Front Immunol 11: 1560

Immune Evasion Strategies of Relapsing Fever Spirochetes

Inactivation of the Alternative Pathway by Binding of Complement Regulator FH

Acquisition of regulators of complement activation is one of the most common strategies exploited by many human pathogenic microorganisms to evade complement (38–40). At least seven FH-interacting proteins have been described among RFB species including BhCRASP-1 (FhbA1) of B. hermsii HS1 and FhbA2 (FhbA, FHBP19) of B. hermsii YOR, FHBP28 and BpcA of B. parkeri, CbiA of B. miyamotoi, and HcpA of B. duttonii and B. recurrentis (30, 31, 33, 34, 36, 37) (Table 1). All FH-interacting proteins have in common binding to the C-terminal domains implicating that the regulatory domains located at the N-terminus of FH are accessible to retain their Factor I-mediated C3b degradation activity (33, 34, 36, 37) (Table 1). Moreover, BhCRASP-1, HcpA, BpcA, and CbiA, respectively, facilitate complement resistance when ectopically produced in genetically manipulated spirochetes (gain-of-function strains) (33, 34, 36, 37).

Table 1

Characteristics of complement-binding proteins of relapsing fever borreliae.

Complement binding protein	Genospecies	Strain	Gene localization	Gene locus	Gene name/ORF	Synonyms/other designations	Size (kDa)	Interacting complement regulator	Binding regions of complement regulator	Binding of complement component(s)	Interacting with specific host-derived proteins	Complement resistance (GOF)	Complement inhibition	References
STBRF
BhCRASP-1	B. hermsii	HS1	lp174	BHA008	cspH	FhbA1	21.5	FH FHR-1	SCR20	n.d.	Plasminogen	Yes	n.d.	(33, 36)
FhbA	B. hermsii	YOR HS1	lp174	n.d.^a	fhbA, bha008	FHBP19 FhbA2	24	FH FHL-1	n.d.	n.d.	n.d.	n.d.	n.d.	(30, 31, 41)
FHBP28	B. parkeri	RML	n.d.	n.d.	n.d.	none	28	FH	n.d.	n.d.	n.d.	n.d.	n.d.	(30, 42)
BpcA	B. parkeri	RML	lp150	n.d.	n.d.	none	17	FH FHR-1	SCRs 19-20 SCRs 3-5	n.d.	Plasminogen	n.d.	n.d.	(36)
BtcA	B. turicatae	91E135	lp159	A7978_04350	n.d.	none	20.5	none	n.d.	n.d.	Plasminogen	n.d.	n.d.	(36)
BHA007	B. hermsii	HS1	lp174	BHA007	bhA007	none	39	C4BP	n.d.	n.d.	Fibronectin	n.d.	n.d.	(43)
HTBRF
CbiA	B. miyamotoi	FR64b	lp70	CNO09_05070	cbiA	none	21	FH	SCRs 8-20 SCRs 15-20 SCRs 19-20	C3, C3b, C4b, C5	Plasminogen	Yes	CP, TS	(37, 44)
LBRF
HcpA	B. recurrentis	A1 A17	lp124	n.d.	hcpA	none	21	FH FHR-1	SCRs 19-20 SCRs 3-5	C3, C3b, C4b	Plasminogen	Yes	TS	(34)
CihC	B. recurrentis	A1 A17	lp124	n.d.	cihC	none	40	C4BP C1-INH	n.d.	n.d.	Fibronectin	Yes	n.d.	(35)
CihC	B. duttonii	La	lp165	BDU_RSO4550	cihC	BDU_1	40	C4BP C1-INH	n.d.	n.d.	Fibronectin	Yes	n.d.	(35, 45)

n.d.; not determined.

GOF, protein produced in a gain-of-function background; AP, alternative pathway; CP, classical pathway; TS, terminal sequence.

^{Sequence of the fhbA gene could not be detected on lp200 of B. hermsii YOR and lp174 of B. hermsii HS1, respectively, by BLAST searches}.

Within a Borrelia species, the FH-binding proteins are highly conserved, exhibiting sequence identity values of >93% (32) but among RFB, the percentages are quite low (36–45%). Whether the lack of sequence similarity might account for a different fold, appears to be somewhat questionable, in particular in the light of missing three dimensional structures. Interestingly, at least four conserved motifs (LDxNQKQALIxF, LGN-KxKQFLQxLH, SFSSxNFxD, and LEQKKExAL) could be identified in all seven proteins, raising the possibility of a non-continuous FH-binding site. Further studies investigating variants of FhbA2, FHBP28, HcpA, and BpcA also provide evidence that multiple regions are involved in the interaction with FH (30, 34, 36, 41). Of importance, infection studies utilizing a fhbA deletion mutant demonstrated that FhbA2 is the only FH-binding protein of B. hermsii and the absence of FhbA did not have an impact on serum resistance or infectivity of spirochetes, indicating functionally redundant roles played by other complement-interacting proteins as discussed below (46).

