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Fungal Genetics and Biology xxx (2013) xxx–xxx

YFGBI 2598 No. of Pages 12, Model 5G

12 September 2013

Contents lists available at ScienceDirect

Fungal Genetics and Biology

journal homepage: www.elsevier .com/locate /yfgbi

Crossover fungal pathogens: The biology and pathogenesis of fungicapable of crossing kingdoms to infect plants and humans

1087-1845/$ - see front matter � 2013 Published by Elsevier Inc.http://dx.doi.org/10.1016/j.fgb.2013.08.016

⇑ Corresponding author. Address: Department of Medicine, Section of InfectiousDiseases, School of Medicine and Public Health, University of Wisconsin – Madison,1550 Linden Drive, Microbial Sciences Building, Room 3472, Madison, WI 53706,USA. Fax: +1 (608) 263 4464.

E-mail addresses: [email protected] (G.M. Gauthier), [email protected](N.P. Keller).

1 Current address: Department of Medicine and Public Health, Department ofMedical Microbiology, University of Wisconsin – Madison, 1550 Linden Drive,Microbial Sciences Building, Room 3476, Madison, WI 53706, USA.

Please cite this article in press as: Gauthier, G.M., Keller, N.P. Crossover fungal pathogens: The biology and pathogenesis of fungi capable of crossindoms to infect plants and humans. Fungal Genet. Biol. (2013), http://dx.doi.org/10.1016/j.fgb.2013.08.016

Gregory M. Gauthier ⇑, Nancy P. Keller 1

University of Wisconsin – Madison, Madison, WI, USA

a r t i c l e i n f o a b s t r a c t

2526272829303132333435

Article history:Available online xxxx

Keywords:Crossover fungiTrans-kingdom fungiPlant pathogenic fungiHuman pathogenic fungiPathogenesisIronVelvet protein complex

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The outbreak of fungal meningitis associated with contaminated methylprednisolone acetate has thrustthe importance of fungal infections into the public consciousness. The predominant pathogen isolatedfrom clinical specimens, Exserohilum rostratum (teleomorph: Setosphaeria rostrata), is a dematiaceousfungus that infects grasses and rarely humans. This outbreak highlights the potential for fungal patho-gens to infect both plants and humans. Most crossover or trans-kingdom pathogens are soil saprophytesand include fungi in Ascomycota and Mucormycotina phyla. To establish infection, crossover fungi mustovercome disparate, host-specific barriers, including protective surfaces (e.g. cuticle, skin), elevated tem-perature, and immune defenses. This review illuminates the underlying mechanisms used by crossoverfungi to cause infection in plants and mammals, and highlights critical events that lead to human infec-tion by these pathogens. Several genes including veA, laeA, and hapX are important in regulating biolog-ical processes in fungi important for both invasive plant and animal infections.

� 2013 Published by Elsevier Inc.

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1. Introduction

The outbreak of meningitis associated with contaminatedmethylprednisolone acetate from the New England CompoundingCenter has thrust the importance of invasive fungal infections intothe public consciousness (reader is referred to companion piece byAndes and Casadevall, also Kainer et al., 2012; Smith et al., 2012).Exserohilum rostratum (teleomorph: Setosphaeria rostrata), whichbelongs to a group of dematiaceous (highly melanized) fungi thatcause necrosis of grasses (leaf spot, crown and root rot; reader isreferred to companion piece by Turgeon), is the predominantorganism isolated from patient samples (Smith et al., 2012; Pratt,2005, 2003). Moreover, other potential phytopathogens (e.g., Clad-osporium cladosporioides, Rhizopus stolonifer) have been identifiedin contaminated methylprednisolone lots (Smith et al., 2012;Holmes, 2002; CDC). Before this outbreak, human E. rostratuminfections were rarely reported in the medical literature and lim-ited to persons with impaired immunity. Moreover, this outbreak

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highlights the ability for a subset of fungal pathogens to causeinfection in members of plant and animal kingdoms.

Human fungal infections range from superficial nail and skininfections (�1.7 billion infections/year worldwide) to mucocutane-ous candidiasis (>85 million infections/year worldwide) to invasivefungal infections (>2 million infections/year worldwide) (Brownet al., 2012). Invasive fungal infections (IFI) in humans typically af-fect persons with impaired immunity such as those undergoing so-lid organ or hematopoietic stem cell transplantation. In thispopulation, the incidence of IFIs is increasing (Pappas et al.,2010; Kontoyiannis et al., 2010; Bitar et al., 2009). The establish-ment of the transplant-associated infection surveillance network(TRANSNET), which tracks IFIs in the United States, has enabled adeeper understanding of the epidemiology of fungal pathogens.In solid organ transplant recipients (SOT), Candida spp. (53%) andAspergillus fumigatus (19%) are the most common agents of IFI;whereas dematiaceous fungi, Fusarium spp., mucormycetes, andother molds collectively represent 10% of IFIs (Pappas et al.,2010). In hematopoietic stem cell transplant (HSCT) recipientsAspergillus fumigatus (44%) and invasive Candida spp. (28%) arethe most common pathogens (Kontoyiannis et al., 2010). IFI frommucormycetes (8%), dematiaceous fungi (7%), Fusarium spp. (3%),and unspecified molds (6%) occur at a higher frequency in HSCTrecipients than SOT recipients. Although non-Candida, non-Asper-gillus fungi represent a small proportion of IFIs, mortality associ-ated with these pathogens is substantial—39% mortality for SOTrecipients and 72–95.7% mortality for HSCT recipients (Pappaset al., 2010; Kontoyiannis et al., 2010).

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Epidemiologic data for agriculture fungal pathogens on a na-tional scale is hindered by the complexity of monitoring diversetypes of food crops and limited resources for diagnostic testing.Thus, knowledge is primarily limited to large outbreaks of diseaseand global monitoring of wheat rust pathogens. Outbreaks of agri-cultural fungal pathogens are multifactorial in etiology and can in-volve introduction of a novel pathogen, increased host susceptibilityfrom reduced genetic diversity, and changes in climate (Vurro et al.,2010). Cochliobolus species have been responsible for widespreaddestruction of important agriculture crops such as corn, which hasresulted in famine and economic instability (Rossman, 2009). Globalmonitoring of the pathogens responsible for stem (Puccinia gramin-is), leaf (Puccinia triticina, Puccinia tritici-duri), and yellow (Pucciniastriiformis) rust diseases of cereal crops using field surveys has facil-itated interventions to minimize economic losses, which can besubstantial—U.S. $1.12 billion/year (Pardey et al., 2013; Park et al.,2011). In the United States, the establishment of the National PlantDiagnostic Network by the Agricultural Bioterrorism Act of 2002 (inresponse to the 9/11 terrorist attacks), has facilitated identificationand tracking of emerging plant pathogens including Phakopsorapachyrhizi, the etiologic agent of soybean rust.

Of the 1.5–5.1 million fungal species, an estimated 270,000 spe-cies are associated with plants and 325 are known to infect hu-mans (Blackwell, 2011; Hawksworth and Rossman, 1997; Robertand Casadevall, 2009; Woolhouse and Gaunt, 2007). A small subsetof plant pathogens such as E. rostratum can cross kingdoms and in-fect humans. These crossover pathogens include fungi from Asco-mycota and Mucoromycotina phyla (Table 1) (Krishnam et al.,2009; Pearson et al., 2010; Dignani and Anaissie, 2004; Nucci andAnaissie, 2007; Revankar and Sutton, 2010; Ribes et al., 2000;Gomes et al., 2011; USDA ARS, 2013; Horst, 2008). The majorityof ascomycete crossover pathogens belong to a group of highlymelanized fungi collectively referred to as dematiaceous fungi inthe medical literature (Table 1). The majority of the dematiaceousfungi that cross kingdoms are in the dothideomycetes class (Table1). Despite the importance of basidiomycete fungi, none crossoverto cause infection in both plants and humans; however, humanCryptococcus pathogens can infect plants under laboratory condi-tions (Warpeha et al., 2013). The majority of crossover fungi aresoil saprophytes capable of causing disease in plants (e.g., hemibio-trophs, necrotrophs) and humans. In general, crossover fungi areweak human pathogens that cause infection in persons with im-paired immunity or those who have sustained penetrating traumaincluding iatrogenic (accidental medical) inoculation (Sexton andHowlett, 2006; Dickman and de Figueiredo, 2011).

