Review Article

Plant Pathogenic Fungi ─ Novel Agents of Human Diseases: Implications for public Health

Enyiukwu DN*¹, Ononuju CC¹ and Maranzu JO²

¹Department of Plant Health Management, Michael Okpara University of Agriculture, Umudike PMB 7267 Umuahia, Abia State.

²National Environmental Standards Regulation and Enforcement Agency (NESREA) Owerri Imo State, Nigeria.

INTRODUCTION

Fungi (mycota) are spore-forming, achlorophyllous, filamentous (sometimes single celled) eukaryotes whose cells are surrounded by cell walls (Bamgbose, 2012). In nature fungi, are the most ubiquitous decomposers and mycorrhizae which play vital roles in nutrient recycling and absorption in tropical farming systems (Raven et al., 1992; Boundless, 2016; Reference, 2016).  However around the world, fungi also have many undesirable effects on plant health causing a plethora of pathogenic diseases estimated to destroy not less than 125 million metric tonnes (MT) of protein-calorie providing food crops – rice, wheat, maize, potatoes and soybean per annum  (Imperial College, 2012). Furthermore, association of certain fungi with stored agricultural grains could lead to their contamination with fungi-derived toxins (mycotoxins). These toxins due to their ability to suppress hormonal immunity and cause tissue breakdown have been implicated in many forms of allergies, kwashiorkor, immune dysfunctions, cancers, birth defects,  and even death (Nicci and Anaisie, 2007; Enyiukwu et al., 2014a).

Recent scientific evidences showed that since the 1980s at least 100 fungi not previously connected with disease in humans, have been identified as pathogenic in immuno-compromized and sometimes immuno-competent individuals (Raven et al., 1992). These plant pathogenic mycobiota are melanized and melanin is considered as one of their major virulence factors (Revanker et al., 2010; Revanker, 2016). Some plant pathogenic fungi implicated in human diseases are Mucor mucedo, Penicillin chrysogenum, Alternaria teneus, Aspergillus flavus, Curvularia lunata,, Fusarum culmorum, Botrydiplodia theobromae, Trichoderma hazianum, and Bipolaris sp. These and related organisms cause superficial, subcutaneous, systemic and opportunistic infections in humans (Manisha and Pawar, 2012). For example Fusarium oxysporium the well-known basal stem rot pathogen of cowpea has been reported to infect and destroy the lungs of multiplied dozens of patients. Aspergillus flavus digest internal tissues in humans creating pores overlaid with its hyphae while Alternaria alternata reportedly attack cancer patients (Ravenet al., 1992). Simillaly Colletotrichum spp. noted for their ability to cause anthracnose, brown blotch and rots in legumes and stored tubers have recently been implicated as cause of keratitis, corneal ulcers and recalcitrant wound infections while Verticillium spp. were implicated in lymphoblastic leukemia in immunologically compromised individuals (Figtree et al., 2003; Curtis, 2013). Penicillium alliaceus and A. tamarii have been implicated in chronic otitis externa and eyelid infections respectively (Hedeyati et al., 2007). The maize smut fungus Utilagos maydis causes skin lesions in humans, whereas the wood decomposing saprophyte Schizophyllum commune is implicated in fungal meningitis and lung disorders (Botany, 2016).

To cause mycoses, the pathogens assisted by certain enzymes including proteases and keratinases (Kabayashi, 2017) overcome host antimicrobial peptides, phagocytic engulfment, oxidative burst or nutrient deprivation. Damage is reported to result from direct hyphal elongation or by deposits of toxins such as gliotoxin in the host or sometimes by immune response to the agent as in the case of mycotic sinusitis (Casadevall, 2007).  Literature suggested that the high prevalence of cancer, rise in organ transplants, steroid dependence, certain chemo-therapeutics, diabetes and HIV/AIDS resulted in completely or partially suppressed immune systems which culminated in rise in the number of people subject to opportunistic fungal infections (Raven et al., 1992; CDC, 2016).

Though the threats posed by these emerging plant pathogenic fungi are obvious on human health, they are however, not much appreciated and poorly understood (NAP, 2011). Preventive control of these phytonotic infections has been adjudged a major management strategy in public health (Bernette and Klich, 2003; CDC, 2016). Avoiding dusty, spores-laden construction environments and soils on wounds etc. are some preventive measures against aspergillosis, fusariosis and other phytonotic mycoses. Chemotherapy involving certain antifungal agents such as amphotericin B, voriconazole, fluconazole and posiconazole at moderate to high doses are administered to patients in chronic and acute life threatening attacks from these plant pathogenic fungal diseases in humans. However, because of the variable sensitivity and resistance of these novel pathogens to some of these conventional antifungal agents, the danger from these diseases is enormous and increasing in public health (CDC, 2016).

In the light of these therefore, use of atoxigenic species or biotypes of the pathogens to prime human immune systems against the diseases may prove helpful (Enyiukwu et al., 2014b). However, in severely immune compromised individuals this may pose a drawback as the bio-control agents may turn pathogenic in vivo. In recent times, plant-derived pesticides have been used extensively in plant pathology to control the ravages of pathogenic fungi against agricultural crops in both field and storage (Amadioha, 2003; 2004). Characterizing these antifungal agents of plant origin reported to be effective for control of phyto-pathogenic fungi may provide new anti-fungals or be used to improve existing ones in medical mycology (Enyiukwu et al., 2014c).

This review therefore summarizes the plant pathogenic fungal species associated with human diseases, and pin-points the potentials of plant-derived chemicals as possible sources of alternative (or at least complementary) antifungal compounds to fight phytonotic diseases of medical importance.