Inactivation of the Classical and Lectin Pathway by Binding of C1-INH and C4BP

To date, CihC of B. recurrentis is the soley protein displaying complement-inactivating properties on the CP and LP by binding to C1-INH and C4BP-binding protein (35). Orthologous proteins exhibiting sequence identities between 44 and 91% have been detected in B. duttonii Ly (BDU_1026), B. hermsii (BHA007), B. turicatae (BTA001), B. parkeri (BpA001), and B. crocidurae Achema and DOU (BCD_1370) but no homologous sequences could be found in LD spirochetes (42, 43). Functional analyses revealed that, like FH, C4BP bound to the borrelial surface retained its complement-inhibitory activity for factor I-mediated C4b degradation, thus targeting activation of the CP and LP (Figure 1A, Table 1). Previously, Meri et al. also demonstrated inactivation of the CP by binding of functional active C4BP to the surface of B. recurrentis and B. duttonii (45). In addition, CihC also promotes termination of the CP at the initial activation steps by binding of C1-INH, indicating that this borrelial molecule displays multi-functional complement-inhibitory properties. Deletions at the N- and C-terminus of CihC did not abrogate binding of C4BP or C1-INH leading to the assumption that central regions might be responsible for binding (Table 1). A crucial role of CihC in mediating serum resistance of RFB was evidenced by employing cihC-expressing gain-of-function strains which displayed a resistant phenotype upon serum challenge (35). In contrast to CihC, the BHA007 protein of B. hermsii only bound C4BP but not C1-INH (42). Owing to their functional properties to interact with fibronectin, these molecules have generically been named as “fibronectin-binding proteins” and clustered together with the fibronectin-binding BBK32 protein of Lyme disease spirochetes (42). Despite their low sequence similarity, the finding that BBK32 confers bloodstream survival of spirochetes (48) supports the possibility that CihC orthologs might also play a role during infection of the human host. Concerning CP inactivation, CbiA of B. miyamotoi has previously been shown to strongly inhibit activation of the CP, independently from interaction with C4BP by a yet unknown mechanism (37) (Figure 1A, Table 1). It is tempting to speculate whether binding of C4b to CbiA restricts downstream activation of the CP by terminating formation of the C3 convertase (37).

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Figure 1

Immune evasion strategies of RFB. (A) Inhibition of complement by distinct borrelial proteins acting at certain levels of the activation cascade. (B) Immune evasion of RFB by multiphasic antigenic variation. (C) Schematic representation of the structure of the Vsp1 (VspA) dimer of B. turicatae [PDB 2GA0, adapted from (47)]. The monomeric units are represented in dark or light blue. The variable sequences are distributed within the second and third α-helices as well as all loop regions and summarize in variable region (VR) 1–4. The light blue circle at the top of the dimer indicates the region with the highest variability. FH, factor H; FHL-1, factor H-like protein 1; FHR, factor H-related protein; C4BP, C1-INH, C1 esterase inhibitor; C4b binding protein; iC3b, inactivated C3b; iC4b, inactivated C4b, IgG, immunoglobulin G.

Inhibition of the Terminal Sequence and MAC Assembly

Terminating the final activation steps by binding to pore-forming complexes or late complement components negatively affects assembling of the MAC as demonstrated for CbiA and HcpA (37) (Figure 1A, Table 1). In particular, CbiA strongly inhibits the TS, probably through the binding of C5 and C9 whereas HcpA moderately influences complement on this level and BpcA and BtcA, respectively, did not have an impact at all. Interference with the TS enhance the process of complement inactivation mediated by distinct outer surface proteins.

Inactivation of Complement by Acquisition of Plasminogen

Distinct complement-interacting proteins including BhCRASP-1, HcpA, and CbiA exhibit multiple binding specificities to host-derived fluid phase proteins such as plasminogen (33, 34, 36, 44) (Figure 1A, Table 1). Plasminogen is known to bind to C3, C3b, C3d, and C5 and upon activation to plasmin, C3 and C5 degradation takes place (49). Plasminogen is also able to enhance Factor I-mediated C3b degradation in the presence of FH (49). Previous studies demonstrated that plasmin(ogen) bound to B. hermsii HS1, B. recurrentis A1, and B. parkeri decreases the amount of C3b molecules deposited on the borrelial surface (33, 34, 36) or lead to degradation of C3b when purified HcpA, BpcA, and CbiA, respectively, have been employed (34, 36, 44). Thus, degradation of C3 and C5 appears an additional strategy of RFB to successful overcome host immune defenses.