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2. Acquisition of infection and conidial adherence

To establish infection, fungi must attach to a susceptible host,germinate, penetrate tissue, replicate, and evade host immune de-fenses (Table 2). Both plants and humans have developed protec-tive barriers against IFI. Plant defenses include the cuticle, cellwall, basal immunity, and effector-triggered immunity. Human de-fenses include an intact epidermis, architecture of the respiratorysystem, core body temperature of 37 �C, innate immune defenses,and cell mediated (adaptive) immunity.

The ability of fungal spores to adhere to the host is importantfor the pathogenesis of plant and human pathogenic fungi. Mech-anisms for adhesion to plant surfaces and mammalian tissue areheterogenous and include binding via preformed adhesives (se-creted mucilage or extracellular matrix), hydrophobic interactions,and specific protein–protein or protein–carbohydrate interactions(Tucker and Talbot, 2001; Ibrahim, 2011; Srinoulprasert et al.,2009).

Please cite this article in press as: Gauthier, G.M., Keller, N.P. Crossover fungal pdoms to infect plants and humans. Fungal Genet. Biol. (2013), http://dx.doi.or

Ungerminated conidia of plant pathogenic fungi attach to thecuticle, which forms a hydrophobic surface composed of hydroxyland epoxy fatty acids (C16, C18), waxes (epicuticular, intracuticu-lar), phenolic compounds (e.g., cinnamic acids, flavonoids, lignins),and polysaccharides (Dominguez et al., 2011). The cuticle coversstems, leaves, fruits, flowers, and seeds to protect the plant againstbiotic and abiotic stresses (Dominguez et al., 2011). Conidial adhe-sion prevents displacement by water or wind currents, and is asso-ciated with germination and invasion (Mercure et al., 1994a,b).Colletotrichum graminicola conidia adhere to plant tissues using amulti-stage process that involves (i) attachment of ungerminatedconidia to hydrophobic surfaces within 30 min of contact; (ii) re-lease of a glycoprotein containing matrix at the site of conidialattachment; and (iii) strengthening of the initial attachment by re-lease of glycoproteins from the appressorium (Mercure et al.,1994a,b; Mercure et al., 1995; Sugui et al., 1998). Mucilage associ-ated with conidial production provides protection from dessicationbut does not promote attachment to plant surfaces (Mercure et al.,1994a,b). Similarly, Fusarium solani conidia release an extracellularmatrix upon contact with plant surfaces (Kwon and Epstein, 1997).Within this matrix is a 90 kDa glycoprotein (mannoprotein) that ispostulated to function as an adhesin (Kwon and Epstein, 1997).Attachment by this glue-like mechanism is shared by other patho-genic ascomycetes including Magnaporthe oryzae (etiologic agentof rice blast disease) and Blumeria graminis (powdery mildew ofcereals and grasses), and aquatic saphrophytes such as Lemonnieraaquatica (Hamer et al., 1988; Nielsen et al., 2000; Au et al., 1996).Genes that regulate or contribute to conidial adhesion are poorlyunderstood. However, recent identification of TRA1, which encodesa transcription factor in M. oryzae, is beginning to provide insight.Deletion of TRA1 results in reduced spore tip mucilage, impairedadhesion to plant leaves, and altered transcript abundance for100 genes in ungerminated spores (Breth et al., 2013). Deletionof two of these differentially expressed genes, TDG2 and TDG6, alsoreduces conidial adhesion (Breth et al., 2013). Collectively, thesedata suggest TRA1 is an important regulator for genes involvedwith pre-penetrative pathogenesis.

To initiate human infection, conidia must be internalized byinhalation or directly penetrate the epidermis (Table 2). Structuralconstraints of the upper and lower respiratory system effectivelyrestrict the size of particles that enter the alveolar space (Mullinsand Seaton, 1978). Because the epidermis is resistant to fungalinvasion, conidia or mycelial fragments must enter through breaksin the skin from trauma or iatrogenic inoculation. Similarly, dam-age to the epithelial layer of the cornea is often a prerequisite forfungal keratitis. Once inside the body, fungal conidia can interactand bind to epithelia or basement membrane components suchas laminin and type IV collagen (Ibrahim, 2011). Conidial adhesionis thought to be a critical step involved with infection because it al-lows direct access of the infectious propagule to host tissue andminimizes physical removal by ciliated epithelia (Peñalver et al.,1996; Hernández et al., 2010). The conidia of Fusarium solani, a fre-quent cause of keratitis, can adhere to the basement membrane ofthe cornea following damage of the epithelial layer (Dong et al.,2005). Rhizopus oryzae conidia, which cause mucormycosis, can di-rectly adhere to laminin and type IV collagen, but not glycosamino-glycans or fibronectin, prior to germination (Bouchara et al., 1996).Aspergillus flavus weakly binds to fibronectin (Wasylnka andMoore, 2000).

For the vast majority of crossover fungi (Table 1), mechanismsthat promote conidial attachment in human tissue have not beeninvestigated. On the basis of studies on Aspergillus fumigatus,Penicillium marneffei, and Paracoccidioides brasiliensis, mechanismsthat mediate conidial adhesion for crossover fungi are likely to bediverse. A. fumigatus conidia bind to basal lamina componentsincluding fibronectin, laminin, types I and IV collagen, and

athogens: The biology and pathogenesis of fungi capable of crossing king-g/10.1016/j.fgb.2013.08.016


Table 1Invasive infections in plants and humans caused by crossover fungal pathogens.*

Ascomycota Plant disease Human disease

Aspergillus spp. A. flavus Seedling blight Ocular (trauma); otitis externa (trauma); sinus, lung, and SSTI infections (Trauma, SOT,HSCT, PI, Malignancy)

A. niger Rot, seedling blight Otitis externa (trauma), cutaneous (HSCT, ALL, AML, AA), lung (PI, pre-existing cavity)

Fusarium spp. F. oxysporum Wilt disease, stem canker, rot(root, bulb, stem)

Ocular (trauma); sinus, lung, SSTI, and disseminated infections (Trauma, SOT, HSCT, PI,Malignancy)

F. solani Wilt disease, rot (root, stem,crown)

Ocular (trauma); sinus, lung, SSTI, and disseminated infections (Trauma, SOT, HSCT, PI,Malignancy)

DematiaeceousAcrophialophora A. fusispora Secondary invader of plants Keratitis (trauma), brain abscess (ALL), lung infection (SOT)

Aureobasidium� A. pullulans Fruit russet Keratitis (post-operative), Lung (SOT), SSTI (HSCT, SOT), CAPD peritonitis, CRBI,disseminated (AML)

Alternaria� A. alternata Blight, leaf spot, fruit rot Post-traumatic keratitis, Cutaneous (SOT)A. dianthicola Blight, leaf spot, rot (stem, branch) SSTI (trauma)A. infectoria Black point on wheat SSTI (SOT)A. longipes Leaf spot SSTI (PI)A. tenuissima Blight, leaf spot SSTI (SOT, PI)

Bipolaris� B. australiensis Leaf spot, leaf blight Keratitis, brain abscess (AFS)B. hawaiiensis Leaf spot, seedling blight and wilt Keratitis (trauma), endopthalmitis, sinusitis, CNS infectionB. spicifera Leaf spot, root rot Ocular, sinus, CNS (SOT), cutaneous (ALL), CAPD peritonitis

