Abstract
Pulmonary aspergillosis is an opportunistic fungal infection affecting immunocompromised individuals. Increasing understanding of natural killer (NK) cell immunobiology has aroused considerable interest around the role of NK cells in pulmonary aspergillosis in the immunocompromised host. Murine studies indicate that NK cells play a critical role in pulmonary clearance of A. fumigatus. We show that the in vitro interaction between NK cells and A. fumigatus induces partial activation of NK cell immune response, characterised by low-level production of IFN-γ, TNF-α, MIP-1α, MIP-1β, and RANTES, polarisation of lytic granules and release of fungal DNA. We observed a contact-dependent down-regulation of activatory receptors NKG2D and NKp46 on the NK cell surface, and a failure of full granule release. Furthermore, the NK cell cytokine-mediated response to leukaemic cells was impaired in the presence of A. fumigatus. These observations suggest that A. fumigatus-mediated NK cell immunoparesis may represent an important mechanism of immune evasion during pulmonary aspergillosis.
Highlights
Pulmonary aspergillosis is a high mortality fungal infection in immunocompromised hosts
natural killer (NK) cells were incubated with A. fumigatus germlings and cytokine and chemokine production quantified in supernatants by Luminex multiplex assay
This did not result in CD56 downregulation on NK cell surface (Figure 4D), suggesting that CD56 downregulation is dependent on direct contact between NK cells and the fungus
Summary
Pulmonary aspergillosis is a high mortality fungal infection in immunocompromised hosts. Clinical studies have shown that exogenous IFN-γ is beneficial as adjunctive therapy in pulmonary aspergillosis [5, 6]. Initial studies suggested that unstimulated or IL-2 stimulated human NK cells kill A. fumigatus hyphae but not conidia, through perforin-dependent cytotoxicity. This was associated with reduced levels of IFN-γ and GM-CSF production [7]. A further study found that IL-2 pre-stimulated human NK cells release IFN-γ and TNF-α in response to A. fumigatus germlings. NK cell—mediated damage of A. fumigatus germlings was independent of NK cell degranulation and instead found to be a consequence of direct IFN-γ-mediated fungal damage[8]
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