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Cultivation Methods of Spirochetes from Borrelia burgdorferi Sensu Lato Complex and Relapsing Fever Borrelia
Published on: November 25, 2022
Understanding tropism and immunopathological mechanisms of relapsing fever spirochaetes
1Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Charlestown, MA 02129, USA. dcadavid@partners.org
Abstract:
Mice infected with relapsing fever (RF) spirochaetes survive recurrent waves of high-level bacteraemia with little, if any, clinical complications or tissue injury. In the absence of B-cells, peak bacteraemia does not resolve, resulting in multi-organ complications. During peak bacteraemia, large amounts of interleukin-10 (IL-10) are produced in blood and tissues. In mice unable to clear peak bacteraemia, exogenous IL-10 greatly reduced the clinical manifestations, serum levels of CXCL13, cerebral microgliosis, and the pathogen load. In contrast, IL-10 deficiency in mice unable to clear peak bacteraemia resulted in microvascular complications with distinct severities, depending on the serotype: serotype 2 (Bt2), which causes peak bacteraemia of c. 10(8)/mL, resulted in rapid death from subarachnoid and intraparenchymal haemorrhage; in contrast, serotype 1, which causes peak bacteraemia of c. 10(7)/mL, resulted in milder multi-organ haemorrhage and thrombosis. IL-10 deficiency also resulted in multi-organ haemorrhage and thrombosis with infarction in wild-type mice despite lower peak bacteraemia. Two mechanisms for pathogen control have been identified: antibody clearance of peak bacteraemia, and antibody-independent lowering of bacteraemia via phagocytosis in the spleen. IL-10 plays opposite roles in pathogen control, depending on the severity of bacteraemia: during persistent high bacteraemia, IL-10 helps to control it by protecting innate immune cells from apoptosis; in contrast, during transient peak bacteraemia, IL-10 slows down antibody-mediated clearance. A successful outcome from RF depends on a balanced immune response to clear bacteraemia while avoiding microvascular injury, in which production of IL-10, in response to the pathogen load, plays a critical role.
Insights
Interleukin-10 (IL-10) protects against severe complications from relapsing fever (RF) spirochaetes by preventing immune cell death during high bacterial loads. However, it can slow pathogen clearance when bacterial levels are lower.
Area of Science:
- Immunology
- Microbiology
- Pathogen-host interactions
Background:
- Relapsing fever (RF) spirochaetes cause recurrent high-level bacteremia.
- Mice typically tolerate RF spirochaetes with minimal complications, suggesting robust immune regulation.
- B-cell deficiency leads to unresolved bacteremia and multi-organ complications.
Purpose of the Study:
- To investigate the role of interleukin-10 (IL-10) in regulating immune responses and preventing complications during RF spirochaete infection.
- To understand how IL-10 influences pathogen clearance and host tissue injury.
- To elucidate the mechanisms by which IL-10 modulates microvascular integrity in response to varying bacterial loads.
Main Methods:
- Experimental infection of mice with different serotypes of relapsing fever spirochaetes.
- Analysis of immune responses, including cytokine production (IL-10) and cell apoptosis.
- Assessment of clinical outcomes, pathogen load, and tissue pathology in wild-type, B-cell deficient, and IL-10 deficient mice.
- Investigation of antibody-mediated and antibody-independent mechanisms of pathogen clearance.
Main Results:
- IL-10 administration reduced clinical severity, inflammation (CXCL13), and microgliosis in mice with high pathogen loads.
- IL-10 deficiency exacerbated microvascular complications, including hemorrhage and thrombosis, with severity dependent on spirochaete serotype and bacterial load.
- IL-10 exhibited dual roles: protecting innate immune cells during high bacteremia but hindering antibody-mediated clearance during peak bacteremia.
- Two pathogen control mechanisms were identified: antibody clearance and splenic phagocytosis.
Conclusions:
- A balanced immune response is crucial for successful RF infection outcome, clearing pathogens while preventing microvascular injury.
- IL-10 plays a critical role in this balance, protecting against severe disease during high bacterial loads.
- The pathogen load dictates IL-10's function, highlighting its complex role in host defense and pathogenesis.
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