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Complement Genetic Variants and FH Desialylation in S. pneumoniae-Haemolytic Uraemic Syndrome

Irene Gómez Delgado¹, Fernando Corvillo^1,2, Pilar Nozal^2,3

¹Complement Research Group, Hospital La Paz Institute for Health Research (IdiPAZ), La Paz University Hospital, Madrid, Spain.

Frontiers in Immunology

|March 29, 2021

Insights

Genetic variants linked to atypical hemolytic uremic syndrome (aHUS) may predispose individuals to Streptococcus pneumoniae-associated HUS (SP-HUS). Pneumococcal neuraminidase may cause Factor H desialylation, impacting complement regulation and disease severity.

Area of Science:

Immunology
Complement System
Nephrology

Background:

Haemolytic Uraemic Syndrome (HUS) associated with Streptococcus pneumoniae infections (SP-HUS) typically affects infants and can have a poorer prognosis than E. coli-associated HUS.
SP-HUS pathogenesis was primarily attributed to pneumococcal neuraminidase activity, with complement genetic variants common in atypical HUS (aHUS) not thought to play a role.
Previous studies identified complement pathogenic variants and risk polymorphisms in Hungarian SP-HUS patients.

Purpose of the Study:

To investigate the potential contribution of complement genetic variants and Factor H desialylation to SP-HUS in a Spanish cohort.
To functionally assess the impact of desialylated Factor H on complement regulation.
To explore the interplay between SP-HUS, aHUS-risk variants, and pneumococcal neuraminidase activity.

Main Methods:

Genetic analysis of complement pathway genes and CFH-CFHR3-CFHR1 haplotypes in 13 Spanish SP-HUS patients.
Detection of Factor H (FH) and FH-Related protein desialylation in plasma samples from Spanish and Hungarian SP-HUS patients.
In vitro functional assays comparing native and desialylated FH in complement regulatory activities, including C3b binding, Factor I-mediated proteolysis, and haemolytic inhibition.

Main Results:

Five Spanish SP-HUS patients carried rare complement variants of unknown significance.
The frequency of risk haplotypes in the CFH-CFHR3-CFHR1 region in Spanish SP-HUS patients was similar to that observed in aHUS.
Desialylated FH exhibited a reduced capacity to control complement activation on sheep erythrocytes, indicating impaired function due to sialic acid loss.

Conclusions:

Atypical HUS-associated complement genetic variants in the CFH-CFHR3-CFHR1 region may also contribute to SP-HUS predisposition.
Transient desialylation of complement Factor H by pneumococcal neuraminidase is a potential mechanism in SP-HUS pathogenesis.
FH sialic acids appear crucial for its binding to cellular surfaces and effective complement regulation.

Read full analysis

Abstract:

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.

Keywords:

Haemolytic Uraemic Syndrome Streptococcus pneumoniae (pneumococcus)complement system factor H genetic variant

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