期刊
FRONTIERS IN IMMUNOLOGY
卷 12, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2021.641656
关键词
factor H; Streptococcus pneumoniae (pneumococcus); Haemolytic Uraemic Syndrome; genetic variant; complement system
类别
资金
- Spanish Instituto de Salud Carlos III (ISCIII)
- European Regional Development Fund from the European Union [PI16/00723, PI19/00970]
- Spanish Autonomous Region of Madrid (Complement II-CM network) [S2017/BMD-3673]
- Spanish Fundacion Senefro
- Higher Education Institutional Excellence Programme of the Ministry of Human Capacities in Hungary, within Semmelweis University
- National Office for Innovation and Research [KH130355]
- MSCA-ITN (Horizon 2020) CORVOS [860044]
- Premium Postdoctoral Fellowship Program of the Hungarian Academy of Sciences [PPD2018-016/2018]
SP-HUS is a clinically well-known disease that may have a worse prognosis than HUS associated with E. coli infections. Studies suggest that risk variants in the CFH-CFHR3-CFHR1 region could contribute to disease-predisposition to SP-HUS, and transient desialylation of complement FH by the pneumococcal neuraminidase may play a role in disease pathogenesis.
Haemolytic Uraemic Syndrome associated with Streptococcus pneumoniae infections (SP-HUS) is a clinically well-known entity that generally affects infants, and could have a worse prognosis than HUS associated to E. coli infections. It has been assumed that complement genetic variants associated with primary atypical HUS cases (aHUS) do not contribute to SP-HUS, which is solely attributed to the action of the pneumococcal neuraminidase on the host cellular surfaces. We previously identified complement pathogenic variants and risk polymorphisms in a few Hungarian SP-HUS patients, and have now extended these studies to a cohort of 13 Spanish SP-HUS patients. Five patients presented rare complement variants of unknown significance, but the frequency of the risk haplotypes in the CFH-CFHR3-CFHR1 region was similar to the observed in aHUS. Moreover, we observed desialylation of Factor H (FH) and the FH-Related proteins in plasma samples from 2 Spanish and 4 Hungarian SP-HUS patients. To analyze the functional relevance of this finding, we compared the ability of native and in vitro desialylated FH in: (a) binding to C3b-coated microtiter plates; (b) proteolysis of fluid-phase and surface-bound C3b by Factor I; (c) dissociation of surface bound-C3bBb convertase; (d) haemolytic assays on sheep erythrocytes. We found that desialylated FH had reduced capacity to control complement activation on sheep erythrocytes, suggesting a role for FH sialic acids on binding to cellular surfaces. We conclude that aHUS-risk variants in the CFH-CFHR3-CFHR1 region could also contribute to disease-predisposition to SP-HUS, and that transient desialylation of complement FH by the pneumococcal neuraminidase may have a role in disease pathogenesis.
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