Cladosporium� C.cladosporioides

Blight SSTI (PI, HIV, healthy), CNS (healthy), Lung

C. oxysporum Leaf spot SSTI (trauma, Cushing syndrome)C.sphaerospermum

Secondary invader SSTI (healthy)

Colletotrichum C. coccodes Anthracnose, leaf spot, blight, rootrot, wilt

SSTI (NHL), disseminated (NHL)

C. crassipes Fruit rot Cutaneous (SOT)C. dematium Anthracnose, blight, leaf spot Keratitis (trauma)C.gloeosporioides

Anthracnose, seedling blight, leafspot, rot

SSTI (trauma, ALL, PI)

C. graminicola Anthracnose, stalk rot, fruit rot Keratitis

Coniothyrium� C. fuckelii Graft canker, Cane blight Hepatic (AML)

Corynespora� C. cassiicola Leaf spot SSTI (DM)

Curvularia C. geniculata Root rot, leaf mold, blight CAPD peritonitisC. inequalis cranberry rot, root rot, seed mold CAPD peritonitisC. lunata Blight, leaf spot Ocular, SSTI (SOT, ALL, PI), disseminated (SOT), CNS (healthy), prosthetic valve endocarditis,

lung (healthy), breast implants (healthy)C. pallescens Leaf spot, rot Keratitis, CNS and lung (healthy), SSTI

Dichotomophthoropsis D.nymphaearum

Leaf spot Keratitis

Exserohilum� E. rostratum Leaf spot, blight, rot (root, crown) Keratitis (post-operative, trauma), sinusitis (AA, healthy), SSTI (trauma, lymphoma),disseminated (AA, ALL); meningitis, bone, joint, soft tissue due to contaminatedmethylprednisolone

Lasiodiplodia� L. theobromae Blight, canker, dieback, gummosis,rot (collar, root, stem-end)

Ocular (trauma) SSTI (trauma), sinusitis (healthy); pneumonia (SOT)

Macrophomina� M. phaseolina Blight, damping-off, rot SSTI (HSCT, AML), disseminated infection (SOT)

Microascus spp. M. cinereus Branch dieback Brain abscess (HSCT), SSTI (CGD), prosthetic valve endocarditis.M. cirrosus Leaf spot, seed rot Disseminated infection (HSCT)

Mycoleptodiscus M. indicus Leaf spot SSTI (PI, SOT); myositis (PI); septic arthritis (trauma)

Neoscytalidium� N. dimidiatum Blight, canker, gummosis, leafspot, rot

Endophthalmitis (trauma), Disseminated infection (neutropenia, SOT); cerebritis (healthy)

Phaeoacremoniumspp.

P. krajdenii Petri disease SSTI (healthy)

Phoma spp.� P. eupyrena Needle cast and blight of fur trees SSTIP. minutella Leaf spot SSTI (PI)

Ulocladium� U. chartarum Fruit spoilage SSTI (SOT)

BasidiomycotaNone – –

MucoromycotinaMucor M. circinelloides Rot SSTI (DM, AML), Sinus (DM)

M. hiemalis Rot SSTI (DM)

Rhizopus R. arrhizus Rot CNS, sinus, lung, SSTI, GI and disseminated infections (Trauma, DM, SOT, HSCT, PI,

(continued on next page)

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Please cite this article in press as: Gauthier, G.M., Keller, N.P. Crossover fungal pathogens: The biology and pathogenesis of fungi capable of crossing king-doms to infect plants and humans. Fungal Genet. Biol. (2013), http://dx.doi.org/10.1016/j.fgb.2013.08.016


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Table 1 (continued)

Ascomycota Plant disease Human disease

(oryzae) Malignancy)R. microsporus Rot CNS, sinus, lung, SSTI, GI and disseminated infections (Trauma, DM, SOT, HSCT, PI,

Malignancy)

Rhizomucor R. pusillus Rot CNS, sinus, lung, SSTI, GI and disseminated infections (Trauma, DM, SOT, HSCT, PI,Malignancy)

* This table lists the most common crossover pathogens and their associated diseases; thus, this table may not be all-inclusive.� Denotes fungi belonging to the dothideomycetes class of fungi. Underlying medical conditions are listed in parentheses. AA is aplastic anemia; ALL is acute lymphoblasticlymphoma; AML is acute myelogenous leukemia; CAPD is continuous ambulatory peritoneal dialysis; CGD is chronic granulomatous disease; CNS is central nervous system; CRBI iscatheter-related bloodstream infection; DM is diabetes mellitus; Healthy indicates no known immunosuppression; HSCT is hematopoietic stem cell transplant; NHL is non-Hodgkin’s lymphoma; PI is pharmacologic immunosuppression (e.g. prednisone, methotrexate, etc.); SOT is solid organ transplant; SSTI is skin and soft tissue infection.

Table 2Mechanisms for infection for crossover pathogens in plants and humans.

Mechanism Plants Humans

Acquisition of Infection � Conidial adherence to plant stems, leaves, roots � Inhalation of aerosolized conidia into lungs or sinuses� Conidial entry into wounded tissue � Traumatic penetration into the skin and soft tissues

Conidial germination � Factors influencing germination: � Thermotolerance (37 �C)Plant surface hydrophobicity � Suppression of host immune defensesPlant surface hardness � Evasion of immune cellsWater activityConidial densityAmbient temperaturePlant derived compounds (e.g. flavonoids)

Invasion and destruction of tissue � Penetration through intact tissue or openings � Uptake of germinating conidia by pneumocytesHyphal invasion � Hyphal invasion of intact tissueAppressorium formation � Iron acquisition and homeostasis� Iron acquisition and homeostasis � Velvet protein complex� Velvet protein complex



12 September 2013

fibrinogen (Peñalver et al., 1996; Gil et al., 1996; Tronchin et al.,1997; Yang et al., 2000; Upadhyay et al., 2009). Binding of fibronec-tin is mediated by 23 and 30-kDa polypeptides on the conidial cellsurface, whereas 23-kDa, 72-kDA, and CalA proteins facilitate bind-ing to laminin (Peñalver et al., 1996; Gil et al., 1996; Tronchin et al.,1997; Upadhyay et al., 2009). In addition, negatively charged carbo-hydrates (e.g. sialic acids) on the conidial cell surface may alsomediate attachment (Wasylnka and Moore, 2000; Wasylnka et al.,2001). Moreover, affinity for extracellular matrix components isspecies specific. A. fumigatus conidia have a greater affinity for fibro-nectin than less common agents of invasive aspergillosis such as A.flavus and A. wentii, or non-pathogenic A. ornatus (Wasylnka andMoore, 2000). The conidia of P. brasiliensis, the etiologic agent of par-acoccidioidomycosis, possess a 32-kDa protein, PbHAD32, on theconidial surface that mediates binding to laminin, fibronectin,fibrinogen, and pulmonary epithelial cells (Hernández et al.,2012). Silencing PbHAD32 by RNA interference resulted in attenu-ated virulence in a murine model of infection (Hernández et al.,2010). The conidia of Penicillium marneffei, which causes penicillio-sis in immunocompromised persons in Southeast Asia, are capableof adhering to different pattern recognition receptors includingmannose receptors, toll-like receptors (TLR1, 2, 4, 6) and integrins(CD11b, CD14, CD18) (Srinoulprasert et al., 2009).

