Polysaccharide synthesis operon modulates Rickettsia-endothelial cell interactions.
Pathogenic Rickettsia species target vascular endothelial cells and cause systemic vasculitis. As obligate intracellular bacterial pathogens, Rickettsia must secure nutritional resources within the cytoplasm of endothelial cells while simultaneously subverting the innate immune defense system. With...
Saved in:
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2025-06-01
|
| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1013277 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850073704481947648 |
|---|---|
| author | Smruti Mishra Luke Helminiak Hwan Keun Kim |
| author_facet | Smruti Mishra Luke Helminiak Hwan Keun Kim |
| author_sort | Smruti Mishra |
| collection | DOAJ |
| description | Pathogenic Rickettsia species target vascular endothelial cells and cause systemic vasculitis. As obligate intracellular bacterial pathogens, Rickettsia must secure nutritional resources within the cytoplasm of endothelial cells while simultaneously subverting the innate immune defense system. With advances in rickettsial and host genetics, recent studies have identified novel molecular mechanisms involved in the complex interactions between Rickettsia and endothelial cells. However, it remains unclear how Rickettsia shields pathogen-derived immune stimulants, such as lipopolysaccharides (LPS) and peptidoglycan fragments, from immune recognition during intracellular replication. Prior work described two Rickettsia conorii variants with kkaebi transposon insertions in the polysaccharide synthesis operon (pso). Biochemical and immunological analyses revealed that pso is responsible for the biosynthesis of O-antigen (O-Ag) and the proper assembly of surface proteins. In the present work, we document that pso variant HK2 exhibits reduced capacities to adhere to and invade microvascular endothelial cells. Despite the low intracellular abundance, HK2 induced significantly higher levels of proinflammatory cytokines and chemokines, leading to premature cell death. Notably, HK2 exhibited defective intracellular survival in bone marrow-derived macrophages. This inability to dampen endothelial cell-mediated immune stimulation and resist macrophage-induced bactericidal activities resulted in the rapid elimination of viable Rickettsia in the mouse model of spotted fever. Further, when tested as a live-attenuated vaccine, HK2 elicited robust protective immunity against lethal spotted fever pathogenesis. Our work highlights the crucial role of pso in enabling Rickettsia to evade immune surveillance during intracellular replication within endothelial cells, ultimately delaying pathogen-induced programmed cell death and escaping immune defense mechanisms. |
| format | Article |
| id | doaj-art-ad77c3f80c1246dc9fa1c296b4afe33f |
| institution | DOAJ |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-ad77c3f80c1246dc9fa1c296b4afe33f2025-08-20T02:46:44ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742025-06-01216e101327710.1371/journal.ppat.1013277Polysaccharide synthesis operon modulates Rickettsia-endothelial cell interactions.Smruti MishraLuke HelminiakHwan Keun KimPathogenic Rickettsia species target vascular endothelial cells and cause systemic vasculitis. As obligate intracellular bacterial pathogens, Rickettsia must secure nutritional resources within the cytoplasm of endothelial cells while simultaneously subverting the innate immune defense system. With advances in rickettsial and host genetics, recent studies have identified novel molecular mechanisms involved in the complex interactions between Rickettsia and endothelial cells. However, it remains unclear how Rickettsia shields pathogen-derived immune stimulants, such as lipopolysaccharides (LPS) and peptidoglycan fragments, from immune recognition during intracellular replication. Prior work described two Rickettsia conorii variants with kkaebi transposon insertions in the polysaccharide synthesis operon (pso). Biochemical and immunological analyses revealed that pso is responsible for the biosynthesis of O-antigen (O-Ag) and the proper assembly of surface proteins. In the present work, we document that pso variant HK2 exhibits reduced capacities to adhere to and invade microvascular endothelial cells. Despite the low intracellular abundance, HK2 induced significantly higher levels of proinflammatory cytokines and chemokines, leading to premature cell death. Notably, HK2 exhibited defective intracellular survival in bone marrow-derived macrophages. This inability to dampen endothelial cell-mediated immune stimulation and resist macrophage-induced bactericidal activities resulted in the rapid elimination of viable Rickettsia in the mouse model of spotted fever. Further, when tested as a live-attenuated vaccine, HK2 elicited robust protective immunity against lethal spotted fever pathogenesis. Our work highlights the crucial role of pso in enabling Rickettsia to evade immune surveillance during intracellular replication within endothelial cells, ultimately delaying pathogen-induced programmed cell death and escaping immune defense mechanisms.https://doi.org/10.1371/journal.ppat.1013277 |
| spellingShingle | Smruti Mishra Luke Helminiak Hwan Keun Kim Polysaccharide synthesis operon modulates Rickettsia-endothelial cell interactions. PLoS Pathogens |
| title | Polysaccharide synthesis operon modulates Rickettsia-endothelial cell interactions. |
| title_full | Polysaccharide synthesis operon modulates Rickettsia-endothelial cell interactions. |
| title_fullStr | Polysaccharide synthesis operon modulates Rickettsia-endothelial cell interactions. |
| title_full_unstemmed | Polysaccharide synthesis operon modulates Rickettsia-endothelial cell interactions. |
| title_short | Polysaccharide synthesis operon modulates Rickettsia-endothelial cell interactions. |
| title_sort | polysaccharide synthesis operon modulates rickettsia endothelial cell interactions |
| url | https://doi.org/10.1371/journal.ppat.1013277 |
| work_keys_str_mv | AT smrutimishra polysaccharidesynthesisoperonmodulatesrickettsiaendothelialcellinteractions AT lukehelminiak polysaccharidesynthesisoperonmodulatesrickettsiaendothelialcellinteractions AT hwankeunkim polysaccharidesynthesisoperonmodulatesrickettsiaendothelialcellinteractions |