRD.
Funding:
F30HD102093, F30HL151182, T32HL144909, R01HL138628. This research has been funded by the University of Illinois at Chicago Center for Clinical and Translational Science (CCTS) award UL1TR002003.
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- Microbiology and Infectious Disease
In the Firmicutes phylum, GpsB is a membrane associated protein that coordinates peptidoglycan synthesis with cell growth and division. Although GpsB has been studied in several bacteria, the structure, function, and interactome of Staphylococcus aureus GpsB is largely uncharacterized. To address this knowledge gap, we solved the crystal structure of the N-terminal domain of S. aureus GpsB, which adopts an atypical, asymmetric dimer, and demonstrates major conformational flexibility that can be mapped to a hinge region formed by a three-residue insertion exclusive to Staphylococci. When this three-residue insertion is excised, its thermal stability increases, and the mutant no longer produces a previously reported lethal phenotype when overexpressed in Bacillus subtilis. In S. aureus, we show that these hinge mutants are less functional and speculate that the conformational flexibility imparted by the hinge region may serve as a dynamic switch to finetune the function of the GpsB complex and/or to promote interaction with its various partners. Furthermore, we provide the first biochemical, biophysical, and crystallographic evidence that the N-terminal domain of GpsB binds not only PBP4, but also FtsZ, through a conserved recognition motif located on their C-termini, thus coupling peptidoglycan synthesis to cell division. Taken together, the unique structure of S. aureus GpsB and its direct interaction with FtsZ/PBP4 provide deeper insight into the central role of GpsB in S. aureus cell division.