Despite the substantial differences between substrates encoun-tered by conidia from crossover fungi, the presence of hydropho-bins on the conidial surface may represent a shared, althoughlargely unexplored mechanism that may affect adherence.Hydrophobins are amphipathic proteins characterized by 8 con-served cysteine residues and are located on the surface of conidiaand hyphae. The functions of these proteins are diverse and includereduction of water surface tension to promote aerial growth of hy-phae, dispersal of conidia in water droplets, enhancement of adhe-sion for germinated conidia, formation of appressoria, protection ofconidia against phagocytosis, and evasion of innate immune


defenses (Linder et al., 2005; Aimanianda et al., 2009; Dagenaiset al., 2010). Recent analysis of Hyd2, which encodes a hydrophobinfound on the conidial cell surface of Beauveria bassiana, demon-strated that Hyd2 is important for adherence of ungerminated con-idia to insect epicuticle (Zhang et al., 2011). B. bassiana is a plantendophyte capable of infecting several species of insects (Zhanget al., 2011). Thus, it is tempting to speculate that hydrophobinsmay promote the ability of conidia to adapt to different environ-ments (plant surface, insect epicuticle, mammalian lung) to facili-tate adhesion. In fact, there is interest in exploring the potential offungal hydrophobins as orthopedic implant coatings due to theirnative adherent properties (Boeuf et al., 2012).

3. Conidial germination: physicochemical stimuli, structuralbarriers, and temperature adaptation

The conidia of crossover fungi can germinate on seed, root, oraerial plant surfaces and in lung, corneal, or cutaneous tissues.Conidia are capable of remaining in a dormant state until the prop-er stimuli induce germination, which consists of isotropic sporeswelling, development of cell polarity, germ tube formation, andinfection structure differentiation (e.g. appressorium, haustoria,or hyphae). Moreover, the conidia of plant pathogenic fungi cancontain inhibitory molecules to inhibit germination until specificenvironmental and host conditions are met (Leite and Nicholson,1992). The diverse host-ranges for these crossover fungi reflectthe ability of these pathogens to adapt to and sense a wide rangeof stimuli to promote germination and subsequent infection.

Factors that induce conidial germination on plants include thesurface architecture, water activity, ambient temperature, conidialdensity, and plant-derived compounds such as flavonoids, waxesand root exudates (Bagga and Straney, 2000; Barhoom and Sharon,2004; Srivastava et al., 2005; Nanguy et al., 2010) (Table 2). Nutri-



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tional signals such as exogenous glucose are postulated to play aminor role in germination of plant pathogenic fungi. Architecturalfeatures that induce germination include hydrophobicity and hard-ness of the plant surface (Chaky et al., 2001; Kim et al., 1998; Liuet al., 2007). The ability to sense surface hardness or thigmotro-pism, is important for germination and formation of infectionstructures for many plant pathogens (Kim et al., 1998; Liu et al.,2007). The conidia of Colletotrichum species including C. graminico-la and C. gloeosporioides preferentially germinate on rigid ratherthan soft surfaces (Chaky et al., 2001; Kim et al., 1998). The combi-nation of a hard, hydrophobic surface along with plant-derivedcompounds affects the number of germ tubes that emerge, forma-tion of appressoria, and virulence (Barhoom and Sharon, 2004).Germination of C. gloeosporioides in soft media prior to plant inoc-ulation results in decreased pathogenicity when compared to con-idia directly inoculated onto the plant surface or pre-germinated inpea extract (Barhoom and Sharon, 2004). Moreover, C. gloeosporio-ides uses different germination strategies for saprophytic and path-ogenic growth (Barhoom and Sharon, 2004).

The molecular mechanisms underpinning conidial germinationare slowly being elucidated. In C. gloeosporioides, calcium-calmodu-lin signaling promotes germination and formation of appressoriafollowing physicochemical stimulation (hard surface plus ethylene)(Kim et al., 1998). Contact with hard surfaces induces transcriptionof calmodulin and protein phosphorylation by calmodulin kinase(Kim et al., 1998). In addition, specific sets of genes that encodeColletotrichum hard-surface induced proteins (CHIP1-8) are inducedfollowing contact with hard surfaces; however, they are not knownto impact conidial germination or formation of appressoria (Kimet al., 2002). Investigation of thigmotropism in the grass pathogenMagnaporthe has demonstrated that RGS1, a GTPase acceleratingprotein that directly interacts and inhibits MagA (Gas), is involvedwith the genetic program in response to germination on hard sur-faces (Liu et al., 2007).

In addition to their role in thigmotropism, G protein signalingaffects conidial germination. Deletion of Fgb1, which encodes aG protein b subunit in the plant vascular wilt fungus F. oxysporum,results in higher germination frequency and elevated intracellularcAMP levels (Jain et al., 2003). Conidia of F. solani germinate in re-sponse to various flavonoid compounds, which are lipophilic andcan easily penetrate the conidial cell wall. The mechanism under-lying flavonoid-mediated germination involves inhibition of cAMPphosphodiesterase, which results in elevated conidial cAMPconcentrations (Bagga and Straney, 2000). Moreover, higher germi-nation frequency is often associated with stronger inhibition ofcAMP phosphodiesterase (Bagga and Straney, 2000). In contrastto F. solani, deletion of CGB1, which encodes a G protein subunitin the corn blight pathogen Cochliobolus heterostrophus (anamorph:Bipolaris maydis) impairs conidial germination (Ganem et al.,2004). In addition to cAMP-mediated pathways, other signalingcascades such as RAS/MAPK cascades are involved with the germi-nation of agricultural pathogens. Genome-wide gene expressionanalysis of the cereal pathogen Fusarium graminearum has shownthat substantial alteration in gene transcription occurs at differentstages of conidial germination (Seong et al., 2008).

To cause infection in humans, conidia must not only overcomestructural barriers that impede entry into the host (e.g. skin, lungarchitecture), but need to germinate under conditions of elevatedtemperature, slightly alkaline pH of 7.4, and evade the immunesystem (Table 2) (Casadevall, 2005; Robert and Casadevall, 2009).Core human body temperature (37 �C) is postulated to serve as amajor defense mechanism against IFI by restricting growth (Robertand Casadevall, 2009). Computational modeling predicts that36.7 �C provides the greatest degree of protection against invasivefungal infection with the least metabolic cost (Bergman and Casa-devall, 2010). Analysis of a large collection of animal, insect, plant,

Please cite this article in press as: Gauthier, G.M., Keller, N.P. Crossover fungal pdoms to infect plants and humans. Fungal Genet. Biol. (2013), http://dx.doi.org

and soil saprophytic fungi demonstrated that for every 1 �C in-crease in temperature above 30 �C, the number of fungi that couldgrow progressively declined (Robert and Casadevall, 2009). Theconidia of crossover pathogens such as A. niger, B. australiensis,B. hawaiiensis, C. clavata, C. pallescens, C. senegalensis, F. solani andL. theobromae (Table 1) are capable of germination and hyphalgrowth at 37 �C in vitro; however, hyphal development and replica-tion is suboptimal when compared to lower temperatures (Alma-guer et al., 2013; Yang, 1973; Araujo and Rodrigues, 2004; Mehland Epstein, 2007; Saha et al., 2008). In contrast, A. flavusgermination frequency is enhanced at 37 �C compared to 30 �C,but germination kinetics are substantially slower than A. fumigatus,which is the predominant pathogen for invasive aspergillosis (Ara-ujo and Rodrigues, 2004). The ability for humans to maintain bodytemperature higher than the surrounding environment creates a‘‘thermal exclusionary zone’’ that can inhibit or impede germina-tion and growth for the vast majority of fungi (Casadevall, 2012).However, temperature is not uniform throughout the body;extremity and corneal tissues are lower than core body tempera-ture of 37 �C (Kessel et al., 2010). This slight reduction in temper-ature has the potential to allow for infection by fungi whosegermination and growth would otherwise be compromised at37 �C.

