C3 Binding Proteins: a potential novel Complement System evasion mechanism in pathogenic leptospires

• Grant number: 24/14352-0
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: June 01, 2026
• End date: July 31, 2029
• Field of knowledge: Biological Sciences - Immunology - Immunochemistry
• Principal Investigator: Lourdes Isaac
• Grantee: Ana Carolina Mikejevs Lorga
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Leptospirosis is a neglected tropical disease responsible for about one million cases and 60,000 fatalities annually around the world. Although it predominantly affects underdeveloped tropical countries, its incidence in developed countries has increased over the last few years. This is mainly due to climate change and the lack of a commercial vaccine for humans. Patients affected by leptospirosis can either remain asymptomatic or develop acute fevers (90%). Given its non-specific symptoms - fever, nausea, myalgia, headache and conjunctival suffusion - and its precarious diagnosis, it is believed to be an underreported disease. This infection is caused by spirochete bacteria of the Leptospira genus, but not all of which are capable of provoking pathology. One of the reasons for this difference is that saprophytic species are susceptible to complement-mediated killing. In contrast, pathogenic leptospires manage to escape through a wide arsenal of immune evasion strategies. These are subdivided into three mechanisms: recruitment of (i) Complement System regulators and (ii) proteases from the host's bloodstream; and (iii) secretion of proteins that cleave peptides from the Complement activation cascade.Proteins capable of binding to and inhibiting C3 have been described in various pathogens, such as Candida albicans, Streptococcus pneumoniae, Staphylococcus aureus and Moraxella catarrhalis. To our knowledge, this mechanism has not yet been described in the Leptospira genus. However, previous studies from our group have indicated the deposition of C3, the central protein of the Complement System, in pathogenic leptospires. To better understand this phenomenon and its importance, we will try to identify proteins that bind to C3. To achieve this, native and recombinant proteins from L. interrogans serovar Copenhageni L1-130 (Fiocruz) will be incubated with C3. Those that show a promising binding will be subjected to mass spectrometry and cloned. Further characterization will be carried out in terms of growth phase, cellular location and optimum expression temperature. In addition, we will evaluate the functional activity of the Alternative Pathway in the presence of the recombinant proteins to assess their potential inhibitory effects on protein-C3 interaction. (AU)