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.
Highlights
TB remains a major global health problem
We further demonstrated that ficolin-2 could defend against virulent Mycobacterium tuberculosis (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
These findings suggest that a ficolin-2-deficient host might be more susceptible to infection by Mtb H37Rv
Summary
One-third of the world’s population is infected with Mycobacterium tuberculosis (Mtb), the etiologic agent of TB, which kills over 1.7 million people a year. The only tuberculosis vaccine currently available is an attenuated strain of Mycobacterium bovis, termed bacillus Calmette–Guérin (BCG), which has variable and limited efficacy in tuberculosis-endemic regions. BCG provides little protection against adult lung tuberculosis, and protection in adults varies from zero to 80%. The increasing prevalence of multidrug resistant (MDR) TB has greatly contributed to the increased difficulties in the control of TB. There has been an increased incidence of drug-resistant TB cases among human immunodeficiency virus (HIV)-infected patient populations [1,2]. The development of new anti-TB molecules or drugs without cross-resistance to known antimycobacterial agents is urgently needed
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