Direct Interaction With Individual Complement Components

HcpA and CbiA also bind to some extent to individual complement components, namely C3, C3b, C4, and C4b, respectively, as well as C5 (CbiA) though the relevance of these interactions on complement inactivation require further investigation (37) (Figure 1A, Table 1).

In conclusion, these findings suggest an involvement of these molecules in immune evasion in particular as the inactivation of the key complement component C3b is thought to be an efficient instrument for bacterial survival and may account for the extraordinary pathogenesis of RFB in the human host.

Institute of Medical Microbiology and Infection Control, University Hospital of Frankfurt, Goethe University Frankfurt, Frankfurt, Germany

Edited by: Reinhard Würzner, Innsbruck Medical University, Austria

Reviewed by: Taru Meri, University of Helsinki, Finland; Job E. Lopez, Baylor College of Medicine, United States

*Correspondence: Peter Kraiczy ed.trufknarf-inu.me@yzciark

This article was submitted to Microbial Immunology, a section of the journal Frontiers in Immunology

Institute of Medical Microbiology and Infection Control, University Hospital of Frankfurt, Goethe University Frankfurt, Frankfurt, Germany

Edited by: Reinhard Würzner, Innsbruck Medical University, Austria

Reviewed by: Taru Meri, University of Helsinki, Finland; Job E. Lopez, Baylor College of Medicine, United States

Received 2020 Apr 9; Accepted 2020 Jun 12.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Abstract

Relapsing fever (RF) is claimed a neglected arthropod-borne disease caused by a number of diverse human pathogenic Borrelia (B.) species. These RF borreliae are separated into the groups of tick-transmitted species including B. duttonii, B. hermsii, B. parkeri, B. turicatae, B. hispanica, B. persica, B. caucasica, and B. myiamotoi, and the louse-borne Borrelia species B. recurrentis. As typical blood-borne pathogens achieving high cell concentrations in human blood, RF borreliae (RFB) must outwit innate immunity, in particular complement as the first line of defense. One prominent strategy developed by RFB to evade innate immunity involves inactivation of complement by recruiting distinct complement regulatory proteins, e.g., C1 esterase inhibitor (C1-INH), C4b-binding protein (C4BP), factor H (FH), FH-like protein-1 (FHL-1), and factor H-related proteins FHR-1 and FHR-2, or binding of individual complement components and plasminogen, respectively. A number of multi-functional, complement and plasminogen-binding molecules from distinct Borrelia species have previously been identified and characterized, exhibiting considerable heterogeneity in their sequences, structures, gene localization, and their capacity to bind host-derived proteins. In addition, RFB possess a unique system of antigenic variation, allowing them to change the composition of surface-exposed variable major proteins, thus evading the acquired immune response of the human host. This review focuses on the current knowledge of the immune evasion strategies by RFB and highlights the role of complement-interfering and infection-associated molecules for the pathogenesis of RFB.

Keywords: spirochetes, Borrelia, relapsing fever, immune evasion, complement, antigenic variation, innate immunity, adaptive immunity

Abstract

Acknowledgments

We thank Arno Koenigs and Yi-Pin Lin for critical reading and helpful suggestions on the manuscript. We also would like to thank the two reviewers for their careful reading of our manuscript and their valuable and insightful comments.

Acknowledgments

Glossary

Abbreviations

BpcA	B. parkeri complement regulator-binding protein A
BtcA	B. turicatae plasminogen-binding protein
CbiA	complement binding and inhibitory protein A
CihC	complement inhibition via C4BP
C1-INH	C1 esterase inhibitor
C4BP	C4b binding protein
FhbA	FH-binding protein A
FH	Factor H
FHL-1	FH-like protein-1
FHR	FH-related protein
HcpA	human complement regulator and plasminogen-binding protein A
HTBRF	hard tick-borne relapsing fever
GAG	glycosaminoglycans
LBRF	louse-borne relapsing fever
MAC	membrane attack complex
RCA	regulators of complement activation
RF	relapsing fever
RFB	relapsing fever borreliae
SCR	short consensus repeats
STBRF	soft tick-borne relapsing fever
Vlp	variable large protein
Vmp	variable major protein
Vsp	variable small protein.

Glossary

Footnotes

Funding. This work was supported by the LOEWE Center DRUID (Novel Drug Targets against Poverty-Related and Neglected Tropical Infectious Diseases), project C3 (PK).

Footnotes

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