---
title: "Host-Directed Strategies to Remodel the Immune Microenvironment in Carbapenem-Resistant Klebsiella"
id: "pubmed-42700871"
canonical_url: "https://medichelpline.com/clinical-feed/pubmed-42700871"
content_type: "clinical_feed_article"
specialty: "Critical Care"
source_name: "PubMed / NCBI"
source_url: "https://pubmed.ncbi.nlm.nih.gov/42700871/"
doi: "10.1016/j.ijantimicag.2026.108000"
published_at: "2026-09-05T00:00:00.000Z"
evidence_level: "Journal Article"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Host-Directed Strategies to Remodel the Immune Microenvironment in Carbapenem-Resistant Klebsiella
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/pubmed-42700871
- **Specialty:** [Critical Care](https://medichelpline.com/clinical-feed/critical-care.md)
- **Primary Source:** PubMed / NCBI
- **Source URL:** [Original Journal Publication](https://pubmed.ncbi.nlm.nih.gov/42700871/)
- **DOI:** [10.1016/j.ijantimicag.2026.108000](https://doi.org/10.1016%2Fj.ijantimicag.2026.108000)
- **Published At:** 2026-09-05T00:00:00.000Z
- **Evidence Rating:** Journal Article
## Executive GIST (TL;DR)
- **Klebsiella pneumoniae** is a WHO priority pathogen, with treatment complicated by the emergence of carbapenem resistance and hypervirulent strains. - Pathogen-directed antibiotics are increasingly limited; **host-directed therapy (HDT)** offers an alternative that bypasses carbapenemase-mediated resistance by targeting host responses. - K. pneumoniae remodels the host immune microenvironment through four principal mechanisms: suppression of NF-κB/MAPK/interferon signaling; inhibition of inflammasome activation and oxidative-burst effectors; reprogramming macrophages into an intracellular **M(Kp)** sanctuary; and depletion of the lymphocyte compartment. - The authors map each immune-evasion node to candidate pharmacological agents and natural products, graded by the directness of available evidence. - Four interventions carry direct evidence in carbapenem-resistant or multidrug-resistant K. pneumoniae: recombinant **IL-22**, L-arginine supplementation, autophagy-inducing sensitization, and T-cell correction strategies. - Two deployment principles are emphasized: (1) HDT effects are largely **resistance-agnostic** regarding carbapenemases; (2) interventions are phase- and compartment-dependent and may be beneficial in one context but harmful in another. - Most mapped claims rely on data from K. pneumoniae generally or are extrapolated from sepsis and oncology; only four nodes have direct evidence using resistant isolates, so the map is hypothesis-generating rather than a validated clinical algorithm. - Key caveats include: hypervirulent carbapenem-resistant K. pneumoniae (CRKP) can repress **autophagy**, reversing benefits seen in non-hypervirulent isolates; many natural products promote M2 macrophage polarization, which could favor persistence; and concurrent antibiotics can antagonize microbiota-restoring interventions, supporting the need for sequential strategies. - Biomarkers with preliminary stratification value include mHLA-DR and the neutrophil-to-lymphocyte ratio for immunoparalysis, and an inverted CD4/CD8 ratio documented in CRKP cohorts; integration into a continuous, multi-marker intervention-window score remains unvalidated. - The authors convert remaining evidence gaps into a structured research agenda aimed at validating and prioritizing HDT approaches against CRKP.
