Scavenger Receptor A Modulates the Immune Response to Pulmonary Cryptococcus neoformans Infection

Abstract

Scavenger receptors represent an important class of pattern recognition receptors shown to mediate both beneficial and detrimental roles in host defense against microbial pathogens. The role of the major macrophage scavenger receptor, scavenger receptor A (SRA), in the immune response against the pathogenic fungus, Cryptococcus neoformans, is unknown. To evaluate the role of SRA in anticryptococcal host defenses, SRA+/+ mice and SRA−/− mice were infected intratracheally with C. neoformans. Results show that infection of SRA−/− mice resulted in a reduction in the pulmonary fungal burden at the efferent phase (3 wk) compared with SRA+/+ mice. Improved fungal clearance in SRA−/− mice was associated with decreased accumulation of eosinophils and greater accumulation of CD4+ T cells and CD11b+ dendritic cells. Additional parameters were consistent with enhanced anti-cryptococcal immunity in the infected SRA−/− mice: 1) increased expression of the costimulatory molecules CD80 and CD86 by lung APCs, 2) decreased expression of Th2 cytokines (IL-4 and IL-13) and IL-10 in lung leukocytes and in cryptococcal Ag-pulsed splenocytes, 3) diminished IgE production in sera, and 4) increased hallmarks of classical pulmonary macrophage activation. These effects were preceded by increased expression of early pro-Th1 genes in pulmonary lymph nodes at the afferent phase (1 wk). Collectively, our data show that SRA can be exploited by C. neoformans to interfere with the early events of the afferent responses that support Th1 immune polarization. This results in amplification of Th2 arm of the immune response and subsequently impaired adaptive control of C. neoformans in the infected lungs.

Cryptococcal Heat Shock Protein 70 Homolog Ssa1 Contributes to Pulmonary Expansion of Cryptococcus neoformans during the Afferent Phase of the Immune Response by Promoting Macrophage M2 Polarization

“…In contrast, Ssa1 directly modulates macrophage- C. neoformans interactions only during the innate phase, with little to no effect on the development of adaptive immunity. In an attempt to specifically address the mechanism of Ssa1-dependent effects on macrophages, our laboratory has performed studies using mice deficient in the SRA receptor, which we originally thought to be the major receptor for the Ssa1 protein (53). Through our investigation, we have found that it is possible that some effects of Ssa1 on macrophages could be induced by SRA; however, the data were not very clear, hinting that multiple receptors and signaling pathways were likely to be involved.…”

Early or Late IL-10 Blockade Enhances Th1 and Th17 Effector Responses and Promotes Fungal Clearance in Mice with Cryptococcal Lung Infection

“…Our data shows that sustained IL-10 production plays a central role in determining this balance during both the developing and established phases of infection. Numerous Cryptococcal virulence strategies are associated with increased expression of IL-10 including expression of its polysaccharide capsule, laccase, and its interference with macrophage scavenger receptor A (14, 26, 53–56), showing that C. neoformans can exploit the IL-10 signaling pathway to oppose protective effector mechanisms. Importantly, the current study illustrates our ability to block this regulatory pathway, thereby restoring and potentially enhancing protective immune effector mechanisms which improve fungal clearance.…”

Role of Dendritic Cell–Pathogen Interactions in the Immune Response to Pulmonary Cryptococcal Infection

“…Using an in vitro shRNA screen of mouse macrophages during cryptococcal stimulation, Means et al demonstrated that the scavenger receptors CD36, SCARF1 and SCARB2 promote IL-1β generation and are protective during cryptococcal immune responses [129]. Conversely, studies using Scavenger Receptor A (SRA)-deficient mice demonstrated that SRA signaling contributed to nonprotective immunity via decreased DC and CD4 + T-cell accumulation, decreased DC1 polarization and an increase in the hallmarks of nonprotective immune responses including eosinophilia and IL-10 production [130]. This suggests that C.neo exploits SRA to modulate the host response, promoting responses that favor survival and persistence of the microbe.…”