Viral infection triggers interferon-induced expulsion of live Cryptococcus neoformans by macrophages

Abstract

Cryptococcus neoformans is an opportunistic human pathogen, which causes serious disease in immunocompromised hosts. Infection with this pathogen is particularly relevant in HIV + patients, where it leads to around 200,000 deaths per annum. A key feature of cryptococcal pathogenesis is the ability of the fungus to survive and replicate within the phagosome of macrophages, as well as its ability to be expelled from host cells via a novel nonlytic mechanism known as vomocytosis. Here we show that cryptococcal vomocytosis from macrophages is strongly enhanced by viral coinfection, without altering phagocytosis or intracellular proliferation of the fungus. This effect occurs with distinct, unrelated human viral pathogens and is recapitulated when macrophages are stimulated with the anti-viral cytokines interferon alpha or beta (IFNα or IFNβ). Importantly, the effect is abrogated when type-I interferon signalling is blocked, thus underscoring the importance of type-I interferons in this phenomenon. Lastly, our data help resolve previous, contradictory animal studies on the impact of type I interferons on cryptococcal pathogenesis and suggest that secondary viral stimuli may alter patterns of cryptococcal dissemination in the host.

Dangerous Liaisons: Interactions of Cryptococcus neoformans with Host Phagocytes

“…The authors of this study proposed that the host response to viral infection, rather than the virulence of the virus, stimulates fungal cell expulsion via induction of type-I interferon signaling [82]. This effect of viral coinfection on NLE was not observed in C. albicans infection [82].…”

“…For example, coinfection of macrophages with HIV or measles virus enhanced NLE without altering fungal uptake or intracellular proliferation [82]. The authors of this study proposed that the host response to viral infection, rather than the virulence of the virus, stimulates fungal cell expulsion via induction of type-I interferon signaling [82]. This effect of viral coinfection on NLE was not observed in C. albicans infection [82].…”

“…Lastly and unsurprisingly, the immune state of the host affects the ability of cryptococcal cells to undergo NLE. For example, coinfection of macrophages with HIV or measles virus enhanced NLE without altering fungal uptake or intracellular proliferation [82]. The authors of this study proposed that the host response to viral infection, rather than the virulence of the virus, stimulates fungal cell expulsion via induction of type-I interferon signaling [82].…”

Influenza challenging the diagnosis and management of pulmonary coccidioidomycosis

“…One of the effects of influenza on local immunity is the induction of type I interferon responses, which has a paradoxical effect on macrophages and neutrophils functions, especially on phagocytosis and early killing [ 5 ]. An in vitro study showed that viral infection triggers interferon-induced expulsion of live Cryptococcus neoformans previously phagocyted by macrophages [ 20 ]. This could be a potential triggering factor for reactivation of fungal infections such as coccidioidomycosis.…”

What came first, the virus or the egg: Innate immunity during viral coinfections

“…Finally, coinfection of macrophages with either HIV or measles virus impaired immunity to the fungal pathogen Cryptococcus neoformans in a type I IFN–dependent manner. The mechanism is most unique and results from IFN‐mediated enhancement of vomocytosis, which results in the fungus being vomited back out of the macrophage unharmed 58 . In all, IFNs produced during a primary viral infection appear to enhance susceptibility to secondary bacterial or fungal pathogen invasion.…”