Bruton's Tyrosine Kinase (BTK) and Vav1 Contribute to Dectin1-Dependent Phagocytosis of Candida albicans in Macrophages

Abstract

Phagocytosis of the opportunistic fungal pathogen Candida albicans by cells of the innate immune system is vital to prevent infection. Dectin-1 is the major phagocytic receptor involved in anti-fungal immunity. We identify two new interacting proteins of Dectin-1 in macrophages, Bruton's Tyrosine Kinase (BTK) and Vav1. BTK and Vav1 are recruited to phagocytic cups containing C. albicans yeasts or hyphae but are absent from mature phagosomes. BTK and Vav1 localize to cuff regions surrounding the hyphae, while Dectin-1 lines the full length of the phagosome. BTK and Vav1 colocalize with the lipid PI(3,4,5)P3 and F-actin at the phagocytic cup, but not with diacylglycerol (DAG) which marks more mature phagosomal membranes. Using a selective BTK inhibitor, we show that BTK contributes to DAG synthesis at the phagocytic cup and the subsequent recruitment of PKCε. BTK- or Vav1-deficient peritoneal macrophages display a defect in both zymosan and C. albicans phagocytosis. Bone marrow-derived macrophages that lack BTK or Vav1 show reduced uptake of C. albicans, comparable to Dectin1-deficient cells. BTK- or Vav1-deficient mice are more susceptible to systemic C. albicans infection than wild type mice. This work identifies an important role for BTK and Vav1 in immune responses against C. albicans.

The Bruton tyrosine kinase inhibitor ibrutinib abrogates triggering receptor on myeloid cells 1-mediated neutrophil activation

“…Therefore, this might reflect the fact that BTK is also involved in the TLR and Dectin-1 signaling pathways. 12,13 However, in contrast to this, the TREM-1-mediated oxidative burst and CD62L shedding were strongly suppressed in PMNs from ibrutinib-treated patients, while TREM-1 ligation in PMNs from healthy donors was unaffected in both effector assays. Our data should be interpreted with caution as to the clinical significance of these findings since we have not controlled for patient individual variability of the assays, having analyzed PMN functions pre and post dosing of ibrutinib only in one patient ( Figure 2E).…”

Immunity against fungi

“…In otherwise nonphagocytic cells, dectin-1 expression promotes phagocytosis of nonopsonized β-glucan particles (5, 9). Bruton's tyrosine kinase (BTK) and VAV-1 interact with dectin-1 in macrophages during C. albicans phagocytosis, a process impaired by genetic loss of either protein (41). Dectin-1/SYK/ CARD9 signaling in NADPH oxidase activity is controversial, as dectin-1-dependent (24) and -independent (42) control of β2 integrin (CD18) activation and the respiratory burst have been reported in vitro.…”

Innate immune cell response uponCandida albicansinfection

“…107 Recently, BTK (Bruton's Tyrosine Kinase) and Vav1, 2 new interactors localized to the Candida-containing phagocytic cup, are found to contribute to dectin-1-mediated phagocytosis in macrophages. 108 Although dectin-1 signals are sufficient to trigger phagocytosis, collaboration with TLR2 signals does help up-regulate NF-kB responses and cytokine production (IL-6, TNF-a). The recognition signal of dectin-1, transferred through its ITAM-like motif, usually results in the activation of Src and Syk, and the release of IL-2, IL-10 and IL-1b in macrophages.…”