Host tropism determination by convergent evolution of immunological evasion in the Lyme disease system
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Evaluation Summary:
This work builds on previous work by the same team, demonstrating that the bacterial protein CspA, which inactivates host complement by binding to the host complement inhibitor FH, is a determinant of host range for the Lyme disease bacterium. Additionally, the authors present phylogenetic analysis of CspA and related protein sequences, which supports the hypothesis that inactivation of host complement has evolved independently in three bacterial genospecies.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)
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Abstract
Pathogens possess the ability to adapt and survive in some host species but not in others–an ecological trait known as host tropism. Transmitted through ticks and carried mainly by mammals and birds, the Lyme disease (LD) bacterium is a well-suited model to study such tropism. Three main causative agents of LD, Borrelia burgdorferi , B . afzelii , and B . garinii , vary in host ranges through mechanisms eluding characterization. By feeding ticks infected with different Borrelia species, utilizing feeding chambers and live mice and quail, we found species-level differences in bacterial transmission. These differences localize on the tick blood meal, and specifically complement, a defense in vertebrate blood, and a polymorphic bacterial protein, CspA, which inactivates complement by binding to a host complement inhibitor, Factor H (FH). CspA selectively confers bacterial transmission to vertebrates that produce FH capable of allele-specific recognition. CspA is the only member of the Pfam54 gene family to exhibit host-specific FH-binding. Phylogenetic analyses revealed convergent evolution as the driver of such uniqueness, and that FH-binding likely emerged during the last glacial maximum. Our results identify a determinant of host tropism in Lyme disease infection, thus defining an evolutionary mechanism that shapes host-pathogen associations.
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Evaluation Summary:
This work builds on previous work by the same team, demonstrating that the bacterial protein CspA, which inactivates host complement by binding to the host complement inhibitor FH, is a determinant of host range for the Lyme disease bacterium. Additionally, the authors present phylogenetic analysis of CspA and related protein sequences, which supports the hypothesis that inactivation of host complement has evolved independently in three bacterial genospecies.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
Numerous previous publications, primarily by the authors of this manuscript, have demonstrated that the CspA outer surface protein of Lyme disease Borrelia spp. can bind to host complement factor H, and thereby confer resistance to killing by the host's alternative pathway of complement activation. They also previously demonstrated that sequence variations in CspA can alter ability to bind factor H of various host species, leading to a conclusion that CspA is a determinant of whether or not a particular Borrelia strain can infect a particular species of host.
The authors make a step forward with experiments using blood of quail, a bird species. The results are very similar to those of earlier publications. One of the tested strains ZQ1, was previously demonstrated to be killed by mammalian blood but not bird …
Reviewer #1 (Public Review):
Numerous previous publications, primarily by the authors of this manuscript, have demonstrated that the CspA outer surface protein of Lyme disease Borrelia spp. can bind to host complement factor H, and thereby confer resistance to killing by the host's alternative pathway of complement activation. They also previously demonstrated that sequence variations in CspA can alter ability to bind factor H of various host species, leading to a conclusion that CspA is a determinant of whether or not a particular Borrelia strain can infect a particular species of host.
The authors make a step forward with experiments using blood of quail, a bird species. The results are very similar to those of earlier publications. One of the tested strains ZQ1, was previously demonstrated to be killed by mammalian blood but not bird blood (Kurtenbach et al, 1998, Infect. Immun 66:1248).
The species Borrelia burgdorferi (sensu lato) has been split into 20+ "genospecies", including B. burgdorferi (sensu stricto), B. afzelii, B. garinii, and others. The authors make an inaccurate statement on page 4, lines 71-72, claiming that B. afzelii and B. garinii "are selectively infectious in a few host taxa (e.g. B. afzelii for rodents and B. garinii for birds)". Actually, B. afzelii and B. garinii have been isolated from infected humans, with B. garinii stains exhibiting a tendency to cause neurological symptoms in human Lyme disease patients.
A weakness is that the authors examined only three strains of Lyme Borrelia, one each of B. burgdorferi (sensu stricto), B. afzelii, and B. garinii. Therefore it is not known whether results are applicable to other than these three strains. Attempts were made to correlate sequences of CspA of those three strains to evolutionary history. Because of the small number of specimens, the significance of the conclusions remains unknown.
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Reviewer #2 (Public Review):
This work demonstrates that the bacterial protein CspA, which inactivates host complement by binding to the host complement inhibitor FH, is an important determinant of host range for the Lyme disease (LD) bacterium. Additionally, the authors present phylogenetic analysis of CspA and related protein sequences, which supports the hypothesis that inactivation of host complement has evolved independently in three bacterial genospecies.
First, the authors present a rigorous series of experiments demonstrating that CspA governs host range in three bacterial genospecies (Figs 1-4). By feeding infected ticks on live mice, quail, or artificial feeding chambers, the authors demonstrate that the genospecies differ in their host range, and that these differences only occur when hosts/blood have functional complement. …
Reviewer #2 (Public Review):
This work demonstrates that the bacterial protein CspA, which inactivates host complement by binding to the host complement inhibitor FH, is an important determinant of host range for the Lyme disease (LD) bacterium. Additionally, the authors present phylogenetic analysis of CspA and related protein sequences, which supports the hypothesis that inactivation of host complement has evolved independently in three bacterial genospecies.
First, the authors present a rigorous series of experiments demonstrating that CspA governs host range in three bacterial genospecies (Figs 1-4). By feeding infected ticks on live mice, quail, or artificial feeding chambers, the authors demonstrate that the genospecies differ in their host range, and that these differences only occur when hosts/blood have functional complement. By engineering a CspA-deficient bacteria strain to express CspA from different genospecies, the authors show that host-specific transmission is governed by the CspA protein. The authors previously published similar experiments demonstrating that CspA is key to tick-to-mouse transmission (Hart et al. 2018); the current paper confirms these findings and extends them to avian hosts. These experiments are well-designed and support the authors' key claims.
Second, the authors present a phylogenetic analysis of CspA and related proteins in the Pfam54-IV family (Figs 5-6). The authors identify CspA orthologs in multiple bacterial strains based on sequence similarity. Based on phylogenetic analysis, the authors hypothesize that the host-specific FH-binding activity of CspA evolved independently in each genospecies. The data presented support this hypothesis.
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