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

Paula I Seoane,David Stirling,Mahdad Noursadeghi,Lucy C K Bell,Leanne M Taylor-Smith,Dalan Bailey,Robin C May

doi:10.1371/journal.ppat.1008240

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 non-lytic 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.

Highlights

Since their discovery in 1957 by Isaacs and Lindenmann [1], the antiviral effects of type I interferons have been well documented [2,3,4]
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
We investigate how the innate immune response to the fatal fungus Cryptococcus neoformans is influenced by viral coinfection

Summary

Introduction

Since their discovery in 1957 by Isaacs and Lindenmann [1], the antiviral effects of type I interferons have been well documented [2,3,4]. Different bacterial stimuli have been shown to elicit type I interferon production, and in turn these so-called “antiviral cytokines” play a role in the outcome of bacterial infections [7,8,9] This stems in part from the complex and sometimes contradictory effects that type I interferons have on host cells, for instance in enhancing inflammatory responses in some infectious settings [6] to preventing hyperinflammation in others [10, 11], and even affecting the priming of immune responses at lymph nodes [12]. Little is known about the interplay between type I interferons and fungal infections, despite the fact that many life-threatening fungal infections occur in the context of chronic viral infection This is true of Cryptococcus neoformans, a globally distributed opportunistic pathogen that is responsible for nearly 200,000 deaths per year in human immunodeficiency virus (HIV) infected patients, where it causes cryptococcal meningitis [13]. Most studies to date have focused on the interaction of Cryptococcus with healthy host cells, and the impact of viral coinfection on this intracellular lifestyle remains largely unknown

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