3,3'-Diindolylmethane Improves the Viral Pneumonia Outcomes After Influenza and SARS-CoV-2 Infection in Animal Models

Influenza and SARS-CoV-2 are often associated with viral pneumonia, resulting from direct exposure of the virus to lung tissue. 3,3'-Diindolylmethane (DIM) is a naturally occurring substance with multi-target activity, including anti-inflammatory and epigenetic modulation. In this study, we evaluated the therapeutic efficacy in vivo of a DIM formulation with fish oil (Cesarox Epi) against influenza A (H1N1) infection in mice and against SARS-CoV-2 infection in Syrian hamsters. In a model of lethal influenza pneumonia induced by A/California/04/2009 (H1N1)pdm09 virus, we showed that 5 days' treatment with DIM Epi at 10, 20, and 60 mg/kg/day delayed the time to death, prevented body weight loss, and resulted in significant improvements in survival. DIM Epi tested in hamsters infected with SARS-CoV2 Dubrovka (Wuhan-like) strain at doses 50 and 100 mg/kg/day reduced clinical signs, weight loss, temperature elevation, and lung pathology. In both models of infections, treatment with DIM Epi did not significantly decrease viral titer in the animals' lungs. DIM Epi and Oseltamivir were more effective against influenza infection when given in combination than given singly, while co-administration of DIM Epi with Molnupiravir did not yield an additive benefit against SARS-CoV-2 infection. These findings support DIM Epi as a promising host-directed adjunct therapy for viral pneumonia with potential to enhance outcomes in respiratory infections.