The concept that core body temperature can influence host sus-ceptibility to fungal infection is not limited to humans and is rele-vant to other mammals, insects, and amphibians. Geomycesdestructans (recently renamed as Pseudogymnoascus destructans(Minnis and Lindner, in press)), the etiologic agent of white nosedisease in insectivorous bats, is a psychrophile (cold loving) fungusthat infects the nose, muzzle, ears, and wings leading to hypotonicdehydration, electrolyte disturbances, disordered acid–base bal-ance, and premature fat depletion (Lorch et al., 2011; Warneckeet al., 2012, 2013). White-nose disease has killed >5 million batsin 19 U.S. states and 4 Canadian provinces since it was first discov-ered in New York state in 2006 (Blehert, 2012). G. destructans rep-lication is optimal at 12.5–15.8 �C with an upper limit of 19.0–19.8 �C in vitro (Verant et al., 2012). Bats are susceptible towhite-nose syndrome only during hibernation, which is when theydrop their core body temperature to a level that is permissive for G.destructans growth (Blehert, 2012). Several species of insectsincluding the housefly (Musca deomestica), locusts (Locusta migra-toria, Schistocerca gregaria), and grasshoppers (Oedaleus senegalen-sis, Melanoplus sanguinipes) can induce fever by basking in warmtemperatures to combat invasive fungal infections (Anderson,2013; Ouedraogo et al., 2002). These behavioral fevers are postu-lated to impair fungal growth by elevating core body temperatureand stimulating a robust immune response (Anderson, 2013).Houseflies infected with Beauveria bassiana or Entomophthora mus-cae seek locations with high ambient temperature when comparedto uninfected flies (Anderson et al., 2013; Watson et al., 1993). Forflies infected with B. bassiana, behavioral fever delays death and al-lows females more time to lay eggs (Anderson et al., 2013). Incontrast, elevation in core body temperature facilitates cure andincreases survival following E. muscae infection (Watson et al.,1993). Behavioral fever in L. migratoria locusts infected with Meta-rhizium anisopliae serves to maintain hemocyte concentration inthe hemolymph, increase phagocytic activity, and inhibit fungalgrowth (Ouedraogo et al., 2002, 2003). To combat the beneficial ef-fect of elevated temperature, Metarhizium robertsii produces a sec-ondary metabolite, destruxin A, which interferes with behavioralfever and leads to the death of S. gregaria locusts (Hunt andCharnley, 2011).

Similar to behavioral fever, external application of heat can beused to treat certain fungal infections of amphibians and humans.Batrachochytrium dendrobatidis, the etiologic agent of chytridiomy-cosis, which is devastating amphibian populations worldwide,

athogens: The biology and pathogenesis of fungi capable of crossing king-/10.1016/j.fgb.2013.08.016


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grows between 6 and 28 �C with optimal replication at 17–23 �C(Voyles et al., 2009; Woodhams et al., 2003). This pathogen infectskeratinized epithelial cells resulting in disordered electrolyte (Na+,K+, Cl�) balance and H2O absorption, which culminates an asystoliccardiac arrest (Voyles et al., 2009). In addition, diseased frogs dis-play elevated corticosterone concentrations, increased resting met-abolic rate, suppressed appetite, reduced body mass, and alteredleukocyte counts (Peterson et al., 2013). Exposure of infected frogsto 37 �C for 16 h or 30 �C for 10 days results in 100% and 96.4% curerate, respectively (Woodhams et al., 2003; Chatfield and Richards-Zawacki, 2011). In humans, the dimorphic fungal pathogen Sporo-thrix schenckii causes cutaneous nodules and ulcers following trau-matic inoculation. Local hyperthermia (42–43 �C) can be used asadjunctive therapy for patients with fixed cutaneous sporotrichosis(Kauffman et al., 2007). The elevation in temperature is postulatedto inhibit growth of S. schenckii and enhance killing by neutrophils(Hiruma and Kagawa, 1986). The utility of local hyperthermia forother human fungal pathogens remains limited; however, it hasbeen successfully used to treat cutaneous Alternaria alternata infec-tion and chromoblastomycosis (Torres-Rodriguez et al., 2005;Hiruma et al., 1993).

The molecular mechanisms underlying thermotolerance arecomplex and poorly understood. Research on temperature adapta-tion has primarily focused on the most common agents of invasivemycosis. Gene expression analysis of A. fumigatus following an in-crease in temperature from 30 �C to 37 �C identified 726 differen-tially expressed genes with many involved with translation,amino acid, carbohydrate, lipid, and energy metabolism (Doet al., 2009). Temperature elevation also induced increased geneexpression of heat shock proteins which was associated with atransient decrease in transcripts involved with carbohydrate andenergy metabolism during the early stages (<60 min) of germina-tion (Do et al., 2009). Similarly, Lamarre and colleagues identified787 differentially expressed genes during the first 30 min of A.fumigatus conidial germination at 37 �C (Lamarre et al., 2008).These genes were predicted to be involved with respiration, trans-lation, RNA biogenesis, and amino acid, protein, carbohydrate andlipid metabolism (Lamarre et al., 2008). Moreover, in ungermi-nated conidia, pre-processed mRNA transcripts were detected for27% of the total genome (Lamarre et al., 2008). The presence ofpre-processed transcripts has also been detected in ungerminatedconidia of A. niger (25% of genes) and F. graminearum (42%) (vanLeeuwen et al., 2013; Seong et al., 2008). The large percentage ofpre-formed transcripts is postulated to facilitate rapid growthand adaptation to the external environment once the genetic pro-gram inducing germination is initiated (van Leeuwen et al., 2013).

The ability to adapt to elevated temperature is necessary butnot sufficient for crossover fungi to establish infection. Thesepathogens must also overcome innate and adaptive immune hostdefenses. In contrast to primary human fungal pathogens such asBlastomyces dermatitidis, Histoplasma capsulatum, Coccidioides spp.and Paracoccidioides brasiliensis, crossover fungi are often unableto survive attack by host immune cells. Thus, impairment of the in-nate (neutrophils, macrophages, NK cells) and adaptive (Th1 andTh17 T lymphocytes) immune systems is required for the vast amajority of fungi to establish invasive infection (LeibundGut-Landmann et al., 2012). Immune host defenses for most patientswith crossover fungal infections are impaired by hematologicmalignancy, pharmacologic immunosuppression, and transplanta-tion (Table 1).

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4. Tissue invasion and manifestations of disease

Following conidial germination, plant pathogenic fungi launch amultifaceted attack to invade and feed on host tissues. The degree


of plant damage depends on the invasive lifestyle of the fungus.Following penetration of the cuticle and plant cell wall, biotrophssuch as mildews and rusts cause minimal damage and live insidethe plant cell (intercellular, intracellular, subcuticular) withoutcausing death (Mendgen and Hahn, 2002). In contrast, necrotophssuch as Alternaria and Fusarium spp. kill the host before an effectiveimmune response can be generated and feed on the dead plantmaterial. Plant death is mediated by hyphal invasion, secretion ofdegradative enzymes, phytotoxins, and reactive oxygen species(Horbach et al., 2011). Some fungi such as Colletotrichum spp. havea hemibiotrophic lifestyle in which they infect the host as a bio-troph and then switch to necrotrophic growth to kill the plant(Münch et al., 2008).

Mechanisms for invasion of crossover fungi are diverse and in-clude entry through natural openings (e.g. stomata), wounds, orpenetration through intact plant tissue by hyphae or appressoria(Table 2). The hyphae of F. oxysporum surround and invade the pri-mary and lateral roots without forming specialized structures.Invasion results in plant cell collapse from loss of turgor pressure,cessation of root growth and eventual collapse of root structure(Czymmek et al., 2007). Following entry into the root, F. oxysporuminvades vascular tissue, grows rapidly (>2.8 lm/min), and chokesoff nutrient and water transport leading to wilt and plant death(Czymmek et al., 2007). In addition, the phytotoxin fusaric acidcontributes to water loss and high concentrations can be detectedin leaves, which are not invaded by F. oxysporum (Dong et al.,2012). The molecular mechanisms underlying Fusarium invasionand virulence involve activation of Fmk1 MAPK, cAMP-PKA andG-protein signaling pathways, proper regulation of nitrogenmetabolism by Fnr1, assimilation of alternative carbon sources byFrp1 and Snf1, peroxisomal biogenesis, Zn(II)2Cys6 transcriptionfactors (Fow2, Ftf1), and detoxification of plant derived compoundsby Tom1-mediated hydrolysis or the b-ketoadipate pathway(Michielse and Rep, 2009; Divon et al., 2006; Imazaki et al.,2007; Jonkers et al., 2009; Ospina-Giraldo et al., 2003; Pareja-Jaimeet al., 2008; Michielse et al., 2012). Similar to F. oxysporum, G-pro-tein Cbg1 and MAPK kinase Chk1 in C. heterostrophus (anamorph:B. maydis) are important for invasion of corn leaves (Ganemet al., 2004; Lev et al., 1999). MAPK, cAMP-PKA and G-protein sig-naling pathways, in particular, are universally conserved signalingpathways important in pathogenesis of both plants and humans(reviewed in Kozubowski et al., 2009; Li et al., 2012).

