Leukotriene B4-Mediated Neutrophil Recruitment Causes Pulmonary Capillaritis during Lethal Fungal Sepsis

Area of Science:

• Immunology
• Infectious Diseases
• Pulmonary Medicine

Background:

• Candida albicans bloodstream infections cause high mortality.
• Polymorphonuclear leukocytes (PMN) are crucial for combating invasive candidiasis.
• The dual role of PMNs in host defense versus sepsis-induced organ injury remains unclear.

Purpose of the Study:

• To investigate the role of PMNs in host defense and organ injury during Candida albicans sepsis.
• To elucidate the mechanisms underlying PMN-mediated tissue damage in fungal sepsis.
• To explore therapeutic strategies targeting PMN-induced injury.

Main Methods:

• Utilized a lethal septic mouse model and human pulmonary circulation models.
• Observed PMN intravascular swarming and clustering in response to C. albicans.
• Investigated the role of complement activation and Leukotriene B4 (LTB4) in PMN behavior and capillaritis.
• Assessed the impact of LTB4 receptor blockade and pharmacological inhibition on fungal clearance and organ injury.

Main Results:

• PMNs swarm and cluster intravascularly in response to C. albicans, sequestering yeast to the endothelium.
• Complement-dependent PMN chemotaxis is essential for host survival.
• LTB4-mediated PMN clustering causes capillaritis, pulmonary hemorrhage, and hypoxemia, a phenomenon unique to fungi.
• Blocking LTB4 signaling attenuated capillaritis without impairing fungal phagocytosis or host survival.

Conclusions:

• PMN clustering, driven by LTB4, contributes significantly to organ injury during fungal sepsis.
• Targeting LTB4-mediated capillaritis represents a promising therapeutic approach.
• Disrupting PMN-induced capillaritis may limit organ damage without compromising essential host defense mechanisms against Candida albicans.