Plant pathogenic fungi as novel agents of human diseases

One of the questions commonly asked in the field of modern plant pathology and public health is whether plant pathogenic organisms can cross biological kingdom lines to infect humans? Surprisingly, scientific evidences reveal that the human poliovirus and hepatitis E virus share strong structural, molecular and genetic relatedness to cowpea mosaic virus (CPMV) (Secoridae), Theiler’s murine encephalomyelitis virus (TMEV) (Picornavirus) and beet mosaic yellow vein virus (Benyvirus) respectively (Balique et al., 2015). So do human eukaryotic cells to several pathogenic mycobiota  (Inglis-Arkell, 2017).  These similarities raise suspicion which in the view of many investigators suggests that these organisms could potentially infect humans (Balique et al., 2015).

Scientific findings have revealed that a plethora of plant pathogenic fungi causing diseases such as blights, smuts, anthracnose and post-harvest rots and deterioration of agricultural crops (potato, cassava, onion, cowpea, soybean etc.) in the field and storehouse have been implicated for human mycoses in recent times (Enyiukwu et al., 2014a). Many of these plant pathogens including Aspergillus spp., Fusarium spp., Curvularia spp., Alternaria spp. or Trichosporon beigeli were initially thought to represent harmless wound colonies.  Since the 19^th century however, clinical reports of plant pathogenic fungi being recognized and established as novel agents of serious human diseases in both healthy and immunologically compromised individuals have been documented the world over (Anaissie et al., 1989; Raven et al., 1992; Hedayati et al., 2007).

In affected individuals, attacks from these fungi have been reported in all organs of the body including the nails, skin, eyes, nose and sinuses, lungs, blood, liver, heart valves etc.  While the attacks are localized in immuno-competent hosts, they are usually disseminated and frequently highly lethal in immuno-deficient hosts (Anaissie et al., 1989; Stevens et al., 2000).  The frequency (incidence) and relative importance (severity) of these diseases are now on the rise especially in developing countries due to increasing rates of immunity compromising and predisposing diseases such as HIV/AIDS infection, malignant tumors and cancers, intensive cytotoxic therapies, transplantations following organ dysfunctions and better or improved prophylaxis/therapy for Candida infections (Stevens et al., 2000; NAP, 2011). Some emerging human diseases due to common plant pathogens of agricultural crops are presented in Table 1.

Spores and propagules from Fusarium, Alternaria, Phytophtora, Aspergillus Bipolaris, Curvuaria, Colletotrichum, Verticillium, Mucor, Penincillin and yeasts pose serious public health challenges. Community acquired mycotic infections from soil-borne plant pathogens, hospital acquired fungilosis and opportunistic fungal infections have been attributed to them (CDC, 2016). For example, aspergillosis caused by the soil-borne pathogen A. niger is common amongst horticultural workers who are reported to inhale peat, soil and dust particles (Marsha and Pawar, 2012). Inhalation of spores of Aspergillus spp., Alternaria spp., Mucor spp. and Puccinia gluacum trigger allergic reactions in human hosts such as allergic broncho-pulmonary diseases (ABPD) (similar to tuberculosis)  presenting symptoms such as sneezing, coughing, fatigue, pneumonia, and running nose. Once established in susceptible human hosts, these diseases are difficult to treat (NAP, 2011).

Table 1: Some emerging human diseases caused by plant pathogenic fungi

Aspergillosis

Aspergillosis comprised of a variety of ill-health manifestations in humans (or animals) caused by Aspergilli. Aspergilli are worldwide in distribution with about 200 species identified in the genera. These organisms require high oxygen tension, carbon-rich substrates and sometimes xerophillic environments to thrive. As such they are ubiquitous and can be found in several ecologies including dead vegetation, damp walls of living houses and dirty hospital air conditioners. Species of these organisms have been implicated in several forms of blights, rots and deterioration of crops or their produce such as tubers, corm, bulbs or storage roots either in the field or storage (Enyiukwu et al., 2014b). In Humans, Aspergilli can cause diseases such as lung infections, allergic reactions and infections of vital organs (CDC, 2016). About 16 species including A. niger, A. fumigatus and A. flavus have been reported as dangerous to humans, causing medically important aspergillosis. In susceptible individuals especially in those with compromised immunity, some of these species have been found to cause hearing problems as well as infecting human lungs with fungal balls. In some cases, A. fumigatus have been reported to induce allergies and trigger bouts of asthma in man (Blackmould, 2016). Others are otomycosis, onychomycosis, primary cutaneous infections and sinusitis (PatientPlus, 2016). Aspergillosis though not contagious (NHS UK, 2017); is categorized into three main types:

Allergic broncho-pulmonary aspergillosis (ABPA)

This is the most common (and sometimes non-life threatening) form of aspergillosis and usually occurs in people hypersensitive to spores of the fungi; or in some cases, in those with cystic fibrosis or asthma. People with the later medical conditions are especially vulnerable. Medical statistics suggests that 5% of asthma and 1-5 % cystic fibrosis cases are as a result of allergic broncho-pulmonary aspergillosis (ABPA) (CDC, 2016; Blackmould, 2016).  Recently A. flavus and A. oryzae were implicated in these conditions in India and Japan respectively (Hedeyati et al., 2007). Worldwide 1.2 billion individuals are living with ABPA with nearly 2.0 million deaths recorded from those infected on annual basis (Meyer et al., 2016). The disease presents difficulty in breathing (or shortness of breath), wheezing, coughing up mucus, anorexia, fever, general malaise and lung damage (fibrosis). In some cases the sinus may be infected (allergic sinusitis) leading to headache, stuffy and occasionally runny nose and reduced ability to smell (CDC, 2016). Oral steroids in combination with itraconazole are used in treating the condition (Blackmould, 2016).

