Hypoxic conditions modulate IL-12 and IFN-γ levels as prognostic markers in intracellular infections: a rat model...

Hypoxia modulates immune responses during intracellular infections, yet quantifiable cytokine thresholds for prognostication remain undefined in experimental models. The immunological basis of increased mortality when hypoxemia coexists with bacterial infection remains incompletely understood.

In a randomized study, 175 male Sprague-Dawley rats were stratified into seven groups combining normoxia (21.5% O₂), sub-lethal hypoxia (18% O₂) or lethal hypoxia (5% O₂, far below clinically sustainable human levels), with or without Mycobacterium tuberculosis H37Ra infection (10⁴ bacilli, intravenous). Serum IL-12 and IFN-γ were quantified by ELISA at Days 2, 4 and 17. Cytokine dynamics were analyzed by linear mixed-effects models with Kenward-Roger degrees of freedom and Tukey-adjusted post hoc contrasts; informative dropout was addressed by joint modelling of the cytokine trajectory and time-to-death. Prognostic performance was assessed by ROC analysis; thresholds are exploratory and lack external validation.

Infected animals showed 2-fold to 6-fold elevations in IL-12 and IFN-γ versus controls (p < 0.001). Lethal hypoxia was associated with impaired resolution, producing persistently elevated or biphasic trajectories by Day 17. A significant Infection × Hypoxia interaction was observed (IL-12 F = 8.92, p = 0.003; IFN-γ F = 11.34, p < 0.001). Combined lethal hypoxia and infection produced 66.7% mortality versus 53.3% (infection alone) and 23.3% (hypoxia alone); the Cox survival interaction was not significant (p = 0.11). Day 2 IFN-γ ≥ 82 pg/mL yielded moderate-to-good discrimination (AUC 0.79, 95% CI 0.73 to 0.85).

In this rat model, severe hypoxia with mycobacterial infection produced increased mortality and impaired cytokine resolution. Early serum IFN-γ and IL-12 offer exploratory prognostic thresholds requiring independent human validation.