Schizophyllum commune Fr. 1815: an odyssey of case reports for an emerging pathogen

Schizophyllum commune Fr. 1815: an odyssey of case reports for an emerging pathogen | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 27 March 2025 V1 Latest version Share on Schizophyllum commune Fr. 1815: an odyssey of case reports for an emerging pathogen Authors : Mirko Benvenuti 0000-0001-6026-7143 [email protected] , Ilaria Trave , and Emanuele Claudio Cozzani Authors Info & Affiliations https://doi.org/10.22541/au.174307683.33982145/v1 602 views 174 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Schizophyllum commune (SC) has garnered increasing attention in the medical field due to its capacity to cause a variety of infections in humans. This review provides a comprehensive overview of the epidemiological characteristics, clinical features, and diagnostic approaches for SC infections. This opportunistic pathogen predominantly affects immunocompromised individuals, particularly those with underlying hematological malignancies or organ transplantation. The clinical manifestations of SC infections can range from localized sinusitis to disseminated and potentially life-threatening conditions. Epidemiological investigations indicate that is a ubiquitous fungus, widely distributed in the environment. However, in immunocompromised individuals, this fungus can lead to serious infections, such as rhinosinusitis, cutaneous lesions, and disseminated disease. Accurate diagnosis can be challenging, as the clinical presentation may resemble that of other fungal or bacterial pathogens. The development of advanced diagnostic techniques, including molecular identification through DNA sequencing and sensitive antigen detection assays, has significantly improved the ability to detect pathogenic fungi. Schizophyllum commune Fr. 1815: an odyssey of case reports for an emerging pathogen Mirko Benvenuti 1 , Ilaria Trave 1 , Emanuele Claudio Cozzani 1 1 Section of Dermatology, Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy Corresponding author: Mirko Benvenuti, MB Via A. Pastore 1 16132 Genova, Italy Email: [email protected] Manuscript word count : 2917 Abstract word count : 151 References : 69 Figures: 1 Tables: 1 Abstract Schizophyllum commune (SC) has garnered increasing attention in the medical field due to its capacity to cause a variety of infections in humans. This review provides a comprehensive overview of the epidemiological characteristics, clinical features, and diagnostic approaches for SC infections. This opportunistic pathogen predominantly affects immunocompromised individuals, particularly those with underlying hematological malignancies or organ transplantation. The clinical manifestations of SC infections can range from localized sinusitis to disseminated and potentially life-threatening conditions. Epidemiological investigations indicate that is a ubiquitous fungus, widely distributed in the environment. However, in immunocompromised individuals, this fungus can lead to serious infections, such as rhinosinusitis, cutaneous lesions, and disseminated disease. Accurate diagnosis can be challenging, as the clinical presentation may resemble that of other fungal or bacterial pathogens. The development of advanced diagnostic techniques, including molecular identification through DNA sequencing and sensitive antigen detection assays, has significantly improved the ability to detect pathogenic fungi. Keywords : Schizophyllum commune , fungal infections, skin, lung, brain, antifungal Abbreviation: SC ( Schizophyllum commune ) NSCLC (non-small cell lung cancer) 1 Introduction Fungi are eukaryotic organisms with numerous ecological roles. The human and animal health problems that they cause can essentially be attributed to three major groups: mycoses, infectious diseases caused by the proliferation of fungi within the host; mycotoxicoses, diseases caused by the ingestion of food contaminated with mycotoxins produced by molds; and mycetisms, intoxications caused by the consumption of carpophores of macrofungi (usually Basidiomycetes or Ascomycetes ) containing endogenously produced toxins [1] (Fig.1). The trend of fungal infections is increasing globally. This leads to new infections or the re-emergence of rare and difficult-to-treat infections [2-7]. The ability to infect a host is not a trait that evolved in a single group of closely related taxa but is a trait that has appeared repeatedly in fungal taxa even very distant phylogenetically [3,4]. Fungi are a diverse and widespread kingdom of organisms; they can colonize practically every environment on the planet and are recognized as a source of food and a yet underexplored reservoir of molecules with beneficial action for human health [8,9]. However, there are fungal species that can behave as pathogens to humans and other animals. There are about 600 recognized species capable of behaving in this way [10]. Fungi are ubiquitous organisms in the environment and spores, which constitute both one of their forms