# Phage PM16 Therapy Induce Long-Term Protective Immunity Against Proteus mirabilis via Macrophage Priming

## TL;DR

Phage PM16 therapy not only fights Proteus mirabilis infection but also boosts long-term immunity by activating macrophages.

## Contribution

Phage PM16 primes macrophages to enhance adaptive immunity and long-term protection against bacterial reinfection.

## Key findings

- PM16 phage therapy controls Proteus mirabilis infection and induces long-term humoral immunity in mice.
- PM16 activates macrophages to produce proinflammatory cytokines and improves bactericidal activity against P. mirabilis.
- The phage primes innate immune cells, leading to better bacterial clearance and immunological memory formation.

## Abstract

Bacteriophages, traditionally viewed solely as antibacterial agents, are increasingly being studied for their immunomodulatory properties. In this study, we demonstrate that PM16 phage therapy not only effectively controls subcutaneous Proteus mirabilis infection in mice but also induces long-term specific humoral immunity against subsequent reinfection. This immunomodulatory effect was dose-dependent. In vitro, PM16 directly activates macrophages, leading to increased production of proinflammatory cytokines (tumor necrosis factor-α and interleukin-1β) and inducible nitric oxide synthase, and enhances macrophage bactericidal activity against P. mirabilis. We assume that the enhancement of the adaptive immune response is mediated not by the phage acting as a classical antigenic adjuvant but by its ability to prime innate immune cells, specifically macrophages. This priming leads to more efficient bacterial clearance, antigen presentation, and the formation of protective immunological memory.