BackgroundSevere pneumonia (sCAP) remains a global health challenge with high mortality despite advances in antibiotic therapy and supportive care. Immunoglobulin (Ig) therapies, especially IgM-containing ones, have shown promise in enhancing host defence and reducing inflammation. The CIGMA trial highlighted trimodulin's potential to lower mortality of sCAP patients with high C-reactive protein and low IgM levels.MethodsWe investigated the protective effects of trimodulin on clinical status, bacterial burden, lung integrity, and inflammatory responses in murine models of lung injury, including both ventilator-induced lung injury (VILI) and infection-induced models with non-sterile inflammation.FindingsIn mice, trimodulin significantly protected against lethal pneumococcal pneumonia by reducing bacterial burden and disease severity while preserving alveolar barrier integrity and limiting lung edema. The antibacterial action of trimodulin was mediated through opsonophagocytosis, and its anti-inflammatory effects operated independently of the latter. When combined with ampicillin, trimodulin exhibited enhanced suppression of inflammation.InterpretationOur findings in preclinical pneumonia models suggest that trimodulin could be a promising therapy for sCAP patients. We provide evidence that trimodulin enhances host defence, reduces detrimental pulmonary inflammation and barrier dysfunction, and limits pulmonary edema, which may explain its beneficial effects observed in sCAP patients.

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