Granule-Dependent Natural Killer Cell Cytotoxicity to Fungal Pathogens

Abstract

Natural killer (NK) cells kill or inhibit the growth of a number of fungi including Cryptococcus, Candida, Aspergillus, Rhizopus, and Paracoccidioides. Although many fungi are not dangerous, invasive fungal pathogens, such as Cryptococcus neoformans, cause life-threatening disease in individuals with impaired cell-mediated immunity. While there are similarities to cell-mediated killing of tumor cells, there are also important differences. Similar to tumor killing, NK cells directly kill fungi in a receptor-mediated and cytotoxic granule-dependent manner. Unlike tumor cell killing where multiple NK cell-activating receptors cooperate and signal events that mediate cytotoxicity, only the NKp30 receptor has been described to mediate signaling events that trigger the NK cell to mobilize its cytolytic payload to the site of interaction with C. neoformans and Candida albicans, subsequently leading to granule exocytosis and fungal killing. More recently, the NKp46 receptor was reported to bind Candida glabrata adhesins Epa1, 6, and 7 and directly mediate fungal clearance. A number of unanswered questions remain. For example, is only one NK cell-activating receptor sufficient for signaling leading to fungal killing? Are the signaling pathways activated by fungi similar to those activated by tumor cells during NK cell killing? How do the cytolytic granules traffic to the site of interaction with fungi, and how does this process compare with tumor killing? Recent insights into receptor use, intracellular signaling and cytolytic granule trafficking during NK cell-mediated fungal killing will be compared to tumor killing, and the implications for therapeutic approaches will be discussed.

Natural Killer Cells in Antifungal Immunity

“…The importance of the receptor is underlined by the observation that NCR1-deficient mice were unable to clear C. glabrata systemic infection ( 77 ). Because several fungi including Aspergillus, Cryptococcus , and Coccidioides express adhesins ( 78 ), further studies have to evaluate whether and to what extent these fungal adhesins are recognized by which of the NK cell receptors ( 79 ).…”

“…For example, the use of monensin, which inhibits granule secretion, partially abrogated the growth inhibition of C. neoformans by human NK cells [reviewed in Ref. ( 79 )]. It further became clear that mainly perforin and granulysin mediate the direct NK cell cytotoxicity toward fungal pathogens ( 67 , 82 ).…”

Microbial killing by NK cells

“…NK cells possess microbicidal activity against a divergent group of pathogens. NK cells are key elements of the innate immune system that kill intracellular microbes or directly kill microbes including fungi, parasites, and bacteria . NK cells constitute ∼15% of the cells in peripheral blood, and low numbers are associated with increased prevalence of fungal infection .…”

Memory and Memory-Like NK Cell Responses to Microbial Pathogens

“…In summary, a growing body of evidence suggests that NK cells have the capacity to mount memory or memory-like responses to a diverse range of viral and bacterial pathogens, and possibly even eukaryotic pathogens such as Plasmodium falciparum (Table 1 and Figure 1). It will be interesting to see whether future studies uncover memory NK responses against other eukaryotic organisms, and in particular the various fungal pathogens controlled by NK-mediated host defenses (reviewed in Ogbomo and Mody, 2016;Mody et al, 2019). In some experimental models, memory NK responses are clearly pathogen-specific.…”