TY - JOUR
T1 - Structural evolution of an immune evasion determinant shapes pathogen host tropism
AU - Marcinkiewicz, Ashley L
AU - Brangulis, Kalvis
AU - Dupuis, Alan P
AU - Hart, Thomas M
AU - Zamba-Campero, Maxime
AU - Nowak, Tristan A
AU - Stout, Jessica L
AU - Akopjana, Inara
AU - Kazaks, Andris
AU - Bogans, Janis
AU - Ciota, Alexander T
AU - Kraiczy, Peter
AU - Kolokotronis, Sergios-Orestis
AU - Lin, Yi-Pin
N1 - Funding Information:
We thank Simon Starkey, Quinton Smith, Deirdre Torrisi, and Joey Anderson from the Wadsworth Veterinary Sciences facility for animal husbandry; Richard Marconi, Utpal Pal, Patricia Rosa, Gary Wormser, and Ira Schwartz for providing the Bb strains; David Vance and Nicholas Mantis for sharing the E. coli strain; Susan Madison-Antonucci to allow us using her fluorescence microscope; Timothy Czajka for the assistance of SPR analysis; Nikhat Parveen, Klemen Strle, and Grace Chen for insightful comments; Carly Fernandes for assistance with making media; and Laurel Lown for assistance with running PCRs. We also appreciate Leslie Eisele and Renjie Song of Wadsworth Biochemistry and Immunology Core for CD spectroscopy, SPR, and flow cytometry; and Karen Chave of the Wadsworth Protein Expression Core for the help of the materials to purify FH. We thank the Wadsworth Center ATGC core for plasmid sequencing. Diffraction data for B. burgdorferi CspZ proteins and CspZ-human FH were collected on BL14.1 at the BESSY II electron storage ring operated by the Helmholtz-Zentrum, Berlin. We would particularly like to acknowledge the help and support of Manfred S. Weiss and Jan Wollenhaupt during the diffraction data collection. This work was supported by NSF IOS1754995 (S.-O.K.), NSF IOS1755286 (Y.-P.L., A.L.M., T.A.N., A.P.D., J.L.S., and A.T.C.), DoD TB170111, NIHR21AI144891, NIH R21AI146381, New York State Department of Health Wadsworth Center Start-Up Grant (A.L.M., T.A.N., and Y.-P.L.), and LOEWE Center DRUID Novel Drug Targets against Poverty-Related and Neglected Tropical Infectious Diseases, project C3 (P.K.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Funding Information:
and Ira Schwartz for providing the Bb strains; David Vance and Nicholas Mantis for sharing the E. coli strain; Susan Madison-Antonucci to allow us using her fluorescence microscope; Timothy Czajka for the assistance of SPR analysis; Nikhat Parveen, Klemen Strle, and Grace Chen for insightful comments; Carly Fernandes for assistance with making media; and Laurel Lown for assistance with running PCRs. We also appreciate Leslie Eisele and Renjie Song of Wadsworth Biochemistry and Immunology Core for CD spectroscopy, SPR, and flow cytometry; and Karen Chave of the Wadsworth Protein Expression Core for the help of the materials to purify FH. We thank the Wadsworth Center ATGC core for plasmid sequencing. Diffraction data for B. burgdorferi CspZ proteins and CspZ-human FH were collected on BL14.1 at the BESSY II electron storage ring operated by the Helmholtz-Zentrum, Berlin. We would particularly like to acknowledge the help and support of Manfred S. Weiss and Jan Wollenhaupt during the diffraction data collection. This work was supported by NSF IOS1754995 (S.-O.K.), NSF IOS1755286 (Y.-P.L., A.L.M., T.A.N., A.P.D., J.L.S., and A.T.C.), DoD TB170111, NIHR21AI144891, NIH R21AI146381, New York State Department of Health Wadsworth Center Start-Up Grant (A.L.M., T.A.N., and Y.-P.L.), and LOEWE Center DRUID Novel Drug Targets against Poverty-Related and Neglected Tropical Infectious Diseases, project C3 (P.K.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Publisher Copyright:
Copyright © 2023 the Author(s).
