Raw and analyzed data used in Figs 1–5.

Respiratory infections are among the leading causes of illness and death. The lack or limited effectiveness of vaccines for many respiratory pathogens underscores the urgent need for alternative, broadly protective strategies. While adaptive immunity is commonly used in vaccine development, the therapeutic potential of activating and enhancing innate immunity remains underutilized. Innate immune–focused interventions could offer rapid, pathogen-independent protection, bridging the gap until pathogen-specific responses develop. Therefore, exploring new broad-spectrum innate immune-targeting immunomodulatory agents can be an effective way to prevent and treat respiratory infections. Heat-killed Caulobacter crescentus (HKCC) is a potential innate immune modulator. We tested its preventive and therapeutic effects against key respiratory bacterial (Mycobacterium avium, Mav) and viral (SARS-CoV-2 and influenza) infections in animal models. Notably, intranasal or oral treatment with HKCC significantly lowered bacterial loads in mice infected with Mav, while activating mucosal innate immune responses and enhancing downstream cellular and antibody responses. Additionally, decreased viral loads and improved pathogenesis were seen in mice and hamsters infected with influenza and SARS-CoV-2, respectively. HKCC showed promising ability to induce strong, localized, and systemic immunity, making it a compelling candidate for developing as a human preventive or adjunct therapy for multiple respiratory diseases.