Immunotherapy for fungal infections Darius Armstrong-James 1 and Thomas S Harrison 2 Invasive fungal infections have become a major cause of mortality in immunocompromised individuals. Despite the current availability of number of highly active antifungal agents, overall mortality remains around 40%. Importantly, it is clear that a failure to restore host immunity leads to worse outcomes. These observations provide clear rationale for the development of novel immunotherapies to improve outcomes in immunocompromised individuals with invasive fungal infections. In this article we summarise the key advances that have been made in the field of immunotherapy for fungal infections in recent years, with a particular focus on clinical studies of interferon-g therapy, adoptive T cell therapy, and gene therapy for chronic granulomatous disorder. In addition a number of pre-clinical approaches are reviewed. Addresses 1 Section of Infectious Diseases and Immunity, Imperial College London, London, United Kingdom 2 Infection and Immunity, St. Georges University of London, London, United Kingdom Corresponding author: Harrison, Thomas S (tharriso@sgul.ac.uk) Current Opinion in Microbiology 2012, 15:434–439 This review comes from a themed issue on Host–microbe interactions: Fungi Edited by Mihai G Netea and Gordon D Brown For a complete overview see the Issue and the Editorial 1369-5274/$ – see front matter, Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.mib.2012.06.001 Introduction Invasive fungal infections are a major cause of death worldwide [1]. This is despite the availability of a number of novel antifungal agents with good in vitro activity over the past two decades [2]. Invasive fungal infection is most commonly seen in the context of underlying immune- compromise. In resource poor settings the primary driver for infection is advanced HIV disease, with up to 625 000 deaths from cryptococcal meningitis per annum [3], and a substantial burden of Pneumocystis jiroveci pneumonia and endemic mycoses [4]. In advanced healthcare settings, stem cell and solid organ transplantation are major risk factors for invasive candidiasis and invasive mould infec- tions, with further significant drivers being corticosteroid usage and prolonged critical care [5,6]. Even in the context of gold standard levels of care for these infections, mortality from the major infections invasive candidiasis, invasive aspergillosis and cryptococcal meningitis remains above 40% overall [7]. It has been observed that even with highly active antifungal therapy, responses are limited unless immunity is reconstituted. Furthermore, the emergence of significant fungal resistance to the current antifungal armamentarium further emphasises the need for novel approaches to the cure of invasive fungal infections [8]. Taken together, these observations provide a rational basis for the urgent development of novel immunother- apeutic modalities to augment antifungal treatment in the immuno-compromised host. The past decade has wit- nessed major progress in our understanding fungal immuno-biology, which has enabled the development of a number of novel molecular and cell-based immu- notherapeutic approaches for invasive fungal infections [9]. In this review we will summarise some of these approaches as well as progress with previously described immunotherapies. Cytokine therapy – recombinant human interferon-g There is increasing evidence from animal models that susceptibility to invasive fungal infections is associated with impaired interferon-g responses in the lung, and that inflammatory pathology may be driven by a Th17 response, where Th1 responses are impaired [10]. Further murine studies indicate that early NK cell- derived interferon-g is required for immunity to asper- gillosis, and interferon-g knockout mice have enhanced susceptibility to aspergillosis [11,12]. Human genetic studies further link IFNG polymorphisms to risk of aspergillosis in stem cell transplantation [13]. Our studies in solid organ transplant recipients with invasive fungal infections suggest these individuals have an impaired interferon-g response. These observations suggest recombinant human interferon-g therapy may have uti- lity in the treatment of invasive fungal infections in patients with impaired T cell immunity [14  ]. Our initial studies indicate that such an approach may be useful in transplantation, leading to effective clearance of refrac- tory or disseminated fungal infections in all patients treated thus far [14  ]. Whilst there are further concerns that recombinant interferon-g therapy may provoke allo- graft rejection in transplant patients, we have not seen evidence for this thus far, and there is an established literature that indicates that interferon-g may be beneficial in the context of chronic allograft rejection or graft-versus-host disease [15]. Both our studies in organ transplant recipients and others in stem cell trans- plantation indicate such an approach appears safe, with no episodes of graft rejection [14  ,16  ]. Further small- scale clinical studies in HIV patients with refractory Available online at www.sciencedirect.com Current Opinion in Microbiology 2012, 15:434–439 www.sciencedirect.com