Chronic pulmonary aspergillosis (CPA) and aspergilloma

Chronic pulmonary aspergilloma is caused by species of aspergilli growing in the human body and attacking the lung cavities previously created by health maladies such as tuberculosis and sarcoidosis (chronic obstructive pulmonary disease). In the cavities of infected lungs, the mycobiota may grow into a ball of intertwined fungal hyphae matted together with fibrin, mucus and cellular debris (aspergilloma or mycetoma) which releases toxins that sickens the patient (Stevens et al., 2000; Blackmould, 2016). Medical evidences reveal that A. flavus is the chief cause of superficial infections in humans while A. niger could be associated with aspergilloma in diabetic patients (Hedeyati et al., 2007). Symptoms such as difficulty in breathing, chronic coughing, coughing up blood, weight loss, tiredness and fatigue accompany the attacks of the disease (CPD) in the individual (CDC, 2016). Outbreaks of invasive aspergillosis in high risk individuals usually occurs in hospitals following reconstructions or renovations which lead to increase in amount of air-borne spores ofthe organisms released into the micro-environment; thus resulting to high respiratory inhalation and irritations as well as post-operation sites infections (CDC, 2016). Worldwide estimates show that 400,000 people are living with CPA, while another 1.2 million cases are traceable to tuberculosis related infections and 70,000 others due to complications arising from sarcoidosis (CDC, 2016). In some cases, bone infection (osteomylitis), skin lesions, ulcers may result in highly immune deficient patients, while cutaneous aspergillosis or soft tissue infections may follow poorly managed burn wounds (Steven et al., 2000).  Medical management of the disorder usually begins with x-ray and blood tests to ascertain presence and extent of damage by the fungi, followed by chemotherapy involving injecting itraconazole or voriconazole into the lungs of the patient, whereas In extreme cases surgical removal of the aspergilloma may be recommended (CDC, 2016).

Invasive and disseminated aspergillosis

Invasive aspergillosis is common with people who are already sick and whose immume systems have been compromised, such as patients exposed to high corticosteroid levels or cancer chemotherapy and in some instances as fall out of stem cell or organ transplants; and hence making it difficult to pin down to aspergilli (CDC, 2016). A. flavus is reported as the major aetiological agent of invasive aspergillosis in both Sudan and Saudi Arabia (Hedeyati et al., 2007). The disease presents episodes of fever, chest pain, cough and shortness of breath. It is a major cause of mortality in immuno-compromised individuals even in the face of therapy (Stevens et al., 2000) and survival rate in organ transplanted patients is generally low (≤25%).  Statistics reveal that invasive aspergillosis is the most common type of fungal infection following stem cell transplant and the second most common amongst organ transplant patients. A 1998 survey in the USA indicated that about 2 cases of invasive aspergillosis occur in every 100,000 people in the country (CDC, 2016). Invasive aspergilloma is a devastating infection that affects patients with neutropenia, macrophage or neutrophile dysfunction. The disease first attacks the sinus, then lungs and radiates to the central nervous system (CNS). Surgery is reported as its definitive treatment though success is reportedly low due to high post-operation morbidity and mortality (Stevens et al., 2000). Though Aspergilli-induced meningitis is unusual, it may affect people living with tuberculosis, diabetes, neutropenia or those on prolonged corticosteroids therapy. Medical management may involve treatment with lipid formulation of amphotericin B (AmB) especially in patients with impaired renal function (Stevens et al., 2000).

Alternariosis

Alternaria spp. are soil-borne cosmopolitan phyto-pathogens whose spores could be found in indoor air (Laemmlan, 2001). Members of the genus form polymorphous conidia characterized by long, oblique septa, borne either singly or on short or long chains. The orrganisms survive in soils, infected agricultural seeds or crop debris and require high moisture or relative humidity (92%) and temperature of 16-24^oC for conidiation and host infection (Laemmlan, 2001; Nayyar et al., 2014). Alternaria spp. have wide host range  causing early blight and fruit rot in tomato (A. solani), carrot leaf blight (A. dauci), black rot of carrot (A. radiata), fruit rot of pepper (A. alternata, A. teneus) and leaf spot of conifers (A. brassicola, A. brassocae). The frequency and severity of attacks by the pathogen on susceptible crops are crop-age dependent and toxins from the organisms  diffuse into infected host tissues, tubers and fruits, causing irregular and depressed chlorotic lesions (Laemmlan, 2001; Tsedaley et al., 2014).

Several pathogenic and opportunistic human mycoses have been attributed to Alternaria spp. with A. alternata being the most commonly implicated species. Superficial, subcutaneous phaeohyphomycosis and invasive infections due to attacks of Alternaria spp. in humans have been documented. A. alternata is associated with onychomycosis, bakers’ asthma, sinusitis and pneumonitis. They may also be associated with edema, bronchiospasms and emphysema in severe cases. Subcutaneous infections may result from implantation of contaminated soils, thorns and wood splinter in human hosts with verrucous lesion forming in immumo-deficient persons (Fry and Fry, 2015). Superficial infections however, leading to skin lesions, hay fever, allergic reactions as well as asthma have been recorded due to A. teneus. Others are opportunistic infections in HIV/AIDS immuno-suppressed persons and phaeohyphomycosis following renal transplant (Marsha and Pawar, 2012).   

