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Splenectomy predisposes to fungal sepsis through defective phagosome formation
J E McCarthy1, H P Redmond, W Watson
1Department of Surgery, Beaumont Hospital, Dublin, Ireland.
Abstract:
Postsplenectomy septic sequelae may be fatal, but the mechanisms are unclear. We hypothesized that peritoneal macrophage (PM phi) antimicrobial function is abnormal following splenectomy and that this may predispose to increased mortality from the fungal pathogen Candida albicans. Study 1 (in vivo): female CD-1 mice were randomized into control (C), laparotomy (L), or laparotomy+splenectomy (L + S) and inoculated with C. albicans (10(7) organisms, ip) and were studied for mortality. Study 2 (in vitro): mice were randomized to C, L, or L + S groups. Twenty-four hours later, PM phi were harvested and studied for their antifungal activity, including percentage PM phi ingestion of C. albicans and vacuolar sealing of C. albicans within PM phi, percentage C. albicans killing, and superoxide anion (O2-) generation, the mechanism by which candida are killed. Results showed decreased phagocytosis and killing of C. albicans in the L + S group (P < 0.05 vs C) and reduced vacuolar sealing (P < 0.05 vs C) but significantly higher O2- release compared to that in other groups (P < 0.05). Mortality in the L + S group from C. albicans sepsis was significantly higher than that in the other groups (60% compared to 20% in the L group and 13% in C, P < 0.02). This may have resulted from L + S-induced defective phagocytosis of C. albicans and depressed C. albicans killing but increased O2- release in response to candida. This discrepancy between decreased killing and increased O2- may result from increased leakage of O2- from more unsealed vacuoles in the L + S group. Thus, L + S may predispose to candida-induced mortality through defective PM phi intracellular candida killing while enhancing the release of O2- extracellularly from unsealed vacuoles, causing tissue injury.
Insights
Splenectomy impairs peritoneal macrophage function, increasing Candida albicans sepsis mortality. Defective fungal killing and extracellular superoxide release contribute to this risk.
Area of Science:
- Immunology
- Microbiology
- Surgical Pathology
Background:
- Post-splenectomy sepsis poses a fatal risk, with unclear underlying mechanisms.
- The spleen's role in immune defense against fungal pathogens like Candida albicans is critical.
Purpose of the Study:
- To investigate the impact of splenectomy on peritoneal macrophage (PM phi) function.
- To determine if altered PM phi activity contributes to increased mortality from Candida albicans sepsis.
Main Methods:
- In vivo: Mice underwent sham surgery or splenectomy, followed by Candida albicans inoculation to assess mortality.
- In vitro: Peritoneal macrophages were harvested from control and splenectomized mice to evaluate phagocytosis, killing, and superoxide anion generation against Candida albicans.
Main Results:
- Splenectomized mice exhibited significantly higher mortality rates when infected with Candida albicans.
- Peritoneal macrophages from splenectomized mice showed reduced Candida albicans phagocytosis and killing.
- A decrease in vacuolar sealing and an increase in extracellular superoxide anion release were observed in macrophages post-splenectomy.
Conclusions:
- Splenectomy impairs peritoneal macrophage-mediated killing of Candida albicans.
- Increased extracellular superoxide release from unsealed vacuoles may exacerbate tissue injury and contribute to mortality.
- Altered macrophage function following splenectomy predisposes to severe Candida albicans infections.