Journal of Fungi Review The Host Immune Response to Scedosporium/Lomentospora Idoia Buldain, Leire Martin-Souto , Aitziber Antoran, Maialen Areitio , Leire Aparicio-Fernandez , Aitor Rementeria * , Fernando L. Hernando and Andoni Ramirez-Garcia * Fungal and Bacterial Biomics Research Group, Department of Immunology, Microbiology and Parasitology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), Barrio Sarriena s/n, 48940 Leioa, Spain; [email protected] (I.B.); [email protected] (L.M.-S.); [email protected] (A.A.); [email protected] (M.A.); [email protected] (L.A.-F.); fl[email protected] (F.L.H.) * Correspondence: [email protected] (A.R.); [email protected] (A.R.-G.) Abstract: Infections caused by the opportunistic pathogens Scedosporium/Lomentospora are on the rise. This causes problems in the clinic due to the difficulty in diagnosing and treating them. This review collates information published on immune response against these fungi, since an understanding of the mechanisms involved is of great interest in developing more effective strategies against them. Sce- dosporium/Lomentospora cell wall components, including peptidorhamnomannans (PRMs), α-glucans and glucosylceramides, are important immune response activators following their recognition by TLR2, TLR4 and Dectin-1 and through receptors that are yet unknown. After recognition, cytokine synthesis and antifungal activity of different phagocytes and epithelial cells is species-specific, high- lighting the poor response by microglial cells against L. prolificans. Moreover, a great number of Scedosporium/Lomentospora antigens have been identified, most notably catalase, PRM and Hsp70 for their potential medical applicability. Against host immune response, these fungi contain evasion mechanisms, inducing host non-protective response, masking fungal molecular patterns, destructing host defense proteins and decreasing oxidative killing. In conclusion, although many advances have been made, many aspects remain to be elucidated and more research is necessary to shed light on the Citation: Buldain, I.; Martin-Souto, L.; immune response to Scedosporium/Lomentospora. Antoran, A.; Areitio, M.; Aparicio- Fernandez, L.; Rementeria, A.; Hernando, F.L.; Ramirez-Garcia, A. Keywords: Scedosporium; Lomentospora; immune response; cytokine; macrophage; lymphocyte; The Host Immune Response to monocyte; antigen; epithelium Scedosporium/Lomentospora. J. Fungi 2021, 7, 75. https://doi.org/10.3390/ jof7020075 1. Introduction Received: 22 December 2020 Among microbial pathogens, fungi have historically been treated as a minor threat to Accepted: 19 January 2021 human health compared to other infectious agents such as viruses or bacteria, because they Published: 22 January 2021 affected a lower percentage of patients and antifungal treatments were effective for most of them. In recent decades, however, the outlook has been changing radically, as fungal Publisher’s Note: MDPI stays neutral infections increase in frequency as a result of a substantial increase in immunosuppressive with regard to jurisdictional claims in infections, such as those generated by the human immunodeficiency virus (HIV), as well as published maps and institutional affil- in the use of more potent immunosuppressive drugs and in invasive medical interventions. iations. Moreover, resistance to drugs has become more and more common, which may be due to several reasons, including the use of environmental fungicides as reported in Aspergillus resistance to azole [1]. Even amongst pathogenic fungi, there has been a discriminatory behavior in favor Copyright: © 2021 by the authors. of genera such as Candida, Cryptococcus or Aspergillus, because of the higher incidence of Licensee MDPI, Basel, Switzerland. infections they cause compared to other fungi [2–5]. However, rare mycoses, especially This article is an open access article those caused by filamentous fungi, are on the rise [5], probably as a result of the use of distributed under the terms and antifungal prophylaxis in all patients at risk of opportunistic fungal infection. This routine conditions of the Creative Commons has proven effectivity in preventing the most frequent molds [6] but may be contributing Attribution (CC BY) license (https:// to the emergence of less common mold infections such as those caused by the Lomentospora creativecommons.org/licenses/by/ 4.0/). and Scedosporium species, which are highly resistant to current antifungal drugs [7,8]. J. Fungi 2021, 7, 75. https://doi.org/10.3390/jof7020075 https://www.mdpi.com/journal/jof J. Fungi 2021, 7, 75 2 of 20 The species of the genera Scedosporium has been reclassified in recent years. The genus currently includes 10 species [9–11] formerly classified within the