Curvulariasis

Curvularia spp. are virulent soil-borne, metropolitan and destructive plant pathogens with strong presence in India, Pakistan, Gambia, and Nigeria (Louis et al., 2014). The organisms grow as wooly colonies with brown, cross-walled hyphae and conidiophores. The conidia (poroconidia) are straight, piriform, and multi-septate with dark basal protuberant hila (Marsha and Parwar, 2012). In agriculture, the organisms are associated with diseases in cereals, vegetables and legumes resulting in up to 60% potential yield reduction of the crops (Lal et al., 2013; Banupal and Sharma, 2015; Chukwu and Enyiukwu, 2016).

In the last half century,Curvularia spp. have been reported as causal agents of not less than 43 different human mycoses in both immuno-competent and immuno-deficient individuals. In an immuno-competent African-American with an underlying medical history of asthma, C. lunatus induced a fatal CNS infection which in which the patient presented symptoms of headache, dizziness, unsteady gait, anorexia, fever, chills, night sweats and weight loss (Carter et al., 2004). Drechslera (Exserohilum) spp. close relatives of Alternaria spp. are also soil inhabiting and plant pathogenic groups of fungi. They have been implicated in post trauma superficial mycoses of the human eyes and skin as well as invasive infections of the sinus, lungs, heart linings and bone (CDC, 2017). Accoding to Douhet et al. (1985) D. longirostrata is associated with endocarditis and spindyloiditis; D. rostrata and D. spicifera with several phaeohyphomycoses whereas the association of D. hawaiiensis with pulmonary mycoses have been reported in literature. Also, in Hawaii, McAleer et al. (1981) attributed the septate mycelia of D. hawaiiensis and C. lunata recovered from sputum and clinical materials of 3 patients with allergic broncho-pulmonary disease (BPD) as cause of the disease.  Similarly, dermaticeous hyphae and germinating conidia of C. lunata were recovered from all five toes and finger nails of a patient diagnosed of leprosy (Barde and Singh, 1981). The authors concluded the organism as inciting the onychomycosis in the patient. Wound infections, cerebral abscess, pneumonia, cerebritis, endocarditis and dialysis-associated perotinitis as well as disseminated infections according to Yau et al. (1994) and Marsha and Pawar (2012) have been attributed C. lunata in both immuno-competent and immuno-suppressed individuals.

DermaticeousC. lunata for example produces a non-host specific furanoid toxin (methyl 5-(hyroxymethyl) furan-2-carboxylate.) which replicated lesions of the symptoms of the natural infection by the pathogen in vivo (Liu et al., 2009). This toxin and many cell degrading, hydrolytic enzymes may in the view of many investigators play important roles in tissue maceration of the affected humans (Amadioha, 1995).   Control of curvularial mycoses have been by use of voriconazole, itraconazole, posaconazole and amphotericine B (AmB) or their combinations especially in cases involving cerebral abscesses where surgery is not recommended (Chowdhary et al., 2014).

Fusariosis

Fusarium spp, are one of the most common cosmopolitan agricultural pathogens found extensively in soils, host plant debris, organic matter and as water structure biofilms which they utilize as efficient sources of carbon (Nucci et al., 2007). The organisms cause crown rot, head blight, scab, basal stem rot, vascular wilt and storage rot of tubers and vegetables amongst other diseases during transit or marketing; on a wide range of hosts including legumes, cereals and Solanium spp. (Nucci et al., 2007; Enyiukwu et al., 2014b). Affected crops manifest chlorosis, defoliation, vascular browning, damping-off and stunting (Go Pet America, 2017).

Fusarium spp. are reported to cause a broad spectrum of infections in humans such as superficial, local, invasive and disseminated infections. Clinical manifestations are dependent upon the immune status of the host and portal of entry of the agent and may include debilitations, weight loss, anaemia and chronic diarrhea. These infections (like aspergillosis) occur, mainly in those receiving high doses of corticosteroids; and those with prolonged neutropenia makiing it the second most fatal mycoses in humans (Nucci et al., 2007; Go Pet America, 2017). The organisms enter human systems through inhaled spores causing sinusitis or pneumonia, or sometimes through skin penetration following traumas, bamboo wounds, burns or skin infections (Nucci et al., 2007).  F. solani, F. oxysporum, F. verticilloides, F. culmorum, F. proliferatium, F. sacchari, F. dimerium, F. clamidosporium and F. anthophillum have been implicated in human mycoses such as keratitis (especially in people using contact lenses), sinusitis, and onychomycosis in immuno-competent individuals. However, localized and disseminated infections including pneumonia, fungemia, endophalmitis, septic arthritis and osteomyelitis have been attributed to these organisms in immuno-compromized patients especially in those with prolonged neutropenia or severe T-cell deficiencies (Nucci et al., 2007; Marsha and Pawar, 2012; Nucci and Anaissie, 2016). In haematologic malignancy fusariosis which could be life threatening and resistant to standard drugs predominates amongst leukemia patients who are receiving various forms of chemotherapy (Nucci and Anaissie, 2016; Go Pet America. 2017). Fusarium spp. possess several virulence factors including ability to produce mycotoxins (trichothecenes) which interfere and suppress hormonal and cellular immunity leading to tissue breakdown and rapid colonization of human tissues (Nucci et al., 2007).