PY - 2023/7/4
Y1 - 2023/7/4
N2 - Modern infectious disease outbreaks often involve changes in host tropism, the preferential adaptation of pathogens to specific hosts. The Lyme disease-causing bacterium Borrelia burgdorferi (Bb) is an ideal model to investigate the molecular mechanisms of host tropism, because different variants of these tick-transmitted bacteria are distinctly maintained in rodents or bird reservoir hosts. To survive in hosts and escape complement-mediated immune clearance, Bb produces the outer surface protein CspZ that binds the complement inhibitor factor H (FH) to facilitate bacterial dissemination in vertebrates. Despite high sequence conservation, CspZ variants differ in human FH-binding ability. Together with the FH polymorphisms between vertebrate hosts, these findings suggest that minor sequence variation in this bacterial outer surface protein may confer dramatic differences in host-specific, FH-binding-mediated infectivity. We tested this hypothesis by determining the crystal structure of the CspZ-human FH complex, and identifying minor variation localized in the FH-binding interface yielding bird and rodent FH-specific binding activity that impacts infectivity. Swapping the divergent region in the FH-binding interface between rodent- and bird-associated CspZ variants alters the ability to promote rodent- and bird-specific early-onset dissemination. We further linked these loops and respective host-specific, complement-dependent phenotypes with distinct CspZ phylogenetic lineages, elucidating evolutionary mechanisms driving host tropism emergence. Our multidisciplinary work provides a novel molecular basis for how a single, short protein motif could greatly modulate pathogen host tropism.
AB - Modern infectious disease outbreaks often involve changes in host tropism, the preferential adaptation of pathogens to specific hosts. The Lyme disease-causing bacterium Borrelia burgdorferi (Bb) is an ideal model to investigate the molecular mechanisms of host tropism, because different variants of these tick-transmitted bacteria are distinctly maintained in rodents or bird reservoir hosts. To survive in hosts and escape complement-mediated immune clearance, Bb produces the outer surface protein CspZ that binds the complement inhibitor factor H (FH) to facilitate bacterial dissemination in vertebrates. Despite high sequence conservation, CspZ variants differ in human FH-binding ability. Together with the FH polymorphisms between vertebrate hosts, these findings suggest that minor sequence variation in this bacterial outer surface protein may confer dramatic differences in host-specific, FH-binding-mediated infectivity. We tested this hypothesis by determining the crystal structure of the CspZ-human FH complex, and identifying minor variation localized in the FH-binding interface yielding bird and rodent FH-specific binding activity that impacts infectivity. Swapping the divergent region in the FH-binding interface between rodent- and bird-associated CspZ variants alters the ability to promote rodent- and bird-specific early-onset dissemination. We further linked these loops and respective host-specific, complement-dependent phenotypes with distinct CspZ phylogenetic lineages, elucidating evolutionary mechanisms driving host tropism emergence. Our multidisciplinary work provides a novel molecular basis for how a single, short protein motif could greatly modulate pathogen host tropism.
KW - Animals
KW - Humans
KW - Immune Evasion/genetics
KW - Phylogeny
KW - Viral Tropism
KW - Lyme Disease/microbiology
KW - Borrelia burgdorferi
KW - Bacterial Proteins/metabolism
KW - Complement Factor H/genetics
KW - Complement System Proteins/genetics
KW - Membrane Proteins/metabolism
UR - http://www.scopus.com/inward/record.url?scp=85163411806&partnerID=8YFLogxK
U2 - 10.1073/pnas.2301549120
DO - 10.1073/pnas.2301549120
M3 - Article
C2 - 37364114
SN - 0027-8424
VL - 120
SP - e2301549120
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 27
M1 - e2301549120
ER -