Interaction of the CD43 Sialomucin with the Mycobacterium tuberculosis Cpn60.2 Chaperonin Leads to Tumor Necrosis Factor Alpha Production

Abstract

Mycobacterium tuberculosis is the causal agent of tuberculosis. Tumor necrosis factor alpha (TNF-␣), transforming growth factor ␤ (TGF-␤), and gamma interferon (IFN-␥) secreted by activated macrophages and lymphocytes are considered essential to contain Mycobacterium tuberculosis infection. The CD43 sialomucin has been reported to act as a receptor for bacilli through its interaction with the chaperonin Cpn60.2, facilitating mycobacterium-macrophage contact. We report here that Cpn60.2 induces both human THP-1 cells and mouse-derived bone marrow-derived macrophages (BMMs) to produce TNF-␣ and that this production is CD43 dependent. In addition, we present evidence that the signaling pathway leading to TNF-␣ production upon interaction with Cpn60.2 requires active Src family kinases, phospholipase C-␥ (PLC-␥), phosphatidylinositol 3-kinase (PI3K), p38, and Jun N-terminal protein kinase (JNK), both in BMMs and in THP-1 cells. Our data highlight the role of CD43 and Cpn60.2 in TNF-␣ production and underscore an important role for CD43 in the host-mycobacterium interaction.

Caloric Restriction Promotes Immunometabolic Reprogramming Leading to Protection from Tuberculosis

“…Supervised hierarchical clustering analysis confirmed that a plethora of genes linked to the immune response were upregulated in both CR and AL mice upon MTB infection, but this upregulation was significantly more prominent in CR versus AL MTB-infected spleens, suggesting a CR-dependent increase of the immune-related splenic transcriptional response to MTB (Figures S4D and S4E). Examples of genes important for antimycobacterial host defense found upregulated in CR mice are colony-stimulating factor 1 (Csf1; Sariko et al, 2018); interleukin receptors (Il1rl1, Il2rb, Il12rb1, Il18r1, and Il23r) (Keegan et al, 2018;Zun ˜iga et al, 2012); surface markers of T cells and co-stimulatory molecules (Cd3, Cd4, and Cd28); T cell receptor-associated kinases (Zap70 and Lck); IFN-g and its receptor (Jasenosky et al, 2015);Thy1, Jack3, Stat members, and Spn (Sialophorin;Torres-Huerta et al, 2017); Zbp1 (Z-DNA-binding protein 1; Stutz et al, 2018); members of the guanylate-binding protein family (gbp 2,4,5,6,7,8,9,10,11;Tretina et al, 2019); and T cell-specific guanine nucleotide triphosphate-binding proteins (Tgtp1 and Tgtp2) (Figures 5D, S4D, and S4E; Table S2) (Rodrı ´guez-Contreras et al, 2002). During MTB infection, CR, compared to AL, also induced Irgm2 (immunity-related GTPase family M member 2), known to regulate autophagy in response to intracellular pathogens and already associated with susceptibility to MTB (Zhao et al, 2010); C-C motif chemokine receptor (Ccr5); C-X-C motif chemokine receptors (Cxcr3 and 6); and the associated C-X-C motif chemokine ligand 9 (Cxcl9) (Figures 5D, S4D, and S4E) (Domingo-Gonzalez et al, 2016).…”

Correlation of the expression of tumor necrosis factor-alpha in chronic periapical lesions with the expression of bacterial chaperonin 60

“…Literature data indicate that bacterial heat shock protein (GroEL, Cpn60), originating from different bacteria, induces the expression of cytokines in cells of the host's immune system 30,31 . It is known that chaperonin Cpn60 from Mycobacterium tuberculosis induce production of TNF-α in human monocyte cell line, THP-1 32,33 . TNF-α is a mediator of osteoclastic activity in states of inflammatory osteolysis such as periapical lesion 34 .…”

Negative Regulation of Autophagy during Macrophage Infection by Mycobacterium bovis BCG via Protein Kinase C Activation

“…Within the alveolar region of the lungs, Mtb interacts with various receptors expressed on the plasma membranes of phagocytic cells, initiating its internalization [ 2 ]. This internalization process relies on diverse receptors, including CD43 [ 3 , 4 ], the Dectin-1 receptor [ 5 ], the mannose receptor, scavenger receptor, CD14, pulmonary surfactant protein A, and complement receptors, among others (reviewed in [ 6 ]). Notably, studies using mice lacking some of these receptors have demonstrated that they are not indispensable for mycobacterial invasion of macrophages [ 7 ].…”