of reproduction and the main form of dispersion in the environment, can enter the body through the airways or mucous membranes. Exposure to these organisms by the respiratory system is particularly common. Fungi can behave as pathogens in humans, animals, plants and even other fungi; few are very virulent and capable of infecting immunocompetent individuals. The advent of therapies and diseases capable of altering and compromising the state of the immune system of patients, such as HIV, has brought out a problem of opportunistic fungal infections [11]. Fungal infections can be primary or secondary and are often united by the difficulty in identifying the pathogen and the difficulty in treatment partly because of the emergence of resistance to conventional antifungals as well as their ability to acquire new phenotypes and resistance forms [12]. Approximately 300 million fungal infections are found in the global population each year, and the resulting deaths stand at more than 1,350,000 [13]. The problems encountered by hospital staff in the diagnosis of fungal diseases are many, first the lack of specific symptomatology, many fungal infections present highly non-specific symptoms that are superimposed with those of more common bacterial or viral infections. Many opportunistic pathogens infect patients who are already atypical or in a compromised state. Misdiagnoses lead to incorrect use of therapy and thus to a potential increase in morbidity and mortality. It is also important to note that large-scale events, such as seasonal respiratory virus outbreaks, increase the susceptibility of the most vulnerable population to secondary fungal infections [14]. The incidence of SC infections has been on the rise, with a 10-fold increase in case reports over the last 30 years [15]. This review promises to list the best-known infections caused by SC reported in the literature as case reports by providing a useful consultation tool and explanatory summary. 2 A brief introduction to basidiomycetes and their identification by conventional and molecular methods. Basidiomycota represents one of the most diverse phyla of fungi and is represented by at least 16 classes and 52 orders [16]. Basidiomycota , which when they lead free-living lives develop in their sexed phase producing sporomes, when acting as pathogens often take the form of ”mycelium balls,” moldy clusters that often make macroscopic recognition difficult. Conventional morphological recognition techniques provide rough indications that can be used to identify a pathogenic basidiomycete from an isolate. Colonies grown on plates in the laboratory generally have an unpleasant odor, are sensitive to cycloheximide (on the contrary to dermatophytes fungi) and show resistance to the commonly used fungicide 1-(Butylcarbamoyl)-1H-1,3-benzimidazol-2-yl methylcarbamate at concentrations between 2 and 10 µg/ml [17,18] One of the morphological features of the hyphae of many basidiomycetes are clamp connections, hyphal bridges formed between adjacent hyphae that allow the transfer of nuclei from one cell to another for the formation of a dikaryon, a prerequisite for allowing the sexual phase of the fungus. Considering that most isolates from clinical cases represent fungi in their monokaryon state, clamp connection formation can take place in the laboratory, on plate culture, by simultaneously growing the isolated strain and another monokaryon strain to induce the sexual phase of the fungus. The dikaryon stage can be induced to form fruiting bodies, in laboratory conditions, by alternating 12-hour light-dark cycles although with variable success rates. [18] The use of DNA-based molecular techniques for the identification of pathogenic fungi can be a valuable support. Generally, for fungi, ribosomal rDNA, specifically D1/D2 of the largest subunit, and the ribosomal internal transcribed spacer (ITS) sequence is analyzed. Chowdhary et al., [17] compared data reported from different studies and highlighted how there is often discordance between the positive matches reported in different papers. The problems that have been identified relate to the lack of completeness of databases that would allow confident identification as far as the fungus is concerned. Specifically, it is reported that in GeneBank the sequences of traditionally used markers are very incomplete as far as fungi are concerned, only 8% of the ITS region and 10% of the D1/D2 region of basidiomycetes are complete. Another problem that arises is that often many species are “species complexes” with almost no macroscopic phenotype differences and with little genetic variability in the classically used sequences. These problems highlight how there is a desperate need to set clear limits and rules on how much and what data should be uploaded to usable gene banks and, also, demonstrate how the classical method based on morphological data cannot be set aside in favor of pure molecular identification techniques. Among the fungi that can act as human pathogens, we have both