Penicilliosis

The genus Penicillium which belongs to the family Trichocomaceae consists of 225 species including P. marneffei (Taloromyces marneffei) and   P. chyrysogenum (P. notatum) Thonn.  The organisms are widespread in distribution and can be found as food contaminants, in soils, decaying organic matter and indoors in damp or water damaged walls (Barcus et al., 2005).  The organisms which comprised of hyaline, septate  mycelium and blue-green chains of spores or conidia borne on brush-shaped conidiophores are reported as incitant of rot diseases in several storage and tuber crops in humid tropical locations (Okigbo, 2004). Chrysogine, roquefortine C, secalonic acids, meleagrin, sorbicillin sorrentanone and PR-toxins are amongst the diverse toxic secondary metabolites produced by the organisms. Air-borne spores are human allergens. According to Lyazopoulos et al. (2002) P. chysogenum is associated with occupational hazards including allergic pulmonary disorders in cheese workers. Vacoular and  serine proteases have been implicated in this allergic penicilliosis. Penicillium spp. have been associated with post-valvular cardiac surgery infections, lobular pneumonia, localized granuloma, fungus balls, endophthalmitis and  eosophagitis (Barcus et al., 2005; Aviles-Robles et al., 2016). Two cases of cerebral and paravertebral infections in immuno-competent individuals due to P. chrysogenum were reported by Lyazopoulos et al. (2002) and both did not respond to treatment with amphothericin B. However, chronic granulomatous disease caused by Penicillium spp. in a patient with immune dysfuction the authors noted responded well to same treatment. Infections which usually occur in immuno-incompetent individuals occasioned by HIV or post organ transplant chemotherapy can be direct, hypersensitivity reactions, pulmonary fibrosis or invasive intestinal and disseminated infections (Barcus et al., 2005; Aviles-Robles et al., 2016). P. marneffei induced penicillosis is endemic in some countries of Asia including India, Cambodia, Thailand, China, Taiwan, Vietnam, Myammar, and Malaysia especially amongst HIV immuno-compromised populations (Chent et al., 2013). According to these authors fungus ball in a 56 female year old female (who had negative β-D-glucan and HIV tests) presenting with fever, fatigue and coughingwas linked to P. capsulatum.  Generally, there is no antifungal of choice in its treatment. However, early diagnosis followed by interventions with broad spectrum anti-mycotic drugs including amphotericin B, casofugin and voriconazole have been employed in their managetment (Aviles-Robles et al., 2016).

Botrydiplodiosis

Botrydiplodia theobromae (Syn. Lasiodiplodia theobromae (Pat.) Griffin & Maubi is a member of the phylum Ascomycota (MycoBank, 2017). The fungus is worldwide in distribution affecting about 280 plants including cocoa, cotton and sweet potato; resulting in dieback, blights leafspot, stem end rot, crown rot and other rot diseases. B. theobromae is a weak pathogen requiring wounds or necrotic tissues to infect and colonize susceptible host tissues (Twumasi et al., 2014). In crops following inoculation, the conidia germinate forming a mass of hyphae which destroy the vascular system leading to depletion of starch granules and other growth factors (Markson et al., 2014).

In humans association of the fungus with onychomychosis and phaehyomycoses have been documented (Kindo et al., 2010). The pathogen is reported to be responsible for unusual post-trauma skin lesions in healthy immuno-competent 54 year old man. Also, keratitis, sinusitis, cutaneous lesions and pneumonia have been ascribed to the phyto-pathogen in people with severe underlying diseases or solid organ transplant (Papacostas et al., 2015). Pneumonia remains a significant cause of morbidity and mortality in post organ transplant patients. It is reported to occur 72% in lungs transplants, 17-28% in heart, and 8-23% in liver post-transplant operation cases leading to 50% mortality in affected individuals (Singh et al., 2011). According to Masleen et al. (1996) B. theobromae caused severe persistent sub-cutaneous abscess in a patient in Australia. The mechanism of damage (MOD) adopted by the pathogen in the infection process is thought to involve intercellular and intracellular colonization assisted by the enzymes polygalacturonase (PG) and pectin methyl esterase (PME) leading to degradation of the infected host tissues (Amadioha, 1994).

Zygomycoses (mucormycoses)

These are diseases caused majorly by species of Rhizopus, Mucor and Lichtemia (Absidia) with Rhizopus spp. regarded as the most important causal agent of invasive zygomycosis, followed by Mucor spp. Rhizopus spp. belongs to the order mucorales. They are terrestrial, saprophytic and usually weak pathogens found in soils, and as contaminants of seeds, fruits and food. They are generally referred to as the weeds of the fungal world. In agriculture the organisms have been associated with head rot of sunflower in the field and as weak pathogens involved in soft rot of melons, yam, sweet and Hausa potatoes (Markson et al., 2014; Nwaneri, 2016; Go Pet America, 2017). Affected fruits and tubers become soft as specialized hyphae (rhizoids) ramify the hosts, causing them to exude offensive water.

 In animals they have been associated with necrotic placentitis, ulceration of the gastro-intestinal tract (GIT), abdominal and liver lesions, pulmonary as well as subcutaneous infections etc. Species including R. arrhizus, R. stolonifer, R. microsporus and R. rhizopodiforms have been implicated in these human mycoses. Skin broken through wounds has been adjudged the most important portal of acquisition of rhizopus-induced mycosis (Morace and Borghi, 2012) followed by inhalation of spores of the organisms which could lead to attacks on the sinus, lungs, and skin. Affected individuals are usually predisposed by underlying medical challenges including trauma, burns, steroids use, organ or stem cells transplant, deferaxomine (DFO) therapy in dialysis, HIV, diabetes, ketonic acidosis and leukemia. The disease could be local, and may invade blood vessels and body organs bringing about hemorrhagic tissues necrosis and thrombosis which could culminate to fatal outcomes (Go Pet America, 2017). In immuno-compromised persons with Rhizopus-induced sinusitis, the organisms have been reported to colonize their CNS, leading to altered mental state, coma with death possibly following in just a few days (Morace and Borghi, 2012).

