Pathogenic microbes utilize virulence strategies to subvert host immune responses, highlighting a continuous race between the pathogen and the host. The emergence of multidrug- resistant and hypervirulent strains of Klebsiella pneumoniae (Kp) poses a critical threat to public health. This critical evaluation identifies key gaps in understanding the interplay between Kp and host innate immunity. This review provides a comprehensive overview of the mechanisms by which Kp triggers various forms of cell death. Dysregulated cell death may exacerbate cytokine release, contributing to the hyperinflammatory response characteristic of sepsis. The rise in antimicrobial resistance (AMR) in Kp necessitates the exploration of alternative therapeutic approaches. This review highlights that immunomodulatory approaches targeting cell death regulators or immune checkpoints may offer host-directed strategies against Kp-induced sepsis. Although novel immunotherapies offer potential to restore immune balance, their clinical applicability remains constrained by limited translational evidence.

Mycobacterium tuberculosis (Mtb) continues to pose a significant global health risk, primarily due to its capacity to modulate host immune responses and achieve prolonged persistence. Recent evidence has increasingly underscored the significance of epigenetic reprogramming as a principal mechanism through which Mtb modifies host cellular functions without altering the fundamental DNA sequence. This review gives a full picture of how Mtb secretory proteins work as nucleomodulins to directly target host chromatin and control gene expression. Mtb uses special secretion systems, such as the ESX (Type VII) and SecA2 pathways, to enable effector proteins to enter host cells. Some of these proteins move to the nucleus and interact with machinery that is linked to chromatin. These nucleomodulins facilitate various epigenetic modifications, encompassing non-canonical histone methylation, DNA methylation, and the modulation of histone acetylation, resulting in extensive transcriptional reprogramming of immune-related genes. These changes make important host defence mechanisms less effective, such as macrophage activation, antigen presentation, cytokine production, and antimicrobial responses. This helps bacteria survive and avoid the immune system. Epigenetic remodeling also affects the polarization and metabolic states of macrophages, which further affect the progression of disease. The reversible characteristics of epigenetic modifications offer a significant prospect for host-targeted therapeutic strategies. Targeting enzymes such as histone deacetylases and DNA methyltransferases has shown potential in restoring immune function and enhancing bacterial clearance, particularly when used in combination with conventional anti-tubercular therapies. Even with these improvements, there are still big problems with fully understanding the functional diversity of Mtb secretory proteins and turning these discoveries into useful medical tools. In general, understanding how Mtb-secreted nucleomodulins and host epigenetic regulation interact is important for understanding how tuberculosis works and finding new ways to treat it.