Another conserved molecular pathway regulating virulence inboth plant and human pathogenic fungi is the Velvet complex, firstdescribed in the saprophyte A. nidulans (Bayram et al., 2008). TheVelvet and associated complexes (composed of LaeA, VeA, VelBand VelC) in F. oxysporum regulate fungal development, chromatinremodeling, secondary metabolite production, and contribute topathogenesis. Deletion of veA, velB and laeA, but not velC resultsin attenuated virulence in both plant and mammalian hosts anddecreases production of the mycotoxin beauvericin (López-Bergeset al., 2013). Deletion of these genes in other fungi have also beenassociated with decreased production of degradative enzymes,which also contribute to successful invasion processes in patho-genic fungi (Amaike and Keller, 2009; Karimi-Aghcheh et al.,2013). Several cell wall degrading enzymes such as pectate lyases,polygalacturonases, xylanases, and proteases are released duringroot penetration; however, the contribution of these enzymes to-wards pathogenesis has been difficult to elucidate due to func-tional redundancy (Jonkers et al., 2009; Michielse and Rep, 2009).

Biotrophic, hemibiotrophic, and some necrotrophic fungi use aspecialized invasion structure called an appressorium to penetrateintact plant tissue. The molecular biology underlying appressoriumformation has been an area of intensive investigation with detailedmolecular knowledge obtained from Magnaporthe oryzae, which is astrict phytopathogen (Wilson and Talbot, 2009; Caracuel-Rios and



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Talbot, 2007). Following germination on the leaf surface, adome-shaped appresorium develops at the end of the germ tube.G-protein, cAMP-PKA, and Pmk1 MAPK signaling are required forappressorium formation (Nishimura et al., 2003; Mitchell and Dean,1995; Xu and Hamer, 1996). As the appressorium matures, dihydr-oxynapthalene melanin and chitin is deposited on the cell wall toprovide structural support against high turgor pressure requiredfor penetration (Wilson and Talbot, 2009). Turgor pressure (up to8.0 MPa) is generated by rapid uptake of water driven by elevatedintracellular glycerol concentrations (Wang et al., 2005). Elevationin turgor pressure forces a penetration peg through a fungal porethat lacks a cell wall to facilitate entry into the plant cell. Penetra-tion peg formation is governed by Mps1 MAPK signaling and reac-tive oxygen species generated by NADPH oxidases Nox1, Nox2 andNoxR (Xu et al., 1998; Ryder et al., 2013). Both MAPK signaling andreactive oxygen species promote formation of a heteroligomericseptin ring (Sep3, Sep4, Sep5, Sep6), which functions as a scaffoldfor F-actin at the penetration pore and acts as a diffusion barrierfor proteins involved in membrane evagination (i.e. penetrationpeg) (Dagdas et al., 2012). Following proper migration of nuclei,mitosis, and penetration into the plant host, the conidium on theplant surface undergoes autophagic death. Autophagy, which is crit-ical for invasion and virulence, begins shortly after germination, oc-curs in both conidium and appressorium, requires Pmk1 MAP kinaseactivity, promotes maturation of the appressorium, and inducesconidial cell death (Kershaw and Talbot, 2009).

Following invasion of the plant cell, differentiation of the pene-tration peg is influenced by the lifestyle of the infecting fungus. Forobligate biotrophs, the penetration peg matures into a specializedinfection structure known as haustorium, which is surrounded bythe plant cell membrane and facilitates uptake of nutrients. Forhemibiotrophs, the penetration peg swells to form an infectionvesicle from which large, biotrophic primary hyphae emerge to in-fect the first (epidermal) or second (mesophyll) cell layers under-neath the cuticle. After a period of biotrophic growth (�12–48 h),narrow necrotrophic (secondary) hyphae emerge from the primaryhyphae to kill plant cells (Perfect et al., 1999). The transition be-tween appressorial development to biotrophic growth to necro-trophic plant cell destruction involves substantial changes ingene transcription, which has recently been characterized in Collet-otrichium species. In C. graminicola and C. higginsianum, 22% and44% of genes are differentially expressed during infection(O’Connell et al., 2012). Genes encoding carbohydrate active en-zymes involved with cutin, cellulose, hemicellulose, and pectindegradation are upregulated during appressorium maturation,whereas gene encoding secreted proteases are highly expressedduring the necrotrophic growth (O’Connell et al., 2012). Transcrip-tion of secondary metabolite gene clusters is highest duringappressorial and biotrophic phases, and substantially declines dur-ing necrotophy. Genes encoding secreted effector proteins arehighly transcribed during biotrophic growth. This transcriptionalpattern suggests secondary metabolites in addition to secretedeffector proteins alter or impair the host response to infection tofacilitate invasion and biotrophic growth (O’Connell et al., 2012).

Deep fungal infection in humans results in substantial morbid-ity and mortality due to invasion and subsequent necrosis of lung,ocular, brain, vascular, and cutaneous tissues (Table 2). The contri-bution of specialized infection structures used by some crossoverpathogens (e.g. Collectotrichum appressoria) for invasion of humantissue is unknown. Tissue destruction (e.g. collagen, elastin) andinvasion during infection is postulated to occur through secretedenzymes and invasion of host cells (e.g. epithelial, endothelial).As mentioned above, deciphering the role of degradative enzymeson virulence has been complicated by functional redundancy, how-ever such enzymes are essential for the fungus to obtain nutrients(Abad et al., 2010; Mellon et al., 2007). Receptor-mediated uptake


of germinating conidia and germlings by non-professionalphagocytes has recently been shown to be important for pathogen-esis. During isotropic conidial swelling, b-(1,3)-glucan moieties onthe surface of A. fumigatus conidia become exposed and bind todectin-1 receptors on type II pneumocytes. This binding event acti-vates phospholipase D, which induces internalization of the swol-len conidia into the epithelial cell (Han et al., 2011). In addition todectin-1, E-cadherin on type II pneumocytes can mediate internal-ization of A. fumigatus conidia (Xu et al., 2012). Following theirinteraction with epithelial cells, Aspergillus spp. frequently invadeblood vessels resulting in thrombosis and disseminated disease.In vitro modeling shows that A. fumigatus hyphae directly pene-trate the endothelial cell when growing towards the lumen ofthe blood vessel (abluminal invasion) or when the hyphal tip con-tacts the luminal side of the endothelial cell (luminal invasion)(Kamai et al., 2009). Thus, angioinvasion by Aspergillus is a trans-cellular and not a paracellular process. Moreover, endothelial cellinvasion induces production of TNF-a and tissue factor, whichare involved in inflammation and thrombosis, respectively (Kamaiet al., 2009). Endothelial cell invasion likely contributes to the angi-oinvasive properties of Rhizopus oryzae, the most common agent ofmucormycosis. Following binding of GRP78 on the endothelial cellsurface, R. oryzae germlings are internalized and damage the cell(Liu et al., 2010). Expression of this receptor is upregulated inbrain, sinus, and lung tissues during experimental diabetic ketoac-idosis (serum pH < 7.4, elevated iron, and hyperglycemia) (Liuet al., 2010). These data provide insight into mechanisms used byAspergillus and Rhizopus oryzae to invade tissues commonly dam-aged in patients with invasive aspergillosis and diabetic ketoacido-sis, respectively. On the basis of studies in A. fumigatus and otheropportunistic human pathogens such as Candida albicans and Cryp-tococcus neoformans (Filler, 2013), the mechanisms used by cross-over fungi to invade tissues are likely to be diverse.