obligate pathogenic species and occasional and/or opportunistic pathogens. The characteristics that enable a fungal species to act as a pathogen in animals, including humans, are essentially: the ability to grow at a temperature of 37°C at high humidity, the ability to lysis host tissues by evading the body’s defense mechanisms, not of secondary importance is the ability to take advantage of situations of potential host weakness such as states of immunocompromising or immunosuppression [5-7]. Among emerging pathogens, SC has a relevant role in primary and secondary fungal infections. SC is a species, commonly found on decaying, rotting wood with a wide distribution globally. This is a species belonging to the order Basidiomycota , family Schizophyllaceae . The species generally lives its sexual phase (teleomorph) on decaying wood, even in gardens, and it’s widely distributed [19]. It’s known to be able to complete its life cycle in a short time [20] giving the species an advantage in conquering new habitats. The fungus is known to produce a variety of virulence factors, including cell wall components and extracellular enzymes, that can damage host tissues and evade the body’s immune defenses [21]. Additionally, SC can form biofilms, which can further impede the penetration of antifungal drugs and the host’s immune response. Understanding these pathogenic mechanisms is crucial for the development of more effective therapeutic strategies, such as the use of novel antifungal agents or the targeting of specific virulence factors [22]. Numerous and varied clinical manifestations can be caused by SC, different symptoms, and different body districts that this species can infect. In biological samples isolated from patients, it is possible to characterize SC hyphae as hyaline, and septate. The fungus can be cultured in the laboratory for identification on potato dextrose agar and requires temperatures between 28°C and 37°C. Colonies have a cottony appearance, are generally white or whitish, and are distinguished by a characteristic bleachy odor. Monokaryion strains of this species may lack many of the morphological features associated with basidiomycetes. 3 Pathologies caused by Schizophyllum commune 3.1 Asthma, bronchoallergies and pneumonia . The lungs appear to be the main target for SC. The airways are the primary access of fungal pathogens into the host’s body when they occur in the form of spores. Spores are the dispersal form of fungi, an integral part of their complex biological cycles. In most fungi, we have a haploid stage of asexual reproduction and a diploid teleomorph stage that presides over sexual reproduction. Infections are mainly caused by monokaryon phase mycelium. [23,24]. Considering the airways as the main gateway for access of fungal pathogens in animals, it is understood that all infections displaced to other districts such as the encephalon and soft tissues are to be attributed to secondary dissemination to other districts, probably resulting from granulomatous-type lesions caused by the chronic inflammatory and/or allergic processes that set in [25]Asthma is an inflammatory disease in which numerous cytokines, eosinophils, and T-helper 2 cells are involved. In patients with particularly severe forms, a neutrophil component is associated with recruitment mediated by the cytokines IL-17A and IL-17F [26]. In general, the components of the fungal cell wall influence the recruitment of eosinophils in response to contact between hypha and host cell [27]. The spores of SC contain numerous allergens [28] The best known is schizophyllan, a β-glucan that induces the production of pro-inflammatory cytokines and chemokines, increasing the recruitment of neutrophils into alveolar epithelia. Another component of the spore wall is α-mannan, which induces T17 cell differentiation [29,30]. Increased expression of IL-17 with increased recruitment of immunity cells leads to worsened asthma in affected people exposed to SC spores and cases of asthma and allergic bronchopathy are also known to occur in workers in companies producing mushrooms for food consumption other than SC [31, 32] Allergenic effects of fungal spores may be unclear although, similarly to SC, other fungi produce chitin and B-glucans that can induce eosinophilic inflammatory response [33] Pneumonia is an acute inflammation of the lower respiratory tract with the manifestation of fever, cough, fatigue in breathing, and generalized malaise. The manifestations of pneumonia may vary among different patient cohorts, and there are notable differences between young adults and the elderly. Young adults usually present with fever accompanied by leukocytosis and infiltrate on chest radiography. In the elderly, it is more common to have only the infiltrate without fever or leukocytosis [34]. Although bacterial infections caused by Staphylococcus pneumoniae and viral infections are to be considered the main cause of pneumonia, numerous studies indicate that fungal infections are a problem often