# Host-directed broad-spectrum immunotherapeutic strategy for respiratory infections: Heat-killed Caulobacter crescentus (HKCC) as an innate-immune based biotherapeutic/postbiotic

## TL;DR

Heat-killed Caulobacter crescentus boosts the body's innate immune response to fight respiratory infections caused by bacteria and viruses.

## Contribution

HKCC is shown to be a novel, broad-spectrum innate immune modulator effective against multiple respiratory pathogens.

## Key findings

- HKCC reduced bacterial loads in mice infected with Mycobacterium avium and activated mucosal innate immune responses.
- HKCC decreased viral loads and improved disease outcomes in influenza and SARS-CoV-2 animal models.
- HKCC stimulated strong systemic and localized immunity, including enhanced antibody production.

## Abstract

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.

Respiratory infectious diseases, including major threats like mycobacteria, influenza, and SARS-CoV-2, remain a significant global public health concern. While our body’s initial defense system at the site of entry of these pathogens—the mucosal innate immune response—is key to quickly clearing or lessening early infections, we currently lack effective and safe therapeutic candidates that modulate these innate responses. Consequently, new and comprehensive preventive or therapeutic tools are necessary to control these respiratory infections. Our research has shown that inactivated, non-pathogenic Caulobacter crescentus, delivered through nose or mouth (mucosally), functions effectively as an innate immune modulator. In preclinical models, it effectively boosts key immune players (including innate lymphoid cells and neutrophils), enhances their function, and stimulates robust antibody production. Crucially, this immune activation led to promising reductions in both bacterial and viral loads and resulted in significantly milder disease progression. In summary, prompt use of heat-killed C. crescentus offers an effective, ready-to-use strategy to enhance the body’s primary defenses against a broad range of bacterial and viral respiratory pathogens. It is a highly viable candidate for translation into future human clinical trials.