Clinical manifestations of zygomycoses are similar to aspergillosis and affected individuals present persistent fever, and lung bleeding. Acute meningitis for example which resulted in death of the affected patient in less than 10 days has been attributed to Rhizopus spp. (Go Pet America, 2017).  The damage from the pathogen seems to stem from hyphal extension or production of certain proteins and metabolites toxic to the hosts (Casidevall, 2007; Murace and Borghi, 2012). Angio-invasion, neurotropism and iron uptake are reported to characterize pathogenesis of members of mucorales including Rhizopus spp. For Rhizopus-induced mycoses to occur, therefore, the underlying predisposing factors such as diabetes usually caused plasma iron (Fe) overload, creating  ferric ion availability for the pathogen in the host tissues (Murace and Borghi, 2012). Similarly, Absidia corymbifera a cosmopolitan soil or debris-borne pathogen known to cause food spoilage in refrigerators has been reported to attack lungs, nasal sinus, brain, skin and eyes of humans. In affected individuals, the organism is noted to be associated with inflammation of soft tissues leading to fungal invasion of the blood.  Other zygomycetes which participate in human diseases are Mucor ramosissimus, M. indicus and M. circinelloides. These thermophillic species characterised by lack of stolons and rhizhoids are found in soils, decaying vegetation and plants have been reported to cause invasive vascular infections in humans. Zygomycetes generally are weakly sensitive to most antifungals except amphotericin B. Early diagnosis is critical to treatment and surgical debridement or resection may be employed in severe cases (Fry and Fry, 2015). 

Pythiosis

Pyhium spp. are oomycetic (fungus-like) thalli which produce zoospores. Six species of this group of organisms including P. alphanidermatum and P.ultimum are associated with different plant diseases including damping-off, fruit

and root rots; with affected plants presenting symptoms of stunting, leaf chlorosis and wilting (ipm.ifas.ufl.edu/pdfs/pythium.pdf). However, P. insidum commonly found on decaying plants, in soils, rice paddies, wet swampy areas with dense vegetation and contaminated aquatic ecosystems grows as faint white, non-septate colonies with motile zoospores on PDA. This organism is associated with several cases of human mycoses. Pythiosis is known to be prevalent in Asia due to Pythium-infested rice paddies (Vanttanakom et al., 2004). In the USA, the pathogen has been reported to cause swamp cancer (granulomatous skin lesions) in animals like horses and dogs. Humans exposed to contaminated vegetation or pond could be attacked by the pathogen making them to develop ocular, subcutaneous, vascular and systemic infections such as keratitis, arteritis, periorbital cellulitis and granulomatous skin lesions.  The organism attacks both immuno-competent and immuno-incompetent human hosts. Keratitis has been reported in immuno-competent individuals who wear contact lenses and swim in contaminated lakes in the region. The disease is severe and life-threatening in patients with underlying diseases such as leukemia or thalassemia (Vanttanakom et al., 2004). In susceptible human hosts the pathogen advances rapidly, being stimulated by ions of magnesium, potassium, calcium, and especially iron (Fe) in the cell environment. It also secretes cell killing proteases in advance of its invading hyphae. The disease is difficult to treat with antifungals, and its mortality rate is high making it a strong public health concern (Smith, 2014).

Bipolariosis

Bipolaris spp. are soil or thrash-borne cosmopolitan phyto-pathogens known to attack members of the graminae. Three species of the organism namely B. hawaiinensis, B. australiensis and B. spicifera have been reported to attack both immuno-competent and incompetent human hosts causing nasal, wound, post-operative, lung and subcutaneous infections. Others are corneal ulcers, mycotic keratitis, valvular infections, fungemia and osteoarthritis. In workers working in agricultural fields, association of the fungus with otitis media has been documented (Fry and Fry, 2015). Some of these diseases were reported in patients with underlying medical conditions including diabetes or undergoing chemotherapy due to renal dysfunction (El-Khazzi et al., 2010). However, in people of competent immune status for instance, B. hawaiiensis has been reported to cause allergic broncho-pulmonary disease (APBD) which presented with necrotizing pneumonia (Saenz et al., 2001). In another instance, the pathogen caused allergic sinusitis complicated with fungal brain mass. The affected patient presented fevers, headache and proptosis (George and Sutton, 2010). According to Bouzina et al. (2003) B. spicifera was associated with fungus ball of the sinuses and triggered polypoid chronic rhinosinusitis  in a 19 year old immuno-unsuppressed man. 

Crptococcosis

Crytococcus neoformans and C. gratti are widely distributed fungal organisms found in decaying vegetation and soils contaminated with bird droppings (Casadevall et al., 2014). Their associated with over36 genera of plants across many ecological zones are well documented (Kwon-Chung et al., 2014)..Though the organisms are not known to cause diseases in these plants previously, however Wapeha et al. (2013) recently noted that they could invade wounded plant surfaces and even intact ones. The authors reported that the organisms caused widespread lethal infection and persistent tissue colonization; characterized by germination failure and seedling stem lodging in healthy Arabidopsis thaliana (mouse ear cress). In the study, C. gratti showed superior virulence to C. neoformans which rather exhibited prolonged residence in the plants’ cuticle tissues and vascular spaces.