Pseudallescheria/Scedosporium complex; the dual name was replaced by the genus Scedosporium following the “Amsterdam Declaration on Fungal Nomenclature”, which recommends a single-name system for all fungi [12]. Some years later, the species Scedosporium prolificans was separated and redefined as Lomentospora prolificans [13]. The Scedosporium/Lomentospora species are saprophytes usually found in soil, es- pecially from human-disturbed ecosystems [14], but can also behave as opportunistic pathogens. They are considered as emerging fungal pathogens due to the increasing fre- quency of infections associated with high mortality rates. These infections appear mainly as a consequence of direct inoculation, respiration, and aspiration of polluted water during near-drowning events, with a remarkable prevalence after tsunami catastrophes [9,11,15,16]. In any case, once the infection has disseminated, systemic infections lead to a worse sce- nario. They also show neurotropism, meaning that central nervous system (CNS) infections are a probable consequence [9,17]. Specifically, they can cause a wide variety of diseases from localized infections in immunocompetent individuals to disseminated infections in those that are immunocom- promised [14]. Within the immunocompromised group, transplant recipients and patients with primary hematological malignancies are among those at highest risk of suffering from these mycoses [9,11,15,18,19]. In the case of immunocompetent individuals, those who suffer from cystic fibrosis (CF) are susceptible to chronic airway colonization. In these patients, Scedosporium/Lomentospora species show a prevalence ranging between 0–25%, ranking second among filamentous fungi, after Aspergillus fumigatus [9,11,15,20–24]. This colonization is considered a risk factor for the development of an infection [24] and contributes to chronic inflammation, which can lead to the progressive deterioration of the lung function, as demonstrated for A. fumigatus [24–26]. Diagnosis is still based on culture-dependent methods and serological tests are only performed on a “home-made” basis, [27,28], but are not commercially available. This makes it impossible to differentiate between an airway colonization and a respiratory infection. Treatment is difficult, as these fungi show very limited susceptibility to current antifungals. European guidelines currently recommend voriconazole as a first-line treatment, together with surgical debridement when possible. In some cases, combinations of antifungals are needed, of which the most studied are voriconazole and terbinafine [9,29–32]. However, combination therapy is only supported by some reports and is therefore only moderately recommended. Considering the rise in cases of Scedosporium/Lomentospora and the problematic nature of their diagnosis and treatment, scientific advances are needed. In this regard, an under- standing of all the immune mechanisms involved in a successful response against these pathogens is of paramount importance. This review therefore compiles the information published over recent years to explain this clearly and to make comparisons with other filamentous fungi. 2. Pathogen Recognition As in most microorganisms, activation of an innate immune response to fungal in- fections is induced by the recognition of molecular components shared by many fungal species, found mainly on the cell wall, known as Pathogen Associated Molecular Patterns (PAMPs). To achieve this, the cells in the immune system use Pattern Recognition Receptors (PRRs) which recognize microbial molecules and activate signaling pathways that gener- ate induction of the synthesis of pro-inflammatory cytokines, phagocytosis and adaptive immunity [33,34], as described below. The PRRs most implicated in the recognition of fungal pathogens are usually Toll-like receptors (TLRs), C-type Lectin Receptors (CLRs), Dectin-1 and 2, and Mannose Receptor/CD206 (MR) [33]. Specifically, the recognition of Scedosporium/Lomentospora has not yet been described in depth, but some of these PRRs J. Fungi 2021, 7, x FOR PEER REVIEW 3 of 21 J. Fungi 2021, 7, 75 3 of 20 nition of Scedosporium/Lomentospora has not yet been described in depth, but some of havethese been PRRs indicated have been as beingindicated of paramount as being of importance paramount (Figures importance1 and (Figures2, with references 1 and 2, with in Supplementaryreferences in Supplementary Materials Figures Material S1 ands Figures S2, respectively). S1 and S2, respectively). FigureFigure 1.1. ScedosporiumScedosporium//Lomentospora cell wallwall componentscomponents inducedinduced macrophagemacrophage activationactivation andand PatternPattern Recognition Recognition Receptors Receptors (PRR) (PRR) involved involved in these