Natural Killer Cells in Antifungal Immunity

Abstract

Invasive fungal infections are still an important cause of morbidity and mortality in immunocompromised patients such as patients suffering from hematological malignancies or patients undergoing hematopoietic stem cell transplantion. In addition, other populations such as human immunodeficiency virus-patients are at higher risk for invasive fungal infection. Despite the availability of new antifungal compounds and better supportive care measures, the fatality rate of invasive fungal infection remained unacceptably high. It is therefore of major interest to improve our understanding of the host–pathogen interaction to develop new therapeutic approaches such as adoptive immunotherapy. As experimental methodologies have improved and we now better understand the complex network of the immune system, the insight in the interaction of the host with the fungus has significantly increased. It has become clear that host resistance to fungal infections is not only associated with strong innate immunity but that adaptive immunity (e.g., T cells) also plays an important role. The antifungal activity of natural killer (NK) cells has been underestimated for a long time. In vitro studies demonstrated that NK cells from murine and human origin are able to attack fungi of different genera and species. NK cells exhibit not only a direct antifungal activity via cytotoxic molecules but also an indirect antifungal activity via cytokines. However, it has been show that fungi exert immunosuppressive effects on NK cells. Whereas clinical data are scarce, animal models have clearly demonstrated that NK cells play an important role in the host response against invasive fungal infections. In this review, we summarize clinical data as well as results from in vitro and animal studies on the impact of NK cells on fungal pathogens.

Recent Advances in the Pathogenesis of Mucormycoses

“…Although natural killer (NK) cells are considered part of the innate immune system and are known to possess direct and indirect cytotoxic abilities, they also secrete chemokines and cytokines, such as IFN-γ, TNF-α, and GM-CSF, thus affecting the activity of other immune cells. 37,38 NK cells can damage Mucorales hyphae but do not affect conidia. 17,38 In addition, the extent of caused damage is inversely related to the amount of fungal biomass but is independent of the fungal species.…”

Distinct Effects of Immunosuppressive Drugs on the Anti-Aspergillus Activity of Human Natural Killer Cells

“…In contrast, the impact of activating and inhibitory NK receptors, such as natural cytotoxicity receptors (NCR) 1-3, CD56, CD16 or killer-immunoglobulin-like receptors (KIRs) on the antifungal activity of NK cells has not been fully characterized to date and has to be addressed in future experiments. This is also the fact for the antifungal activity of the different NK subpopulations, such as cytotoxic CD56 dim CD16 bright and immune regulatory CD56 bright CD16 dim cells [5,14]. The in vitro data are supported by animal models, which clearly demonstrate the importance of NK cell-derived IFN-γ in neutropenic mice with pulmonary aspergillosis, and that the adoptive administration of NK cells results in a benefit [15].…”

“…Despite new and potent antifungal agents, morbidity and mortality of invasive aspergillosis in HSCT recipients is unacceptably high, which explains the growing interest in immunotherapeutic approaches, such as adoptively transferring antifungal effector cells or administering of cytokines or interferons in this setting [2,3]. The antifungal host immune response is a complex network consisting of effector cells, such as phagocytes, T cells, and NK cells and soluble mediators which are released by numerous cell populations [4,5]. Human Natural Killer (NK) cells have the potential to kill targets without prior activation, and it has been shown in vitro that NK cells damage fungi of different genera and species [6][7][8][9][10].…”

Natural killer cells are pivotal for in vivo protection following systemic infection by Sporothrix schenckii

“…10,11 Sporotrichosis is an often neglected emerging opportunistic subcutaneous mycosis endemic in many countries but most commonly in those from tropical and subtropical climate regions, 12 which is caused by various thermodimorphic fungi of the Sporothrix genus, including Sporothrix brasiliensis, Sporothrix globosa, Sporothrix luriei and Sporothrix schenckii sensu stricto. 10,11 Sporotrichosis is an often neglected emerging opportunistic subcutaneous mycosis endemic in many countries but most commonly in those from tropical and subtropical climate regions, 12 which is caused by various thermodimorphic fungi of the Sporothrix genus, including Sporothrix brasiliensis, Sporothrix globosa, Sporothrix luriei and Sporothrix schenckii sensu stricto.…”

“…Most studies show that both human and murine NK cells exhibit in vitro activity against diverse fungi, either directly through perforin and granzyme secretion or indirectly through secretion of constitutively produced interferon-c (IFN-c), whereas studies using NK cell-depleted mice have revealed a pivotal role for these cells in the host response against Cryptococcus neoformans, Aspergillus fumigatus, Candida albicans and Histoplasma capsulatum. 10,11 Sporotrichosis is an often neglected emerging opportunistic subcutaneous mycosis endemic in many countries but most commonly in those from tropical and subtropical climate regions, 12 which is caused by various thermodimorphic fungi of the Sporothrix genus, including Sporothrix brasiliensis, Sporothrix globosa, Sporothrix luriei and Sporothrix schenckii sensu stricto. 13 The disease follows the traumatic inoculation of the fungus through soilinoculating injuries, inhalation of conidia, or through zoonotic transmission, especially from cats, affecting immunocompromised individuals in an opportunistic fashion.…”