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Background <p>Antimicrobial resistance has renewed interest in Phage therapy as an alternative or adjunct to antibiotics. However, immune responses to repeated phage exposure may influence treatment outcomes, and the impact of the route of administration on these responses remains incompletely understood. This study evaluated humoral and cytokine responses following repeated administration of a lytic phage cocktail in healthy rats through different parenteral routes.</p> Methods <p>A cocktail of four lytic phages targeting multidrug-resistant <i>Klebsiella pneumoniae</i> was administered repeatedly to healthy rats via the intraperitoneal (IP), intramuscular (IM), intravenous (IV), and subcutaneous (SC) routes. Humoral responses were assessed by measuring anti-phage immunoglobulins (IgM, IgG, and IgA) and neutralising antibodies, while systemic cytokines (TNF-α, IL-1β, IL-6, and IL-10) were quantified.</p> Results <p>Repeated phage administration elicited route-dependent humoral immune responses. Neutralising antibody levels peaked by day 14 in the IP, IM, and IV groups, reflecting early IgM responses. A second peak occurred after the seventh dose, administered 37 days later. The IP route triggered the strongest and sustained antibody response, particularly IgG, whereas responses following SC administration were weaker and delayed. IgA levels remained low across all routes. Cytokine analysis revealed only mild, transient fluctuations in TNF-α, IL-1β, IL-6, and IL-10, with no evidence of sustained systemic inflammatory activation. The observed cytokine profile warrants further investigation to determine whether the phage cocktail exerts anti-inflammatory effects.</p> Conclusions <p>Phage-induced immune responses may be route-dependent and complex. These findings enhance our understanding of host–phage interactions and underscore the need for further pharmacokinetic and immunological studies to assess their relevance to phage therapy.</p>

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Preclinical evaluation of route-dependent immune responses following repeated administration of a Klebsiella pneumoniae lytic phage cocktail in rats

  • 期刊论文

  • 发表日期：

    2026年7月10日

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  • Sonam Rastogi,
  • Mayank Gangwar,
  • Sudhir Kumar Singh,
  • Alka Shukla,
  • Digvijay Singh,
  • Vandana Rastogi,
  • Deepak Kumar,
  • Pooja Sachdeva,
  • Gopal Nath

摘要

Background

Antimicrobial resistance has renewed interest in Phage therapy as an alternative or adjunct to antibiotics. However, immune responses to repeated phage exposure may influence treatment outcomes, and the impact of the route of administration on these responses remains incompletely understood. This study evaluated humoral and cytokine responses following repeated administration of a lytic phage cocktail in healthy rats through different parenteral routes.

Methods

A cocktail of four lytic phages targeting multidrug-resistant Klebsiella pneumoniae was administered repeatedly to healthy rats via the intraperitoneal (IP), intramuscular (IM), intravenous (IV), and subcutaneous (SC) routes. Humoral responses were assessed by measuring anti-phage immunoglobulins (IgM, IgG, and IgA) and neutralising antibodies, while systemic cytokines (TNF-α, IL-1β, IL-6, and IL-10) were quantified.

Results

Repeated phage administration elicited route-dependent humoral immune responses. Neutralising antibody levels peaked by day 14 in the IP, IM, and IV groups, reflecting early IgM responses. A second peak occurred after the seventh dose, administered 37 days later. The IP route triggered the strongest and sustained antibody response, particularly IgG, whereas responses following SC administration were weaker and delayed. IgA levels remained low across all routes. Cytokine analysis revealed only mild, transient fluctuations in TNF-α, IL-1β, IL-6, and IL-10, with no evidence of sustained systemic inflammatory activation. The observed cytokine profile warrants further investigation to determine whether the phage cocktail exerts anti-inflammatory effects.

Conclusions

Phage-induced immune responses may be route-dependent and complex. These findings enhance our understanding of host–phage interactions and underscore the need for further pharmacokinetic and immunological studies to assess their relevance to phage therapy.