underestimated or misdiagnosed [35, 36]. Most infections of this species are concentrated in the upper and/or lower airways. The common localization of these infections in these body districts is consistent with the natural dispersal of spores that occurs by anemochory route (transport via wind and air currents). The ability of the fungus to infect depends on many factors, both endogenous and exogenous. Subsequently, in an advanced state of infection, it may remain localized at the level of the airways or spread to other body districts and organs. It is suspected that granulomatous lesions formed by chronic inflammation may allow parts of the mycelium to detach and move to organs even as far from the main target such as the brain [37-39]. The clinical manifestations resemble in many ways those of Aspergillus spp. infections, and SC is known to be able to form structures, fungal balls, resembling aspergillomas, in the lungs of infected patients under certain conditions. In this case, diagnosis may be difficult if routine examinations such as radiography are conducted because the lesions found are common, like those caused by other conditions such as cancer or tuberculosis. Data involving hypha-cell interactions are scarce and difficult to interpret although the fungus was found, at least in one case, in association with a tumor cavity of NSCLC. [40] Many parasites and opportunistic pathogens are associated with the occurrence of tumor forms in different districts of their body [41, 42], and it would be interesting to investigate this more thoroughly for Basidiomyceta infections. 3.2 Eye infections Fungal infections of the eye, particularly those caused by opportunistic fungi or secondary pathogens, have long been known [43]. SC has emerged as an important causative agent of mycotic keratitis, a serious ocular infection that can lead to reduced vision or even blindness if not treated promptly and effectively, particularly in immunocompromised subjects [44, 45] Ocular infections by SC are a known problem in postoperative cases [46] and are also often associated with sinus infections [47, 48]. The clinical manifestation of SC-induced ocular infections can be variable, ranging from mild conjunctivitis to severe corneal ulceration, with opacification and the presence or absence of mycelium detectable by the naked eye [44] Diagnosis is typically established through a combination of clinical signs, such as feathery ulcer margins and the presence of a convex hyperopyon, and laboratory confirmation through fungal cultures and microscopic examination [44]. Given the potentially devastating consequences of these infections, a rapid and accurate diagnosis is essential to initiate appropriate antifungal therapy with topical antifungal medications, such as natamycin and amphotericin B, are often the first line of treatment, but their effectiveness may be limited by poor ocular penetration [45] to which antibiotic therapy must be adjunct to avoid secondary infections, affecting even other periorbital structures[49, 50-51]. In severe or recalcitrant infections, surgical interventions, such as corneal debridement or transplantation, may be necessary to remove the infected tissue and improve the chances of successful treatment and administration of oral antifungal drugs. 3.3 Brain abscesses A rare but potentially severe pathological condition caused by SC is brain abscesses. Despite the low incidence of this circumstance, it remains essential to question and understand its etiology, treatment, and diagnostic approaches to improve the health and prognosis of patients as much as possible. As in the case of other opportunistic pathogens, the development of brain abscesses in the presence of SC infection is associated with preexisting conditions that affect the patient’s health. There are several routes by which the fungus can reach the central nervous system, either by attracted spread through the cardiovascular system, by dispersal from a primary site of infection, as occurs by fragmentation of pulmonary granulomatous lesions, or by direct spore colonization during surgery. [37, 52]. When the pathogen becomes established at the site of the central nervous system, a strong inflammatory response occurs, with the formation of localized abscesses within the brain parenchyma. The clinical manifestations of a brain abscess from SC may resemble those caused by numerous other infections affecting the central nervous system or of lesions that occupy the intracranial space, impairing the function of the encephalon [53-54] Although abscesses of this nature can be identified with computed axial tomography, the etiologic agent is determined by laboratory culture of material obtained by biopsy, needle aspiration, or surgical excision [17]. Treatment of SC brain abscess may be difficult and often involves a multimodal approach, including antifungal medication, and surgical intervention. The choice of antifungal agent, therapy duration, and surgical intervention extent should be tailored to the individual patient’s clinical status and response to treatment. 