Complement regulator-acquiring surface proteins of Borrelia burgdorferi: Structure, function and regulation of gene expression

Abstract

Borrelia burgdorferi, the etiological agent of Lyme disease, exploits an array of strategies to establish infection and to overcome host innate and adaptive immune responses. One key borrelial immune escape mechanism involves the inactivation of host complement attack through acquisition of human immune regulators factor H (CFH), factor H-like protein 1 (FHL1), factor H-related protein 1 (CFHR1), CFHR2, and/or CFHR5. Binding of these host proteins is primarily mediated by bacterial surface-exposed proteins that have been collectively referred to as complement regulator-acquiring surface proteins, or CRASPs. Different strains of B. burgdorferi produce as many as 5 different CRASP molecules that comprise 3 distinct, genetically unrelated groups. Depending on bacterial genetic composition, different combinations of these proteins can be found on the borrelial outer surface. The 3 groups differ in their gene location, gene regulatory mechanisms, expression patterns during the tick-mammal infection cycle, protein sequence and structure as well as binding affinity for complement regulators and other serum proteins. These attributes influence the proteins’ abilities to contribute to complement resistance of this emerging human pathogen. In this review, we focus on the current knowledge on structure, function, and gene regulation of these B. burgdorferi infection-associated proteins.

Introduction

Lyme borreliosis/Lyme disease is the most commonly reported vector-borne infectious disease in Eurasia and the United States. It is caused by species of the Borrelia burgdorferi sensu lato complex, which includes B. burgdorferi sensu stricto (s.s.) (hereafter referred to as B. burgdorferi), B. garinii, B. afzelii, B. spielmanii, and B. bavariensis (Margos et al., 2009, Richter et al., 2004, Stanek and Reiter, 2011, Steere, 1989, Wang et al., 1999). The ability of Lyme disease spirochetes to perpetuate their natural vertebrate-tick infectious cycle requires an array of strategies to survive in different host environments and necessitates mechanisms to evade innate and adaptive immune responses of their reservoir hosts. Most Lyme disease spirochetes associated with human infection, members of the species B. burgdorferi, B. afzelii, B. spielmanii, and B. bavariensis, are resistant to killing by human complement (Bhide et al., 2005, Brade et al., 1992, Breitner-Ruddock et al., 1997, Herzberger et al., 2007, Kraiczy et al., 2000, Patarakul et al., 1999, van Dam et al., 1997). This is accomplished, at least in part, by the bacteria camouflaging themselves with the host-derived complement regulators factor H (CFH), factor H-like protein 1 (FHL1), and the factor H-related proteins CFHR1, CFHR2, and CFHR5 (Alitalo et al., 2001, Hammerschmidt et al., 2012, Hellwage et al., 2001, Kraiczy et al., 2001a, Kraiczy et al., 2001b, McDowell et al., 2003, Siegel et al., 2010). Binding of those host complement regulators is mediated by surface-exposed lipoproteins that were initially termed CRASPs (complement regulator-acquiring surface proteins) (Kraiczy et al., 2001a, Kraiczy et al., 2001b, Kraiczy et al., 2001c, Kraiczy et al., 2003, Kraiczy et al., 2004b, Wallich et al., 2005). While isolating and characterizing the 5 CRASPs of B. burgdorferi type strain B31, we identified BbCRASP-1 as being encoded by cspA (ORF BBA68), BbCRASP-2 as being encoded by cspZ (ORF BBH06), and BbCRASP-3, BbCRASP-4, and BbCRASP-5 as being identical to the previously named ErpP, ErpC, and ErpA proteins, respectively (Casjens et al., 2000, Hartmann et al., 2006, Kraiczy et al., 2003, Kraiczy et al., 2004a, Kraiczy et al., 2004b, Kraiczy et al., 2003, Stevenson et al., 1996).

Within the last decade, distinct CRASPs interacting with human CFH have been identified among additional borrelial species including B. afzelii, B. spielmanii, B. garinii, B. bavariensis, B. lusitaniae, B. valaisiana, B. bissettii, B. andersonii, B. turdi, B. tanukii, and B. japonica (Alitalo et al., 2001, Alitalo et al., 2005, Bhide et al., 2009, Dieterich et al., 2010, Herzberger et al., 2007, Kraiczy et al., 2001a, McDowell et al., 2003, Metts et al., 2003, Stevenson et al., 2002, van Burgel et al., 2010, Wallich et al., 2005). Some of these molecules can bind different animal CFH molecules, suggesting that these proteins share identical or similar mechanisms to interact with the key inhibitor of the alternative pathway of diverse hosts, e.g. mouse, rat, dog, sheep, cattle, horse, cat, pig, goat, and chicken (Alitalo et al., 2004, Bhide et al., 2009, Haupt et al., 2007, Hovis et al., 2006, Rogers and Marconi, 2007, Stevenson et al., 2002, van Burgel et al., 2010).

CFH and FHL1 are the key fluid-phase regulatory proteins of the alternative pathway of complement. Both glycoproteins control complement activation at the level of C3b by competing with factor B for binding to C3b, accelerating the decay of the C3 convertase (decay-accelerating activity), and acting as cofactors for factor I-mediated degradation of C3b (Zipfel and Skerka, 2009). The CFH protein family also consists of additional 6 factor H-related proteins (CFHR): CFHR1, CFHR2, CFHR3, CFHR4A, CFHR4B, and CFHR5. All share high degrees of similarity at their carboxy-termini with the carboxy-terminal short consensus repeats (SCRs) 18–20 of CFH (Józsi and Zipfel, 2008, Zipfel et al., 1999, Zipfel and Skerka, 2009). CFHR1 regulates complement at the level of C5 by inhibiting C5 convertase activity and assembly of the terminal membrane attack complex (Heinen et al., 2009). The biological function(s) of CFHR2 is (are) as yet unclear. Like CFH, CFHR5 displays cofactor activity for factor I-mediated inactivation of C3b, thereby inhibiting activity of the fluid-phase C3 convertase (McRae et al., 2001, McRae et al., 2005).

A variety of gene and protein names have been used for CRASP proteins in the literature, leading to some confusion about their identities and functions. One objective of this review is to clarify the nomenclature of these particular molecules.