Ficolin-2 Defends against Virulent Mycobacteria Tuberculosis Infection In Vivo, and Its Insufficiency Is Associated with Infection in Humans

Abstract

Human ficolin-2 (ficolin-2/P35) is a lectin complement pathway activator that is present in normal human plasma and is associated with infectious diseases; however, little is known regarding the roles and mechanisms of ficolin-2 during Mycobacterium tuberculosis (Mtb) infection. Here, we describe our novel findings that the ficolin-2 serum levels of 107 pulmonary tuberculosis (TB) patients were much lower compared with 107 healthy controls. In vitro analysis showed that ficolin-2 bound to the virulent Mtb H37Rv strain much more strongly than to the non-virulent M. bovis BCG and M. smegmatis. Ficolin-2 bound to the surface glycolipid portion of H37Rv and blocked H37Rv infection in human lung A549 cells. Opsonophagocytosis was also promoted by ficolin-2. Importantly, we found that administration of exogenous ficolin-2 had a remarkable protective effect against virulent Mtb H37Rv infection in both C57BL/6J and BALB/c mice. Ficolin-A (a ficolin-2-like molecule in mouse) knockout mice exhibited increased susceptibility to H37Rv infection. We further demonstrated that ficolin-2 could defend against virulent Mtb H37Rv infection at least partially by activating JNK phosphorylation and stimulating the secretion of interferon (IFN)-γ, interleukin (IL)-17, IL-6, tumor necrosis factor (TNF)-α, and nitric oxide (NO) production by macrophages. Our data provide a new immunotherapeutic strategy against TB based on the innate immune molecule ficolin-2 and indicate that ficolin-2 insufficiency is associated with higher susceptibility to infection in humans.

Ficolins Promote Fungal Clearance in vivo and Modulate the Inflammatory Cytokine Response in Host Defense against <b><i>Aspergillus fumigatus</i></b>

“…Although ficolins have been identified as important pattern recognition molecules for bacterial and viral pathogens in vivo [20,24,25,26], their role in fungal infection has not been established. Prior work from our research group has shown that human and murine ficolins bind to A. fumigatus in vitro [27,28] .…”

“…Consistent with our data, recent studies demonstrated the ability of ficolins to modulate the inflammatory response. Specifically, it was shown that ficolin-2 stimulated murine macrophages to produce IFN-γ, IL-17A, TNF-α and IL-6 in vitro, and that ficolin-A KO mice exhibited decreased production of TNF-α and IL-17A in vivo upon stimulation with LPS [26]. Other investigators reported that ficolin-A increased the production of IL-8 from human lung epithelial cells following A. fumigatus challenge in vitro [29] .…”

“…In addition, in vivo studies have demonstrated a protective effect of ficolins in murine models of bacterial and viral infections [20,24,25,26]. While in vitro studies suggest that ficolins participate in the elimination of A. fumigatus [27,28,29,30,31], the in vivo role of ficolins during fungal infection has not yet been addressed.…”

Ficolins do not alter host immune responses to lipopolysaccharide-induced inflammation in vivo

“…Another study also reported a reduced survival rate in ficolin-A KO mice using the same S. pneumoniae strain 31 . Reduced survival rates of ficolin-A KO mice compared to WT mice after infection with influenza A virus 30 and Mycobacterium tuberculosis 32 have also been reported. In addition, we showed that ficolin KO mice showed decreased fungal clearance in the early phase of A. fumigatus infection 33 .…”

“…Lipopolysaccharide (LPS) from the outer membrane of Gram-negative bacteria plays a major role in activating the inflammatory response during sepsis, and administration of LPS in animal models has been widely used to study the inflammatory response to Gram-negative bacteria 26 . While a protective effect of ficolins has been demonstrated in clinical studies [27][28][29] and in mouse models of infection 13,[30][31][32] , the contribution of ficolins to inflammatory processes is not well-characterized. However, we recently observed that ficolin deficient mice showed decreased production of pro-inflammatory cytokines during local fungal lung infection in vivo 33 .…”