Mucosal administration of an immunotherapy provides long-term protection against a bacterial respiratory infection

Abstract

Introduction

Acute and chronic respiratory infections are one of the first causes of death worldwide, especially for young children and elderly people. Their threat on human health has significantly increased over the last few years, due to the emergence of new viruses and the increase of antimicrobial multi-resistant strains of bacteria. Therapeutic antibodies (Ab) have proven their efficacy in infection prevention and control. Their administration inside the airways, rather than through parenteral route, allows to potentiate their therapeutic index against respiratory infections. The mode of action of anti-infectious Ab relies mainly on direct neutralization of the pathogen, and the recruitment of effectors immune cells facilitating its elimination. However, some studies suggest an immunomodulator role of therapeutic antibodies. Thus, this project aimed at making a proof-of-concept of mAb-mediated long-term immune protection after mucosal administration during a pulmonary bacterial infection and deciphering the mechanisms underlying this effect.

Methods

We used a mouse model of Pseudomonas aeruginosa (P. aeruginosa) lung infection, resembling to human acute pneumonia. The primary infection was treated using a neutralizing anti-P. aeruginosa mAb delivered through the airways. To investigate long-term protection, mice surviving primary infection were challenged a month later, at a time when circulating/local mAb had disappeared, once again with P. aeruginosa. Local and systemic humoral and cellular immune responses were analyzed thereafter.

Results

Thanks to the, previously presented, model, we have shown that beyond a rapid and efficient containment of a lethal primo infection, an antibacterial Ab, administered in the airways, can interact with the mucosal immune system to develop a long-term immunity, protecting against a secondary infection. Results obtained in vitro and in vivo indicate an essential contribution of immune complexes, formed between the bacteria and the antibody, in the induction of an antibacterial humoral response. This humoral response, persistent, is protective against the pathogenic bacteria. The long-term immunity thus seems to be dependent on both the amount of immune complexes, but also the presence of a local inflammation during the primo infection. Interestingly, the long-term immune response also offers a partial protection against a secondary infection by a heterologous strain of P. aeruginosa.

Conclusion

Complementary studies will be needed to identify all cellular and molecular actors implicated in this long-term protection. Nevertheless, our results suggest that a mucosal administration of an Ab enables the neutralization of a bacterial infection and ensures a long-term protection against a reinfection. This immunomodulatory characteristic of inhaled antibacterial Ab opens new perspectives for the treatment of respiratory infections.