mediates binding to host plasminogen/plasmin (new tern request)

[genegodbold]

There are at least two dozen bacterial sequences of concern that bind host plasminogen to their surfaces. This bound plasmin is generally converted to plasmin which can then mediate serum resistance for the bacteria (this would be through the indirect activation of host complement). See issue #82.

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Preferred term label

Binds host plasminogen/plasmin

Synonyms

None

Textual definition

These proteins of parasites specifically associate with the host protein plasminogen, usually securing it to the surface of the parasite where the plasminogen can be converted to the proteolytically active form and exert its effects which can include serum resistance and dissemination in host.

Examples

• Attachment and subsequent activation of host plasminogen by Complement-inhibitor and Plasminogen-binding protein of Acinetobacter baumannii (CipA) allows the bacteria to penetrate epithelial layers. Bacteria that do not encode CipA are defective at penetrating epithelial monolayers in vitro [PMID26681776].
• ErpP of Borrelia burgdorferi binds to host plasminogen with a dissociation constant of 25 nanomolar. Plasminogen bound to ErpP is successfully converted to plasmin. Factor H and plasminogen do not compete for binding to ErpP [PMID19001079]. When overexpressed in a serum-sensitive mutant bacterium lacking CspA, ErpP increases host factor H binding to the bacterial surface while deposition of components of the membrane attack complex was reduced and serum resistance was increased. In the absence of CspA, ErpP is required for evading complement deposition on the bacterial surface [PMID21282413]. CRASP-3/ErpP binds human plasminogen which can be converted to active plasmin on the bacterial surface [PMID19001079].
• The BpcA lipoprotein of Borrelia parkeri binds host complement factor H, complement factor H-like protein 1, and plasminogen to the surface of the bacterium. Factor H retains its ability to regulate complement when bound to BpcA. Host-derived proteases can activate plasminogen bound to BpcA. BpcA provides resistance to complement-mediated bacterial killing. When expressed in the B. burgdorferi B313 strain that is serum-sensitive because it lacks proteins for binding host complement regulatory proteins, BpcA provided serum resistance [PMID20231403].
• HcpA is a lipoprotein found on the outer surface of Borrelia recurrentis. HcpA confers resistance to complement-mediated destruction of the bacteria. Lack of expression of HcpA renders the bacteria serum-sensitive. HcpA binds control proteins factor H and FHL-1. Bound complement factor H retains its ability to regulate complement activity. HcpA binds human plasminogen. Bound plasminogen is processed to plasmin and can cleave fibrinogen. Bound plasminogen has anti-opsonic activity [PMID19308255].
• Cronobacter plasminogen activator (Cpa) can activate plasminogen and is required for resistance to complement-mediated killing. A mutant C. sakazakii in which the gene encoding Cpa was deleted demonstrated decreased serum resistance as the concentration of serum increased [PMID21245266].
• OmpL1 is a novel leptospiral extracellular matrix-binding protein of 320 residues and a receptor for host plasminogen found on the outer membrane of pathogenic Leptospires. It specifically associates with laminin and plasma fibronectin and is expressed during infection [PMID22802342].
• Leptospiral elongation factor-Tu can be found on the bacterial surface where it binds plasminogen in a dose-dependent manner. The plasminogen is converted to plasmin which can cut host complement component C3b as well as fibrinogen. EF-Tu can also bind the host complement regulator factor H which can mediated C3b degradation by host Factor I. Thus EF-Tu can protect the bacterium from complement-mediated destruction [PMID24312361].
• PfbA is a conserved surface protein of S. pneumoniae and helps the bacterium to colonize the host by recognizing the extracellular matrix (ECM) molecule fibronectin, as well as blood proteins like plasminogen and human serum albumin [PMID28815910].
• The phosphorylcholine esterase domain of CbpE interacts with the kringle domains of host plasminogen (UniProtP00747). Plasminogen bound to the surface of the streptococcal bacterium allows its activation to plasmin. CbpE-bound plasmin allowed the pneumococcus to disseminate across the extracellular matrix in an in vitro model [PMID18070889].
• Histones are antibacterial and hemolytic and complement the innate immune system in the formation of neutrophil extracellular traps (NETs) in defeating bacterial parasites. Streptococcus pyogenes protects itself from histone-killing by the acquisition of plasminogen. Plasminogen bound to the streptococcal surface through streptokinase protects the bacterial cell from histone-mediated killing. The streptokinase-plasminogen complex degrades all classes of histones and abrogates their antibacterial and hemolytic effects [PMID27533300].

Suggested parent term

I don't think it can go lower than be a child of parent PATHGO_0000073 Determinant of pathogenicity. Plasminogen is found in blood and blood-bathed tissues and isn't a cell surface component.

Attribution

https://orcid.org/0000-0002-5702-4690

[genegodbold]

@jproesch I added some examples to this one.

[jproesch]

@genegodbold I'm hesitant to make this a top level term as it is disconnected from the effects it is bringing about. Seems it is contributing primarily to indirect complement inactivation and dissemination in the examples above, both of which are already represented.

In immune evasion and subversion we have: 'inactivates host complement indirectly' -->'inactivates host complement by recruiting vitronectin' (these labels is clunky and probably need to be revised anyway) one solution could be to add a sibling term, something like -->'inactivates host complement by plasminogen binding'

This is not a great solution, but possibly fits better with the existing structure.

for dissemination, currently this would probably be the logical place: mediates dissemination -->mediates host barrier traversal

but additional supporting substructure would be needed.

Overall this hits on the issue of needing to capture primary and downstream effects, and trying to facilitate that while keeping the organizational structure intact...

[genegodbold]

@jproesch There are dozens of things that mediate complement activation/inactivation or dissemination that don't bind plasminogen. This is a way to distinguish the things that do bind. Binding host fibrinogen is similar. I think it is good to note.

[genegodbold]

Also, binding plasminogen doesn't necessarily lead to complement activation OR dissemination. I'm trying to cover the bases.