Date Published: June 26, 2014
Publisher: Public Library of Science
Author(s): Damian J. Krysan, Fayyaz S. Sutterwala, Melanie Wellington, William E. Goldman.
Candida albicans is a commensal organism of the human gastrointestinal and genitourinary systems as well as the most common human fungal pathogen . The organism causes mucosal infections such as oropharyngeal or vulvo-vaginal candidiasis, but it can also cause life-threatening invasive disease. Healthy individuals readily maintain the organism in its commensal state but individuals with defects in the anti–C. albicans immune response are at high risk for developing disease. Phagocytes, particularly macrophages and neutrophils, are critical to the host’s ability to prevent invasive candidiasis .
Much of our understanding of the interaction between C. albicans and macrophages arose from observations using wide-field, confocal, and fluorescence microscopy. Macrophages readily ingest the round yeast form of C. albicans as well as relatively short C. albicans filaments . After ingestion, some C. albicans are killed; however, most survive and form hyphae in response to the phagosome environment (morphogenesis) . Time-lapse microscopy suggests that some macrophages are able to withstand the stress of elongating C. albicans filaments without apparent loss of integrity, whereas other macrophages that have ingested C. albicans undergo lysis . As lysis is temporally linked to filament elongation, the filaments appear to puncture through macrophage membrane , , . Thus, while macrophages are able to damage or kill C. albicans, the fungus also has a significant cytotoxic effect on macrophages.
Because of the visual/temporal association of intracellular filament growth with macrophage lysis, a logically appealing hypothesis is that C. albicans filaments simply grow so long that the macrophage membrane is stretched to the point of failure, resulting in lysis , . Two additional findings support this hypothesis: First, killed or inactivated C. albicans yeast, which obviously do not form filaments within macrophages, trigger minimal levels of macrophage lysis . Second, C. albicans mutant strains that do not form filaments also do not trigger macrophage lysis .
An alternative to the long-held idea that C. albicans physically destroys macrophages is that macrophage lysis in response to C. albicans is actually a macrophage-driven response. In the last decade, there has been an explosion of new data describing programmed cell death pathways in response to infection . The designation “programmed” refers to cell death that is specifically induced by host-cell signaling pathways; thus, programmed cell death is host-driven. The archetypal programmed cell death pathway apoptosis may occur in macrophages responding to Candida; however, apoptosis is non-lytic and cannot account for C. albicans–induced lysis. In contrast, several newly described programmed cell death pathways result in lytic cell death, including: pyroptosis, pyronecrosis, and necroptosis . The most well studied of these is pyroptosis, which results in cell swelling, lysis, and release of inflammatory cytokines (see the PLOS Pathogens Pearl , or  for more detail). This pathway was originally identified in macrophages infected with intracellular bacteria such as Salmonella, Legionella, and possibly Mycobacteria. By undergoing pyroptosis, infected macrophages deprive intracellular bacteria of their immune-protected niche as well as intracellular nutrients.
Another important consequence of pyroptosis is the release of IL-1β/IL-18 . The finding that pyroptosis occurs in response to C. albicans is quite consistent with the ability of C. albicans to trigger IL-1β production in macrophages. Production of mature IL-1β via the NLRP3 inflammasome is tightly regulated in a two-step process: The first, or priming signal, triggers activation of NFκB and transcription of pro-IL-1β . The second signal results in inflammasome assembly, caspase-1 activation, and cleavage of pro-IL-1β into mature IL-1β. As with most biological systems, the two signal “pathways” are not completely separated; priming signals also increase the level of NLRP3 .
Although C. albicans hyphae formation clearly plays a role in macrophage lysis, the death of macrophages that have ingested C. albicans is not simply the result of the hyphae physically rupturing the macrophage . Rather, the current data supports a new model in which C. albicans–induced macrophage lysis occurs via pyroptosis, a host-cell programmed death pathway. These findings represent the first demonstration that pyroptosis occurs in response to a fungal pathogen. One important question raised by these findings is whether pyroptosis is beneficial to the host, C. albicans, or both. The components of the NLRP3 inflammasome as well as IL-1β, IL-18, and the IL-1α/IL-1β receptor IL-1RI, are important for host survival from systemic candidiasis and prevention of dissemination of oropharyngeal candidiasis , . Thus, the NLRP3 inflammasome is clearly important to the host for its role in triggering inflammation; it may also benefit the host by triggering pyroptosis. Alternatively, the host program of pyroptosis could have been “conscripted” during the evolution of C. albicans to provide a mechanism of escape from the macrophage. In that case, triggering pyroptotic macrophage lysis could be a “cost” to the host that is outweighed by the other benefits of inflammasome activation.