For several human fungal pathogens, the ability to assimilatenutrients such as iron contributes to pathogenesis; this is alsotrue for plant pathogenic fungi as well as symbiotic fungi(reviewed in Haas et al., 2008). In A. fumigatus, virulence has beenlinked to siderophore-mediated iron uptake and metabolicreprogramming of the fungal cell in response to iron limitation.Deletion of A. fumigatus genes involved with siderophore biosyn-thesis results in attenuated or complete loss of virulence in amurine model of infection (Schrettl et al., 2007, 2004). Crossoverpathogens A. flavus, A. niger, and F. oxysporum also producesiderophores; however, their role in pathogenesis remains unex-plored (Baakza et al., 2004; López-Berges et al., 2013). Sidero-phore biosynthesis contributes to virulence in plant pathogensC. heterostrophus, Cochliobolus miyabeanus, Fusarium graminearum,and Alternaria brassicicola (Oide et al., 2006). The bZIP transcrip-tion factor, HapX, in A. fumigatus and F. oxysporum facilitatesadaptation to iron poor conditions related to sequestration byiron-binding molecules (e.g. ferritin, transferrin, lactoferrin) inthe human body. HapX functions as part of transcription factorcomplex that inhibits iron-consuming metabolic pathways,refashions the intracellular amino acid pool, and represses SreA(a negative regulator of siderophore biosynthesis) to promotegrowth when exogenous iron is limited (Schrettl et al., 2010;López-Berges et al., 2013). A. fumigatus and F. oxysporum HapXnull mutants are avirulent in murine models of pulmonary andsystemic infection, respectively (Schrettl et al., 2010; López-Ber-ges et al., 2013). Moreover, deletion of HapX in F. oxysporum re-duces the ability of this pathogen to cause disease in tomatoplants and compete for iron against siderophore-producing bacte-ria (Pseudomonas spp.) that reside on the root surface (López-Ber-ges et al., 2013). Collectively these data suggest that adaptation toiron limitation and regulation of iron homeostasis are importantfor fungal infection of mammals and plants.



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Although not as well studied as iron, a requirement for othermetals including copper and zinc has been demonstrated for bothhuman and plant pathogenic fungi. Copper is an essential co-factorfor several enzymes such as laccases, oxidases and dismutases(Mäkelä et al., 2013; Hwang et al., 2002). Work in Cryptococcus neo-formans and Candida albicans have demonstrated the critical needfor homeostasis in maintaining appropriate amounts of copperduring pathogenesis (Waterman et al., 2013; Ding et al., 2011,2013; Hwang et al., 2002). Zinc is a common co-factor for manyregulator genes (e.g. zinc fingers and zinc cluster proteins). A noveluptake system has been recently described in C. albicans (Citiuloet al., 2012) and zinc deprivation leads to poor growth of fungi(Lulloff et al., 2004). Several studies in A. fumigatus have demon-strated a requirement for zinc uptake in pathogenesis (reviewedin Wilson et al., 2012) and, as the genes involved are conservedin fungi, it is likely a similar system is required for pathogenesisin most if not all fungi. This ability of fungi to uptake these metalsis being exploited in bioremediation programs (Hong et al., 2010).

The 2005 – 2006 outbreak of contact lens associated Fusariumkeratitis highlighted the importance of crossover pathogens tomedical and plant pathology communities. Multilocus sequencetyping identified a subgroup of clinical isolates belonging to F.solani species complex group 1 (FSSC 1) were the same species asF. solani f. sp. cucurbitae race 2 (Fsc2), which infects squashes(Zhang et al., 2006; Mehl and Epstein, 2007). Subsequent investiga-tion of a different group of FSSC 1 isolates from clinical specimens,sewage, and plants demonstrated they are all capable of infectingzucchini, reproducing with the opposite mating type, and growingat 37 �C (Mehl and Epstein, 2007). In addition to FSSC 1, F. oxyspo-rum f. sp. lycopersici race 2 (referred to as F. oxysporumlr2), cancause disseminated, fatal infection in a murine model and kill to-mato plants (Ortoneda et al., 2004). Plant and human Fusariumsolani and oxysporum isolates are also capable of killing Galleriamellonella larvae (greater wax moth), a model invertebrate host(Coleman et al., 2011; Navarro-Velasco et al., 2011). These findingshave positioned Fusarium to become a model crossover pathogenfor investigating the genetics underlying shared (and host specific)mechanisms of pathogenesis in plants and mammals. Deletion of aG-protein b subunit (Fgb1) and fmk1 MAP kinase (Fmk1) impairsthe ability of F. oxysporumlr2 DFgb1/DFmk1 to bind fibronectin, se-crete proteases and kill mice (Prados-Rosales et al., 2006). Simi-larly, F. oxysporumlr2 VeA and LaeA null mutants have attenuatedvirulence in mice and are unable to biosynthesize the mycotoxinbeauvericin when grown in human blood (López-Berges et al.,2013). These findings are significant because Fgb1, Fmk1, VeA,LaeA and HapX also contribute to virulence in plants (e.g. tomatoplants).

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5. Crossover fungi outbreaks

The outbreak of fungal meningitis associated with contami-nated lots of methylprednisolone acetate used for epidural and in-tra-articular injections is unprecedented in scope. As of June 2013,745 patients from 20 states have met the Centers for Disease Con-trol case definition and 58 people have died (7.8% mortality) (CDC).Clinical manifestations include meningitis, isolated paraspinalinfection (i.e. epidural abscess, discitis, vertebral osteomyelitis,arachnoiditis, phlegmon), meningitis with paraspinal infection,and septic arthritis (CDC). Histopathologic analysis has demon-strated fungal invasion of the brain, leptomeningeal, and vasculartissues (CDC; Bell et al., 2013). Central nervous system vascularinvasion has been characterized by inflammation (vasculitis),thrombosis, and hemorrhage (CDC; Bell et al., 2013). An estimated9% of patients with fungal meningitis have experienced stroke withinvolvement of the posterior or brainstem circulation occurring in


96% (Smith et al., 2012). Crossover fungi isolated from clinicalspecimens include E. rostratum, A. alternata, Bipolaris spp., andCladosporium cladosporioides (CDC; Smith et al., 2012; Lockhartet al., 2013).

Although smaller in scale than the current fungal meningitisoutbreak, there have been several reports of crossover fungal out-breaks. In 2000–2001, five women were diagnosed with Curvularialunata infection involving saline filled breast implants followingaugmentation mammoplasty (Kainer et al., 2005). The likely sourceof infection was environmental contamination of saline prior toinjection into the implants. Improper airflow in the operatingroom, use of an ‘‘open bowl’’ technique (saline poured into anuncovered, sterile bowl), and fungal contamination of a water-damaged ceiling in the sterile supply room were associated withinfection of the saline implants (Kainer et al., 2005). In 2005–2006, a large outbreak of F. solani and F. oxysporum keratitis oc-curred in the USA and other countries affecting >300 people (Changet al., 2006; Grant and Fridkin, 2007; Mukherjee et al., 2012). Thisoutbreak was associated with use of ReNu with MoistureLoc con-tact lens solution, which has been withdrawn from the market(Chang et al., 2006; Grant and Fridkin, 2007). In contrast to the fun-gal meningitis outbreak, the medical product was sterile at thetime it was manufactured. Fusarium contamination occurred inthe patients’ local environment and involved opened bottles andused contact lens cases (Chang et al., 2006). Potential factors con-tributing to the development of keratitis included reduced biocideefficacy due to its uptake by the contact lens material, nutritiveproperties of lens solution, biofilm formation (F. solani > F. oxyspo-rum) on contact lens surface, and chemical damage to the cornearelated to biocides in the contact lens (Epstein, 2007; Mukherjeeet al., 2012). Penetrating trauma related to natural disasters includ-ing a volcanic eruption in Columbia in 1985 and an EF-5 tornado inJoplin, Missouri in 2011 have resulted in outbreaks of mucormyco-sis (Patiño et al., 1991; Fanfair et al., 2012). Similarly, combat-re-lated blast injuries in Afghanistan and Iraq have resulted insevere fungal infections (Warkentien et al., 2012; Paolino et al.,2012). Crossover pathogens recovered from infected tissue includeMucor spp., A. flavus, A. niger, Acrophialophora fusispora, Alternariaspp., Bipolaris spp., Fusarium spp., and Ulocladium spp. (Warkentienet al., 2012). In addition to contamination of blast injury site withorganic material, other risk factors included systemic acidosis andlarge transfusion requirements (average of 30 units of red bloodcells or fresh frozen plasma per patient), which can result in immu-nosuppression and iron overload (Warkentien et al., 2012).