3.4 Rhinosinusitis SC is increasingly recognized as a cause of rhinitis and rhinosinusitis [55]. Diagnosing the etiologic agent in these cases is particularly difficult since it is an apparently rare occurrence. However, increasingly, cases of chronic upper airway infection are being reported [56]. Noteworthy is the occurrence of SC-associated infections in immunocompetent patients, a fact that would seem to contradict the classic view of these pathogens as opportunists in immunocompromised patients [57]. The site of infection in these cases turns out to be crucial and potentially very dangerous because of the possibility of the spread of infection to lungs, brain, and other sites such as the middle ear. 3.5 Cutaneous lesions Recently, at least two cases have been reported in which SC involvement was present in both granulomatous and ulcerative skin lesions [58, 59]. Although not many cases are reported in the literature, we cannot rule out the possibility that, given the difficulty of diagnosing and finding this unusual pathogen, the involvement of SC in skin lesions is more frequent than, hitherto, assumed and that there is indeed a data gap due to misdiagnosis. 3.6 Infection in animals other than human SC infections are not a problem restricted to humans alone, different cases of infections by this species are known in the literature in numerous animals such as dogs, seals, and cheetahs in captive contexts [60-64]. The literature regarding these case reports on animals is a clear example of how widespread basidiomycete infections are among different species and how they are predominantly an underestimated or misdiagnosed problem even in the human population 4 Conclusions SC has been increasingly recognized as an opportunistic pathogen, particularly in immunocompromised patients. The epidemiology of fungal diseases has undergone significant changes, with a rise in the incidence of systemic and life-threatening mycoses. Diagnosing SC infections can be challenging, as it can present with a wide range of clinical manifestations, from localized infections to disseminated disease. Difficulties in identification using conventional phenotypic and molecular techniques, coupled with the unknown population prevalence and environmental niches, have hindered the ability to effectively control SC infections Treatment options for SC infections are limited, and the emergence of antifungal resistance poses additional challenges. Several areas of ongoing challenge remain, including the absence of reliable markers for early identification of patients at risk of developing invasive fungal disease as the prevalence of SC infections continues to rise, particularly in immunocompromised populations, there is a pressing need for the development of novel diagnostic and therapeutic strategies to combat these opportunistic pathogens. Ongoing research and collaboration between clinicians, mycologists, and researchers will be essential in addressing the challenges posed by emerging fungal threats. Fundings No funding was received for conducting this paper Conflict of interest statement The authors declare no conflicts of interest Data availability statement The data that supports the paper will be provided under request Author contributions Mirko Benvenuti: conceptualization; supervision; resource; validation; writing original draft, review, and editing. Ilaria Trave : data curation; writing, review, and editing. Emanuele Claudio Cozzani: review, editing, data curation. ORCID Mirko Benvenuti https://orcid.org/0000-0001-6026-7143 Ilaria Trave https://orcid.org/0000-0002-5469-4517 Emanuele Claudio Cozzani https://orcid.org/0000-0003-3108-4123 References [1] Benvenuti M, Zotti M, La Maestra S. A guide to mycetisms: A toxicological and preventive overview. Med Mycol. 2024 Mar 28;62(4):myae033. doi: 10.1093/mmy/myae033. [2] Lockhart SR, Guarner J. Emerging and reemerging fungal infections. Semin Diagn Pathol. 2019 May;36(3):177-181. [3] Richardson M, Lass-Flörl C. 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Keywords schizophyllum commune brain fungal infections lung skin Authors Affiliations Mirko Benvenuti 0000-0001-6026-7143 [email protected] Universita degli Studi di Genova Dipartimento di Scienze della Salute View all articles by this author Ilaria Trave Universita degli Studi di Genova Dipartimento di Scienze della Salute View all articles by this author Emanuele Claudio Cozzani Universita degli Studi di Genova Dipartimento di Scienze della Salute View all articles by this author Metrics & Citations Metrics Article Usage 602 views 174 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Mirko Benvenuti, Ilaria Trave, Emanuele Claudio Cozzani. Schizophyllum commune Fr. 1815: an odyssey of case reports for an emerging pathogen. Authorea . 27 March 2025. DOI: https://doi.org/10.22541/au.174307683.33982145/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. 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