            Cryptococcus spp. could infect mammals. In human, infection occurs usually following the inhalation of infective spores, leading to attacks on the lungs and subsequent dissemination through the blood to the meninges and other parts of the body (en.wikipedia. org; Kwon-Chung et al., 2014). In addition to possession of polysaccharide capsule and thermo-tolerance, production of melanin, urease, phospholipase, inositoland laccase are suggested to assist these fungi in human tissue maceration (Casadevall et at., 2014). Cryptococcus spp. are facultative intracellular pathogens that can utilize host phagocytes to spread within the body (en.wikipedia. org). C. neoformans and C. gratti cause a large burden of deaths resulting from infections in both healthy persons and in individuals with compromised immunity. In the former systemic infections have been attributed to them; whereas in the later whose immunity have been compromised by any or a combination of AIDS, prednisolone dependency, cancers, and organ transplant, meningo-encephalitis is common (Wapeha et al., 2013). Cryptococcosis is a highly endemic disease in developing countries of Africa and Asia (Casadevall et al., 2014), with for example17 % amounting to 1 million cases of all AIDS-related deaths in these regions attributed to the disease (Fig. 1).

Other fungi induced human mycoses

Trichoderma spp. which are ubiquitous on plant surfaces and root rhizosphere produce conifer-like branching conidiophores which bear globe-like dark or bluish green conidia. In the rhizosphere, they infect crop roots and help to induce plant growth and protection. They are reported to protect crops against seed and soil-borne pathogens by producing antagonistic chitinases, endoglucanases, cellulases, proteases and antibiotic metabolites (Go Pet America, 2017). However, in Europe T. hazianum, and T. longibrachiatum cause green mould disease, a very devastating biotic challenge in mushrooms (Agaricus bisporus, Plerotus osttreatus) production. Recently Trichoderma spp. have been associated with some forms of human mycoses. Strains of T. longibrachiatum  and T. viride for example have been reported to be disseminated in the brain, liver, and stomach of immuno-incompetent human hosts and in the lungs of patients undergoing peritoneal dialysis (Fry and Fry, 215; Go Pet America, 2017).

Schizophyllum commune is a tree attacking and wood rotting fungus. On SDA the fungus grows as cottony or woolly white hyaline septate colonies with fan-like acervuli. Infectve air-borne propagules of this fungus are reported to attack immuno-competent and immuno-suppressed individuals. Ulcerative lesions of the pallate, meningitis, cerebral abcess, and onychomychosis have been attributed to the pathogen (Swain etal., 2011). In India, it caused pulmonary infection which disseminated to the brain leading to death in a 56 year old patient undergoing empiric corticosteroid therapy and chronic sinusitis in another 46 year old patient (Rihs et al., 1996; Swain et al., 2011). Also in India, a case of maxillary sinusitis which presented with nasal obstruction, purulent nasal discharge, cough, sneezing and headache in a 50 year old female was reported by Premanalini et al. (2011). According to Tulio et al. (2008) this fungus was implicated in broncho-pneumonia in a 59 year old white patient with a history of gastric carcinoma. The organism was sensitive to fluconazole and amphotericin B (Tulio et al., 2008; Swain et al., 2011).In Brazil, a 56 year old man with a medical history of hypertension, auto-prednisolne use and diabetes was reported with post trauma subcutaneous infection linked to C. gloeosporioides. The fungus displayed a significant degree of resistance to antimycotic drugs including fluconazole, miconazole, ketoconazole and itraconazole and to some extent to amphotericine B (Guarro etal., 1998).

In general, inability to diagnose phytonotic mycoses early coupled with dearth of data on effective preventive antifungal regimens, lack of effective antifungal therapies, and toxicity of the anti-mycotic drugs to human systems have been reported to constrain treatment of plant pathogenic mycoses (Singh et al., 2011). The toxic side effects of the antifungal treatments in general and resistance of the pathogens to antifungals in particular therefore gave broad scale impetus for search for alternative or at least complementary therapies for plant pathogenic fungal diseases in humans (Aviles-Robles et al., 2016).

Control of medically important plant pathogenic fungi

The shortcomings of good agronomic practices, disease resistant cultivars and biological control of a wide array of plant pathogenic fungal diseases especially during outbreaks of epidemics warranted the use of chemical interventions in crop production (Enyiukwu et al., 2014a, b, c). However, owing to inappropriate and/or excessive application of synthetic mycotic eradicants in agriculture, there is increasing emergence of hyper-virulent pathogenic fungal isolates which have been reported to cross kingdom barriers to cause resistant human mycoses with associated high death rates (Fig. 1) recorded in hospitals (Meyer et al., 2016). These resistant human mycoses were due to both primary (resistance to the active principle of the drug) and secondary resistances (inadequate drug concentration at infection sites) (Hedeyati et al., 2007).  Aspergillosis for instance is associated with up to 95% mortality(Fig. 1) out of the greater than200,000 individuals affected globally by the disease (Table 2)while over 10,000 Mucor–induced human mycoses occur every year with between about 90% death rates recorded from the disease on a global scale(Fig. 1).

