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Published on: August 14, 2021
Interaction of human complement factor H variants Tyr⁴⁰² and His⁴⁰² with Leptospira spp
Aldacilene Souza Silva1, Mónica Marcela Castiblanco Valencia, Aurora Marques Cianciarullo
1Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo São Paulo, Brazil.
Abstract:
Leptospirosis is a zoonosis caused by pathogenic bacteria from the genus Leptospira. The disease represents a serious public health problem in underdeveloped tropical countries. Leptospires infect hosts through small abrasions in the skin or mucous membranes and they rapidly disseminate to target organs. The capacity of some pathogenic leptospiral strains to acquire the negative complement regulators factor H (FH) and C4b binding protein correlates with their ability to survive in human serum. In this study we assessed the functional consequences of the age macular degeneration-associated polymorphism FH His⁴⁰² or FH Tyr⁴⁰² on FH-Leptospira interactions. In binding assays using sub-saturating amounts of FH, the FH Tyr⁴⁰² variant interacted with all the strains tested more strongly than the FH His⁴⁰² variant. At higher concentrations, differences tended to disappear. We then compared cofactor activities displayed by FH His⁴⁰² and FH Tyr⁴⁰² bound to the surface of L. interrogans. Both variants exhibit similar activity as cofactors for Factor I-mediated cleavage of C3b, thus indicating that they do not differ in their capacity to regulate the complement cascade.
Insights
The age-related macular degeneration-associated polymorphism Factor H Tyr⁴⁰² binds stronger to Leptospira than His⁴⁰². However, both Factor H variants equally regulate the complement cascade, impacting bacterial survival.
Area of Science:
- Microbiology
- Immunology
- Genetics
Background:
- Leptospirosis is a significant zoonotic disease in tropical regions, caused by Leptospira bacteria.
- Leptospira invades hosts via skin or mucous membranes, spreading to target organs.
- Bacterial survival in human serum is linked to acquiring complement regulators like Factor H (FH).
Purpose of the Study:
- To investigate the impact of age-related macular degeneration-associated Factor H (FH) polymorphisms (His⁴⁰² and Tyr⁴⁰²) on FH-Leptospira interactions.
- To determine if these FH variants differentially affect complement regulation during Leptospira infection.
Main Methods:
- Binding assays were performed using different strains of Leptospira and varying concentrations of FH His⁴⁰² and FH Tyr⁴⁰² variants.
- Cofactor activity of bound FH variants was assessed for Factor I-mediated cleavage of C3b on the surface of L. interrogans.
Main Results:
- The FH Tyr⁴⁰² variant showed stronger binding to Leptospira strains than the FH His⁴⁰² variant at sub-saturating FH concentrations.
- At higher FH concentrations, the binding differences between the variants diminished.
- Both FH His⁴⁰² and FH Tyr⁴⁰² exhibited comparable cofactor activity in regulating the complement cascade via C3b cleavage.
Conclusions:
- While FH Tyr⁴⁰² exhibits enhanced binding to Leptospira compared to FH His⁴⁰², this difference does not translate to altered complement regulatory function.
- Both FH variants effectively regulate the complement cascade, suggesting similar roles in controlling Leptospira infection despite differential binding affinities.
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