## Clinical Analysis & Structured Key Points
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Online ahead of print. # Remodeling the Host Immune Microenvironment in Carbapenem-Resistant Klebsiella pneumoniae: An Evidence-Graded Framework for Host-Directed Intervention [Xiaolin Liang](https://pubmed.ncbi.nlm.nih.gov/?term=Liang+X&cauthor_id=42700871)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42700871/#full-view-affiliation-1 "Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.; Department of Pharmacy, Southern Medical University Shenzhen Hospital, Shenzhen 518000, People's Republic of China."), [Junwei Wang](https://pubmed.ncbi.nlm.nih.gov/?term=Wang+J&cauthor_id=42700871)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42700871/#full-view-affiliation-2 "Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, People's Republic of China."), [Chao Liu](https://pubmed.ncbi.nlm.nih.gov/?term=Liu+C&cauthor_id=42700871)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42700871/#full-view-affiliation-3 "Department of Pharmacy, Huangshi Central Hospital, Huangshi 435002, People's Republic of China."), [Qingyuan Gao](https://pubmed.ncbi.nlm.nih.gov/?term=Gao+Q&cauthor_id=42700871)[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42700871/#full-view-affiliation-4 "Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China."), [Xiaoxia Gu](https://pubmed.ncbi.nlm.nih.gov/?term=Gu+X&cauthor_id=42700871)[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42700871/#full-view-affiliation-4 "Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China."), [Weiguang Sun](https://pubmed.ncbi.nlm.nih.gov/?term=Sun+W&cauthor_id=42700871)[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42700871/#full-view-affiliation-4 "Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China."), [Yan He](https://pubmed.ncbi.nlm.nih.gov/?term=He+Y&cauthor_id=42700871)[ 5 ](https://pubmed.ncbi.nlm.nih.gov/42700871/#full-view-affiliation-5 "Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.; Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.. Electronic address: heyan_may@hotmail.com.") Affiliations Expand ### Affiliations * 1 Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.; Department of Pharmacy, Southern Medical University Shenzhen Hospital, Shenzhen 518000, People's Republic of China. * 2 Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, People's Republic of China. * 3 Department of Pharmacy, Huangshi Central Hospital, Huangshi 435002, People's Republic of China. * 4 Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China. * 5 Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.; Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.. Electronic address: heyan_may@hotmail.com. * PMID: **42700871** * DOI: [ 10.1016/j.ijantimicag.2026.108000 ](https://doi.org/10.1016/j.ijantimicag.2026.108000) Item in Clipboard # Remodeling the Host Immune Microenvironment in Carbapenem-Resistant Klebsiella pneumoniae: An Evidence-Graded Framework for Host-Directed Intervention Xiaolin Liang et al. Int J Antimicrob Agents. 2026. Show details Display options Display options Format Abstract PubMed PMID Int J Antimicrob Agents Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Int+J+Antimicrob+Agents%22%5Bjour%5D&sort=date&sort_order=desc) * [ Search in NLM Catalog ](https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22Int+J+Antimicrob+Agents%22%5BTitle+Abbreviation%5D) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42700871/) . 2026 Sep 5:108000. doi: 10.1016/j.ijantimicag.2026.108000. Online ahead of print. ### Authors [Xiaolin Liang](https://pubmed.ncbi.nlm.nih.gov/?term=Liang+X&cauthor_id=42700871)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42700871/#short-view-affiliation-1 "Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.; Department of Pharmacy, Southern Medical University Shenzhen Hospital, Shenzhen 518000, People's Republic of China."), [Junwei Wang](https://pubmed.ncbi.nlm.nih.gov/?term=Wang+J&cauthor_id=42700871)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42700871/#short-view-affiliation-2 "Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, People's Republic of China."), [Chao Liu](https://pubmed.ncbi.nlm.nih.gov/?term=Liu+C&cauthor_id=42700871)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42700871/#short-view-affiliation-3 "Department of Pharmacy, Huangshi Central Hospital, Huangshi 435002, People's Republic of China."), [Qingyuan Gao](https://pubmed.ncbi.nlm.nih.gov/?term=Gao+Q&cauthor_id=42700871)[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42700871/#short-view-affiliation-4 "Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China."), [Xiaoxia Gu](https://pubmed.ncbi.nlm.nih.gov/?term=Gu+X&cauthor_id=42700871)[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42700871/#short-view-affiliation-4 "Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China."), [Weiguang Sun](https://pubmed.ncbi.nlm.nih.gov/?term=Sun+W&cauthor_id=42700871)[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42700871/#short-view-affiliation-4 "Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China."), [Yan He](https://pubmed.ncbi.nlm.nih.gov/?term=He+Y&cauthor_id=42700871)[ 5 ](https://pubmed.ncbi.nlm.nih.gov/42700871/#short-view-affiliation-5 "Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.; Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.. Electronic address: heyan_may@hotmail.com.") ### Affiliations * 1 Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.; Department of Pharmacy, Southern Medical University Shenzhen Hospital, Shenzhen 518000, People's Republic of China. * 2 Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, People's Republic of China. * 3 Department of Pharmacy, Huangshi Central Hospital, Huangshi 435002, People's Republic of China. * 4 Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China. * 5 Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.; Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.. Electronic address: heyan_may@hotmail.com. * PMID: **42700871** * DOI: [ 10.1016/j.ijantimicag.2026.108000 ](https://doi.org/10.1016/j.ijantimicag.2026.108000) Item in Clipboard Cite Display options Display options Format Abstract PubMed PMID ## Abstract 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. **Keywords:** IL-22; Klebsiella pneumoniae; carbapenem resistance; host-directed therapy; immune microenvironment; macrophage polarization; natural products; tissue-resident memory T cells. Copyright © 2026 The Author(s). Published by Elsevier Ltd.. All rights reserved. [PubMed Disclaimer](https://pubmed.ncbi.nlm.nih.gov/disclaimer/) ## Conflict of interest statement Declaration of competing interest The authors declare no competing interests. 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