Table 2: Reported cases of phytonotic and related diseases per annum

                           Source: Meyer et al. (2000)

The attribute of high environmental persistence which characterize most broad-spectrum synthetic fungicides used for the control of fungal diseases of crops and the consequent disruption of ecological health, as well as the development of widespread resistance to the later groups of narrow site fungicides (drugs) which interfere with membrane permeability, cell wall biosynthesis, ergosterol biosynthesis or nuclear function has created urgent room for smart fungicides (drugs) in the present. Smart fungicides (drugs) are novel highly active, low-dose, multi-site (broad-spectrum) fungicides (Meyer et al., 2016). Such new smart fungicides may be developed as improved laboratory copies of characterized isolates of plant-derived antifungal compounds from higher plants (Amadioha, 2003; Enyiukwu et al., 2014c). Cinnnamic acid derivatives with triazole rings have low toxicity to fish and amphibians. They were touted as candidates of new antifungal drugs; demonstrating anti-mycotic activity against C. lunata, A. niger and Pleurotus ostreatus. These pathogenic fungal organisms are known to produce benzoate 4-hydroxylase which participates in hosts’ cell marceration by detoxifying benzoate compounds in the aromatic fungal nutritional metabolism. Korosec et al. (2013) reported that cinnamic acid derivatives exerted their antifungal activity against these pathogenic mycobiota by binding to cytochrome P450 and inhibiting their xylase (CYP53A15) activity. The agriculturally and medically important Botrydiplodia theobromae causing black pod disease of cocoa, rots of sweet potato in storage and post organ-transplant pneumonia has been successfully controlled using extracts of Garcinia kola and Carica papaya both in vitro and in vivo (Markson et al., 2014). Some of the plant extracts and phytochemicals used in agriculture for controlling phytonotic fungi are presented in Table 3. Extracts of Cassia alata,  Dennettia tripetala, Ageratum conyzoides, Piper nigrum, Tridax procumbens and Afromonium meleguata effectively checked the growth and development of Mucor piriformis, Sclerotium rolfsii, Botrydiplodia spp., Penicillium digitatum, F. oxysporum and Rhizopus stolonifer responsible for rots and deterioration of several tubers, fruits and vegetables in the tropics (Nwachukwu and Osuji 2008; Enyiukwu et al., 2014b). Extracts derived from Jacaranda mimosifolia, Polyalthia longifolia, and Terminallia arjunia were also reported to effectively inhibit Pythium myriotylum in culture (Parveen and Sharma, 2014). Flavonoid-rich Tradescantia palluda, Murdania nudiflora and P. nigrum for example demonstrated strong antioxidant, cytotoxic and fungitoxic activities against Aspergillus niger and Rhizoctonia solani (Huq et al., 2016).

                              Source: Meyer et al. (2000); Kwang-Chung et al. (2014)

Figure 1: Annual death rates due to mycoses caused by plant pathogenic fungal organisms in humans

Similarly, methanol and aqueous extracts of Alchornea cordifolia have shown strong antimicrobial effects against Klebsiella sp., pseudomonas aureginosa, Rhizopus stolonifer and Colletotrichum spp. (Okwu and Ukanwa, 2010; Enyiukwu, 2017). Their wound healing activities have been ascribed partly to these antimicrobial effects.

Fractionation of some of these extracts afforded anthocyanidin glycosides and dodecanoic acids (amongst other compounds) which demonstrated antifungal effects against these medically important pathogens by disrupting their cell membrane integrity and enzymes activity both in vitro and in vivo (Okwu and Ukanwa, 2010; Enyiukwu, 2017). Characterizing and exploiting these effective plant extracts or plant derived compounds could provide new antifungal drugs that would contribute immensely in reducing the challenges posed by phytonotic mycoses in humans.

Table 3: Extracts of plant origin used in the control of some plant pathogenic mycobiota

CONCLUSION

The challenges posed by formerly medically unimportant agricultural pathogens are increasing in recent times given that the rates of survival from them are low. Available antifungal therapy such as azoles and amphotericin B used in treating and controlling these phytonotic fungal pathogens are variable in efficacy. Extracts and powder formulations of higher plants such as cinnamon, Xylopia sp.,Vernonia spp., Afromonium sp., Piper sp., Alchornea sp., Cassia alata and Denettia tripetala amongst others have been successfully employed in retarding and arresting their survival, growth, development and spread both in culture and on-farm. These higher plants therefore are veritable sources of wide ranging compounds that can be used as alternatives, synergy or complements to existing antifungal drugs. Characterizing these plant-derived extracts could provide medically important compounds that could contribute towards controlling these diseases in human hosts and therefore help in improving overall health and wellbeing of people.

RECOMMENDATIONS

   Farmhands working in dry agricultural lands as well as construction workers in hospital reconstruction sites should wear protective clothing to shield their nose, eyes and skin to minimize inhalation and skin contact with dust-borne spores and propagules of toxigenic and humans attacking phytonotic fungi.

   Hospital patients should be moved to new wards prior to renovation of hospitals. Wards should be adequately fumigated with user-friendly plant-derived extracts such as neem, Ashanti pepper, Sour sop and Xylopia aethiopica or their neo-products to kill phytonotic and allied fungal propagules post renovations. Hospital air conditioners should be serviced periodically and followed by routine fumigations at about 4 monthly intervals per annum. This will prevent buildup of toxic and harmful spores of mycotic mycoflora on hospital walls and conveniences.

   Characterization of efficacious plant extracts used for control of plant diseases in recent times should be vigorously encouraged to afford compounds to synergize, complement or be used as alternative to known antifungal drugs in medical circles.

   Emphasis should be laid on using tissue cultures and genetic engineering technologies to encode and commandeer rapidly growing saprophytic microbes to produce these characterized fungitoxic phyto-metabolites for possible use in pharmaceutical and medical application. 

   Early diagnosis has been noted as important step to treatment of phytonotic mycoses. Therefore accurate and timely molecular polymerase chain reaction (PCR) and sequence identification of phytonotic isolates from infected patients should be carried out so as to encourage prompt medical interventions.

ACKNOWLEDGEMENTS

We profoundly appreciate Rev. Dr. K. C. Emeasor who criticized and reframed the title of this work. We are also grateful to Prof. Amaechi N of the Veterinary Microbiology Department MOUAU who did pre-publishing review of the manuscript.

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