The Defensive Interactions of Prominent Infectious Protozoan Parasites: The Host’s Complement System

Rashidi, Sajad; Mansouri, Reza; Ali‐Hassanzadeh, Mohammad; Muro, Antonio; Nguewa, Paul A.; Manzano-Román, Raúl

doi:10.3390/biom12111564

Cited by 2 publications

(3 citation statements)

References 153 publications

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“…The viral marker, CMV IgG, was correlated with plasma C4 only in controls, suggesting that in schizophrenia, this linear relationship is disrupted, as similar to our observations of C4A copy number correlations with plasma C4 only in controls. More in-depth mechanistic studies are certainly required, but one explanation may be that these pathogens evade host immune systems in different ways, such as through complement regulation and inactivation [87][88][89].…”

Section: Discussionmentioning

confidence: 99%

Prospects and Pitfalls of Plasma Complement C4 in Schizophrenia: Building a Better Biomarker

Severance,

Prandovszky,

Yang

et al. 2023

Dev Neurosci

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Complex brain disorders like schizophrenia may have multifactorial origins related to mis-timed heritable and environmental factors interacting during neurodevelopment. Infections, inflammation, and autoimmune diseases are over-represented in schizophrenia leading to immune system-centered hypotheses. Complement component C4 is genetically and neurobiologically associated with schizophrenia, and its dual activity peripherally and in the brain makes it an exceptional target for biomarker development. Studies to evaluate the biomarker potential of plasma or serum C4 in schizophrenia do so to understand how peripheral C4 might reflect central nervous system (CNS)-derived neuroinflammation, synapse pruning and other mechanisms. This effort, however, has produced mostly conflicting results, with peripheral C4 sometimes elevated, reduced or unchanged between comparison groups. We undertook a pilot biomarker development study to systematically identify sociodemographic, genetic, and immune-related variables (autoimmune, infection-related, gastrointestinal (GI), inflammatory), which may be associated with plasma C4 levels in schizophrenia (SCH; n=335) and/or in non-psychiatric comparison subjects (NCs; n=233). As with previously inconclusive studies, we detected no differences in plasma C4 levels between SCH and NCs. In contrast, levels of general inflammation, C-Reactive Protein (CRP), were significantly elevated in SCH compared to NCs (ANOVA, F=20.74, p<0.0001), suggestive that plasma C4 and CRP may reflect different sources or causes of inflammation. In multivariate regressions of C4 gene copy number variants (CNVs), plasma C4 levels were correlated only for C4A (not C4B, C4L, C4S) and only in NCs (R Coeff=0.39, CI=0.01-0.77, R2=0.18, p<0.01; not SCH). Other variables associated with plasma C4 levels only in NCs included sex, double-stranded DNA (dsDNA) IgG, tissue-transglutaminase (TTG) IgG, and cytomegalovirus (CMV) IgG. Toxoplasma gondii IgG was the only variable significantly correlated with plasma C4 in SCH but not in NCs. Many variables were associated with plasma C4 in both groups (body mass index (BMI), race, CRP, N-methyl-D-aspartate receptor (NMDAR) NR2 subunit IgG, TTG IgA, lipopolysaccharide (LPS)-binding protein (LBP), and soluble CD14 (sCD14). While the direction of most C4 associations was positive, autoimmune markers tended to be inverse, and associated with reduced plasma C4 levels. When NMDAR NR2 autoantibody-positive individuals were removed, plasma C4 was elevated in SCH versus NCs (ANOVA, F=5.16, p<0.02). Our study was exploratory and confirmation of the many variables associated with peripheral C4 require replication. Our preliminary results point toward autoimmune factors and exposure to the pathogen, T. gondii, as possibly significant contributors to variability of total C4 protein levels in plasma of individuals with schizophrenia.

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Section: Discussionmentioning

confidence: 99%

Prospects and Pitfalls of Plasma Complement C4 in Schizophrenia: Building a Better Biomarker

Severance,

Prandovszky,

Yang

et al. 2023

Dev Neurosci

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“…To avoid and protect the host from unwarranted damage, regulation of the complement system is essential and is carried out by various host regulators. Although complement regulation is crucial for the host, various pathogens including bacteria ( 15 , 16 ), fungi ( 17 ), parasites ( 18 ) and viruses ( 19 ) adopt survival strategies that take advantage of the host complement regulators to prevent complement-mediated attack ( 20 ). Hijacking Factor H (FH), a host negative regulator of the AP, is one such strategy ( 21 ).…”

Section: Introductionmentioning

confidence: 99%

“…For the remaining doses, the data are from a single experiment. The results for the Tulahuen strain are plotted similarly, except for rH [19][20], where all doses reflect the mean and standard deviation from duplicates in two independent experiments. Survival was plotted relative to 0 mM rH fragments (100%).…”

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confidence: 99%

Mechanisms by which Factor H protects Trypanosoma cruzi from the alternative pathway of complement

Menon,

Ramirez-Toloza,

Wycoff

et al. 2024

Front. Immunol.

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Chagas disease, a chronic disabling disease caused by the protozoan Trypanosoma cruzi, has no standardized treatment or preventative vaccine. The infective trypomastigote form of T. cruzi is highly resistant to killing by the complement immune system. Factor H (FH), a negative regulator of the alternative pathway (AP) of complement on cell surfaces and in blood, contains 20 short consensus repeat domains. The four N-terminal domains of FH inactivate the AP, while the other domains interact with C3b/d and glycan markers on cell surfaces. Various pathogens bind FH to inactivate the AP. T. cruzi uses its trans-sialidase enzyme to transfer host sialic acids to its own surface, which could be one of the approaches it uses to bind FH. Previous studies have shown that FH binds to complement-opsonized T. cruzi and parasite desialylation increases complement-mediated lysis of trypomastigotes. However, the molecular basis of FH binding to T. cruzi remain unknown. Only trypomastigotes, but not epimastigotes (non-infective, complement susceptible) bound FH directly, independent of C3 deposition, in a dose-dependent manner. Domain mapping experiments using 3-5 FH domain fragments showed that domains 5-8 competitively inhibited FH binding to the trypomastigotes by ~35% but did not decrease survival in complement. FH-Fc or mutant FH-Fc fusion proteins (3-11 contiguous FH domains fused to the IgG Fc) also did not kill trypomastigotes. FH-related protein-5, whose domains bear significant sequence identity to all known polyanion-binding FH domains (6-7, 10-14, 19-20), fully inhibited FH binding to trypomastigotes and reduced trypomastigote survival to < 24% in the presence of serum. In conclusion, we have elucidated the role of FH in complement resistance of trypomastigotes.

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The Defensive Interactions of Prominent Infectious Protozoan Parasites: The Host’s Complement System

Cited by 2 publications

References 153 publications

Prospects and Pitfalls of Plasma Complement C4 in Schizophrenia: Building a Better Biomarker

Prospects and Pitfalls of Plasma Complement C4 in Schizophrenia: Building a Better Biomarker

Mechanisms by which Factor H protects Trypanosoma cruzi from the alternative pathway of complement

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