Monocyte inflammation and adaptive immune dysfunction in severe Klebsiella pneumoniae pneumonia

Severe Klebsiella pneumoniae pneumonia is associated with substantial mortality and is characterized by intense systemic inflammation that coexists with a failure to control infection. The cellular changes underlying the transition from effective host defense to immune dysfunction remain incompletely defined. Here, we constructed a severity-focused single-cell transcriptomic atlas of 708,894 peripheral blood mononuclear cells from 100 individuals (54 healthy controls, 23 patients with mild disease, and 23 patients with severe disease), complemented by plasma protein measurements and flow cytometry. Mild disease was characterized by a relatively coordinated peripheral immune response, with preserved monocyte regulatory and tissue-repair programs, preserved cytotoxic lymphocyte activity, and coordinated interactions between T follicular helper cells and B cells. Severe disease showed marked monocyte inflammation together with widespread disruption of adaptive immune responses. Classical monocytes expanded and showed increased expression of S100A8/A9/A12 , accompanied by enhanced TLR4–MYD88 signaling and elevated plasma S100 proteins. These changes were accompanied by impaired dendritic cell antigen presentation, expansion of immunoregulatory monocyte states resembling monocytic myeloid-derived suppressor cells, cytotoxicity- and exhaustion-associated changes in CD8 + T cells and natural killer cells, hyperactivated yet poorly coordinated CD4 + T cell states, and weaker B cell receptor signaling despite plasma cell expansion. These findings delineate a severity-associated peripheral immune state characterized by monocyte-centered inflammatory signatures and features of altered adaptive immune coordination, and provide a basis for future mechanistic investigation of monocyte-derived S100 alarmins and severity-associated myeloid remodeling. Graphical Severe Klebsiella pneumoniae pneumonia combines intense inflammation with failure to control infection, yet the cellular basis is unclear. Using a severity-focused single-cell atlas of 708,894 peripheral blood mononuclear cells from 100 individuals, complemented by plasma protein measurements and flow cytometry, we show that disease severity redirects rather than simply amplifies systemic immunity. Mild disease preserves coordinated host defense: immune-regulatory and tissue-reparative monocytes, intact cytotoxic lymphocytes, and T follicular helper–B cell coordination. Severe disease is characterized by S100A8/A9/A12 -high inflammatory monocytes with enhanced TLR4–MYD88 signaling, expansion of monocytic myeloid-derived suppressor cell-like states, and impaired dendritic cell antigen presentation. These myeloid changes accompany dysfunctional CD4 + T cells, cytotoxicity- and exhaustion-associated CD8/NK cells, and weakened expression of B cell receptor signaling-related genes despite plasma cell accumulation. Severe disease is characterized by a systemic pattern of impaired immune coordination, highlighting monocyte-derived S100 alarmins as candidates for future mechanistic and therapeutic investigation. Highlights Klebsiella pneumoniae pneumonia severity maps to distinct peripheral immune states, with relatively coordinated responses in mild disease and altered immune coordination in severe disease. S100A8/A9/A12 -high classical monocytes characterize the inflammatory landscape of severe disease. Severe disease features immunoregulatory monocyte expansion and reduced dendritic cell antigen presentation programs. CD8/NK and CD4 + T cell remodeling accompanies altered adaptive immune coordination in severe disease.