Fungal dissemination is limited by liver macrophage filtration of the blood

Abstract

Fungal dissemination into the bloodstream is a critical step leading to invasive fungal infections. Here, using intravital imaging, we show that Kupffer cells (KCs) in the liver have a prominent function in the capture of circulating Cryptococcus neoformans and Candida albicans, thereby reducing fungal dissemination to target organs. Complement C3 but not C5, and complement receptor CRIg but not CR3, are involved in capture of C. neoformans. Internalization of C. neoformans by KCs is subsequently mediated by multiple receptors, including CR3, CRIg, and scavenger receptors, which work synergistically along with C5aR signaling. Following phagocytosis, the growth of C. neoformans is inhibited by KCs in an IFN-γ independent manner. Thus, the liver filters disseminating fungi from circulation via KCs, providing a mechanistic explanation for the enhanced risk of cryptococcosis among individuals with liver diseases, and suggesting a therapeutic strategy to prevent fungal dissemination through enhancing KC functions.

Mechanisms of Pathogenic Candida Species to Evade the Host Complement Attack

“…Deposition of iC3b facilitates recognition by complement receptor 3 (CR3), that enhances phagocytosis, reactive oxygen species (ROS) production, leukocyte trafficking, and migration of macrophages and neutrophils (Hostetter, 2008;Netea et al, 2008). Macrophages in the kidney and liver are also involved in the clearance of pathogenic fungi (Lionakis et al, 2013;Coelho and Drummond, 2019;Sun et al, 2019). CR3 activation also leads to enhanced NET formation and pro-and anti-inflammatory cytokine production by both neutrophils and macrophages (Löfgren et al, 1999;Huang et al, 2015;Lukácsi et al, 2017).…”

Live Imaging of Innate and Adaptive Immune Responses in the Liver

“…CRIg expression was largely restricted to tissue macrophages, particular in KCs (25,26). This expression profile correlates with the indispensable role of CRIg in KC-mediated immune clearance of various blood-borne microbial species, including parasites (27), fungi (28), and virus (29), all in a complement-dependent manner.…”

Cryptococcal infection in haematologic malignancies and haematopoietic stem cell transplantation

“…Moreover, Kupffer cells (macrophages residing in the liver) have been shown to have a protective effect. Using intravital imaging, a recent publication demonstrated that Kupffer cells have a function in clearing C neoformans and inhibiting its growth, thus reducing its spread to other organs 25 . Patients with liver disease, particularly cirrhosis, may have impaired Kupffer cell activity, providing a possible mechanism for the development of cryptococcosis in this specific patient population.…”