Protein Kinase C - delta (PKC-δ): a critical hub for immunomodulatory functions in macrophages during Mycobacterium tuberculosis infection

Hazra, Rudranil

Protein Kinase C - delta (PKC-δ): a critical hub for immunomodulatory functions in macrophages during Mycobacterium tuberculosis infection

Doctoral Thesis

2023

Abstract

Tuberculosis (TB) has reached epidemic levels and emerged as the second deadliest infectious disease globally after CoVID-19. By evolving the ability to evade host defense via intrinsic mechanisms, Mycobacterium tuberculosis (Mtb), the etiological agent of TB has been deleterious to human health and has necessitated novel therapeutic interventions, the primary notion to combat Mtb infection. Hence, the identification of host-modulating candidate genes involved in immune evasion and putative pathogen-killing pathways during Mtb infection is crucial. Additionally, macrophages are the first line of defense against Mtb infection through activating effector genes, which lead to pathogen killing and acquiring long-lasting immunity. One such candidate gene with potential novel therapeutic intervention, Protein Kinase C – δ (PKCδ) has been recognized as a critical marker with clinical and experimental evidence in recent years. An experimental mouse model of global PKCδ knockout (PKCδ-/- ) revealed mechanistic alterations enhancing the susceptibility to various infectious diseases including Mtb infection, suggesting a protective phenotype of PKCδ against invading pathogens. However, the macrophage-specific role of PKCδ during Mtb infection remains unknown and has not been delineated yet. Because the pulmonary microenvironment during Mtb infection is majorly governed by macrophages, initiating innate and skewing adaptive immune response, we have exploited the role of PKCδ in macrophages using the macrophage-specific PKCδ knockout mice (LysMcrePKCδflox/flox). Our success in characterizing this experimental murine strain has resulted in the establishment of an immunologically comparable PKCδ functional study platform, which has been adopted herein to investigate the immunomodulatory effects of Mtb infection in the ablation of PKCδ in macrophages. An early lymphocytic immune response increased neutrophil turnover, and reduced inflammatory macrophages are all accompanied by PKCδ deficiency in macrophages, which was abolished in the chronic stage of infection. Bonemarrow-derived macrophages from LysMcrePKCδflox/flox murine model further showed that the disease susceptibility is a consequence of an array of cellular intrinsic mechanisms and dysregulated proteome which are modulated by PKCδ. Furthermore, increased expression in bronchoalveolar lavage (BAL) samples from active TB patients and increased bacterial burden in PKCδ silenced human monocyte-derived macrophages with decreased pro-inflammatory cytokine response strongly signify PKCδ as a key hub for immunomodulatory functions during Mtb infection and a potential host-directed therapeutic (HDT) target against TB.

Keywords

Clinical Sciences and Immunology

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Collections

PhD / Doctoral

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