Remodeling the Host Immune Microenvironment in Carbapenem-Resistant Klebsiella pneumoniae: An Evidence-Graded Framework for Host-Directed Intervention.

Klebsiella pneumoniae ranks at the top of the WHO priority pathogen list. The convergence of carbapenem resistance with hypervirulence is exhausting pathogen-directed therapy. Host-directed therapy (HDT) offers a structural alternative: because it acts on host targets, it is largely indifferent to the carbapenemases that confer resistance. K. pneumoniae remodels the host immune microenvironment through four mechanisms: suppressing NF-κB/MAPK/interferon signaling, blunting inflammasome and oxidative-burst effectors, reprogramming macrophages into the intracellular M(Kp) sanctuary, and depleting the lymphocyte compartment. These are now well characterized; their therapeutic corollary has not been assembled. We map each evasion node onto pharmacological agents and natural products, graded by evidence directness. Four strategies carry direct evidence in carbapenem-resistant or multidrug-resistant K. pneumoniae: recombinant IL-22, L-arginine, autophagy-inducing sensitization, and T-cell correction. Two principles govern deployment: resistance-agnostic efficacy against carbapenemases, and a directional, phase-dependent hazard, whereby modulators can help in one phase or compartment and harm in another. Most claims remain graded as K. pneumoniae (not necessarily resistant) or extrapolated from sepsis/oncology, with only four nodes directly evidenced in resistant isolates; this is a hypothesis-generating map, not a validated algorithm. Key caveats: hypervirulent CRKP represses autophagy, potentially reversing agonists validated only in non-hypervirulent isolates; most natural products favor M2 polarization that may reinforce persistence; and antibiotics antagonize microbiota-restoring interventions, requiring sequential use. Individual biomarkers already carry preliminary clinical stratification value: mHLA-DR and the neutrophil-to-lymphocyte ratio have validated thresholds for immunoparalysis, and an inverted CD4/CD8 ratio is documented in CRKP cohorts; what remains unvalidated is their integration into a continuous, multi-marker intervention-window score. We convert residual gaps into a structured research agenda.