Remodelling the host immune microenvironment in carbapenem-resistant Klebsiella pneumoniae: An evidence-graded...

Klebsiella pneumoniae tops the WHO priority pathogen list, and the convergence of carbapenem resistance with hypervirulence is exhausting pathogen-directed therapy. Host-directed therapy (HDT) acts on host targets and is therefore largely indifferent to carbapenemases. The mechanisms by which K. pneumoniae remodels the host immune microenvironment are now well characterised, but their therapeutic corollary has not been assembled. We aimed to map each evasion node onto host-directed interventions and grade the supporting evidence.

Four evasion mechanisms were mapped: suppression of NF-κB/MAPK/interferon signalling, blunting of inflammasome and oxidative-burst effectors, reprogramming of macrophages into the intracellular M(Kp) sanctuary, and depletion of the lymphocyte compartment. Each node was matched to 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 sensitisation, and T-cell correction. Most other claims are graded as K. pneumoniae (not necessarily resistant) or extrapolated from sepsis/oncology. 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. Key caveats: hypervirulent CRKP represses autophagy, potentially reversing agonists validated only in nonhypervirulent isolates; most natural products favour M2 polarisation that may reinforce persistence; and antibiotics antagonise microbiota-restoring interventions, requiring sequential use. mHLA-DR and the neutrophil-to-lymphocyte ratio have validated thresholds for immunoparalysis, and an inverted CD4/CD8 ratio is documented in CRKP cohorts.

This is a hypothesis-generating map, not a validated algorithm; only four nodes are directly evidenced in resistant isolates. Integration of the above biomarkers into a continuous, multi-marker intervention-window score remains unvalidated. We convert residual gaps into a structured research agenda.