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Bloodstream infection (BSI) refers to the infection of blood by pathogens. Severe immune response to BSI can lead to sepsis, a systemic infection leading to multiple organ dysfunction, coupled with drug resistance, mortality, and limited clinical treatment options. This work aims to further investigate the new interplay between bacterial exocrine regulatory protein and host immune cells in the context of highly drug-resistant malignant BSI. Whether interfering with related regulatory signaling pathways can reverse the inflammatory disorder of immune cells. In-depth analysis of single-cell sequencing results in Septic patients for potential immunodeficiency factors. Analysis of key proteins enriched by host cells and key pathways using proteomics. Cell models and animal models validate the pathological effects of DnaK on T cells, MAITs, macrophages, and osteoclasts. The blood of patients was analyzed for the immunosuppression of T cells and MAITs. We identified that S. maltophilia -DnaK was enriched in immunodeficient T cells. The activation of the JAK2/STAT1 axis initiated the exhaustion of T cells. Septic patients with Gram-negative bacterial infections exhibited deficiencies in MAITs, which correspond to IFN-γ. Cellular and animal experiments confirmed that DnaK could facilitate MAIT depletion and M1 polarization of macrophages. Additionally, Fludarabine mitigated M1 polarization of blood, liver, and spleen in mice. Interestingly, DnaK also repressed osteoclastogenesis of macrophages stimulated by RANKL. S.maltophilia -DnaK prompts the activation of the JAK2/STAT1 axis in T cells and the M1 polarization of macrophages. Targeting the DnaK's crosstalk can be a potentially effective approach for treating the inflammatory disorder in the broad-spectrum drug-resistant BSI. [Display omitted] • The mechanism of S. maltophilia -DnaK in the immune interaction between T cells and macrophages during bloodstream infection. • The exocrine of S. maltophilia promotes the activation of the JAK2/STAT1 axis in T lymphocytes and initiates the process of apoptosis. • Septic patients infected with Gram-negative bacteria have quantitative and functional deficits in MAIT in peripheral blood, which correlated with IFN-γ concentrations. • DnaK can promote MAIT depletion and macrophage M1 polarization. Fludarabine attenuates M1 polarization in peripheral blood, liver, and spleen macrophages in mice with S. maltophilia bloodstream infection. Interestingly, DnaK inhibits osteoclastogenesis. [ABSTRACT FROM AUTHOR]