These outbreaks highlight several important events that can leadto infection by crossover pathogens: (i) penetration of the protectivebarriers—direct inoculation of fungi into the cornea, epidural space,subcutaneous tissue, joint, and medical devices; (ii) immunosup-pression; (iii) thermotolerance; (iv) environmental contaminationof medicines, solutions, and tissue; and (v) and the ability of fungito acquire host-derived nutrients to facilitate growth and invasionof tissue (Table 2).

6. Toxins, mycotoxins and mycotoxicosis

A subset of fungi produce toxic secondary metabolites termedmycotoxins that when ingested can result in human disease collec-tively known as mycotoxicoses (Wild and Gong, 2010). Most ofthese fungi are facultative parasites that exist as saprophytes butalso cause diseases of edible parts of the plant. The majority ofthe common mycotoxins are produced by Aspergillus, Fusarium,Penicillium and Claviceps spp. (for reviews, the reader is directedto Subramaniam and Rampitsch, 2013; Woloshuk and Shim,2013). In some cases the mycotoxin, such as trichothecenes pro-duced by F. graminearum (Proctor et al., 1995; Menke et al.,



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2012), is a virulence factor in plant disease development but ingeneral, production of the mycotoxin does not appear toexacerbate plant disease. The different mycotoxins produce aplethora of symptoms in humans and other mammals that can leadto death, as is the case for A. flavus aflatoxin poisoning of both ani-mals and humans (Wouters et al., 2013; Dereszynski et al., 2008;Lewis et al., 2005; Lye et al., 1995). Interestingly, several mycotox-igenic fungi are also human pathogens such as A. flavus; however itis rare to find reports of mycotoxin synthesis in human tissues bythe invading fungi (Mori et al., 1998). Whether this is due to lack ofsynthesis in situ or failure to analyze patient tissues for mycotoxinsis unknown.

While not classified as mycotoxins, several other fungal toxinsare known or suspected to participate in disease development inboth plants and animals (including humans). Many of the plant dis-eases caused by Dothideomycete fungi (e.g. Cochliobolus, Alternaria)are exacerbated by the production of phytotoxins, which can behost-specific, or non-host specific (reviewed in Stergiopouloset al., 2013). A. fumigatus, which is responsible for the majority ofinvasive aspergillosis (IA) cases, produces many toxins thought tocontribute to IA (Yin et al., 2013; Dagenais and Keller, 2009; Gauthi-er et al., 2012). The Velvet complex and LaeA, mentioned earlier, areglobal regulators of toxin production in fungi and have been foundto be virulence factors in both plant and human pathogenic fungi(Amaike and Keller, 2009; Wiemann et al., 2010; Wu et al., 2012;Yang et al., 2013). It is notable that many of the fungi listed in Table1 are known toxin producers; however any possible impact of toxinsynthesis in human infection has not been explored.

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7. Agricultural fungicides and invasive fungal infections inhumans

To minimize agricultural losses from fungal diseases, fungicidesare routinely applied to economically valuable crops. In 2007, anestimated $8 billion was spent on fungicides worldwide (Knightand Turner, 2009). Expenditures in the United States, European Un-ion, and United Kingdom were �$800 million, �$2.9 billion, and�$272 million, respectively (Knight and Turner, 2009; Osteenet al., 2012). Although controversial, there is concern that exten-sive use of agricultural triazoles can induce the resistance of A.fumigatus to medically important triazoles such as itraconazole,voriconazole, and posaconazole (Snelders et al., 2009, 2012; Ver-weij et al., 2009).

In the Netherlands, the prevalence of itraconazole resistance ofA. fumigatus isolated from humans has increased from 1.7% to 6.0%,and 90% to 94% of these resistant isolates contain a 34-base pairtandem repeat and a point mutation in cyp51A (TR34/L98H muta-tion) (Snelders et al., 2008; van der Linden et al., 2011). Cyp51A en-codes 14-a-lanosterol demethylase, which is involved in ergosterolbiosynthesis and inhibited by triazole antifungals. The TR34/L98Hmutant also confers reduced susceptibility or resistance to vorico-nazole and posaconazole (Snelders et al., 2008, 2011). A. fumigatusTR34/L98H mutants are not just found in the Netherlands, but havealso been isolated from humans in several other European coun-tries and Asia (Lockhart et al., 2011; van der Linden et al., 2013).TR34/L98H mutants are derived from a common ancestor and iso-lates recovered from cultivated soils are genetically linked to clin-ical A. fumigatus isolates harboring the TR34/L98H mutation(Snelders et al., 2009; Mortensen et al., 2010; Camps et al., 2012).

The spread of TR34/L98H in Europe, emergence of novel A.fumigatus mutants with high-level voriconazole resistance (TR46/Y121F/T289A), and widespread use of agricultural triazoles withactivity against A. fumigatus have the potential to adversely affectclinical outcomes in patients with invasive aspergillosis (Snelderset al., 2012; van der Linden et al., 2013). Crossover pathogens,


which are the intended targets of agricultural fungicides, are in aunique position to develop resistance, which has the potential tolimit therapeutic options for treating these pathogens in humans.The potential impact of fungicides on clinically significant resis-tance in crossover pathogens remains speculative and is an areafor future research.

8. Allergic inflammation and crossover pathogens

Another area where fungi play a large role in human health isallergenicity where several fungal species elicit severe inflamma-tion responses in a largely non-invasive manner, although localcolonization of lung epithelial tissues may be important in contin-uing allergenic challenge. Aspergillus fumigatus and Alternaria spp.are particularly allergenic but other fungi, including several cross-over spp. can and do play a role in the allergic response. It is be-yond the scope of this current review to address this topichowever, and the reader is referred to several recent reviews onthis topic (Callejas and Douglas, 2013; Mahdavinia and Grammer,2012; Kennedy et al., 2012; Knutsen et al., 2012; Chaudhary andMarr, 2011).

9. Conclusion

Although not common, IFI from crossover fungi are not infre-quent and appear to be on the rise. This latter observation is likelyassociated with the increased numbers of immunocompromisedpatients world wide. Infections are also frequently associated withinjuries or contamination of medical apparati or medicines. How-ever, not all fungi have the capability to crossover; certain proper-ties such as the ability to grow at 37 �C are necessary for robustinfections. A close look at the fungi listed in Table 1 shows thatmany of the crossover fungi are dematiaceous fungi. Many of thesedematiaceous fungi are weak plant pathogens and can survive wellas saprophytes. Possibly it is some of the properties that allow forsaprophytic growth that give them an edge in opportunistic infec-tions of humans. Regardless of the properties allowing for cross-over, once infection occurs many of the same virulence factorsare shared between plant and human pathogenic fungi.

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Fungal Genetics and Biology - Department of Medicine · 116 melanized fungi collectively referred to as dematiaceous fungi in 117 the medical literature (Table 1). The majority of