Fungal primary and opportunistic pathogens: an ecological perspective

Abstract Fungal primary pathogenicity on vertebrates is here described as a deliberate strategy where the host plays a role in increasing the species’ fitness. Opportunism is defined as the coincidental survival of an individual strain in host tissue using properties that are designed for life in an entirely different habitat. In that case, the host's infection control is largely based on innate immunity, and the etiologic agent is not transmitted after infection, and thus fungal evolution is not possible. Primary pathogens encompass two types, depending on their mode of transmission. Environmental pathogens have a double life cycle, and tend to become enzootic, adapted to a preferred host in a particular habitat. In contrast, pathogens that have a host-to-host transmission pattern are prone to shift to a neighboring, immunologically naive host, potentially leading to epidemics. Beyond these prototypical life cycles, some environmental fungi are able to make large leaps between dissimilar hosts/habitats, probably due to the similarity of key factors enabling survival in an entirely different niche, and thus allowing a change from opportunistic to primary pathogenicity. Mostly, such factors seem to be associated with extremotolerance.


Introduction and definitions
The fungi comprise one of the species-rich branches in the Tree of Life.Since the COVID-19 outbreak in 2021, which regionally led to se v er e fungus-associated infections (Ghazi et al. 2021 ), the general public is aware of the fact that microbes may pose a significant health pr oblem unexpectedl y, and among these are fungi.In nearly 160 years of medical mycology r esearc h, ov er 800 fungal species have been proven to be able to infect humans and other v ertebr ate animals (de Hoog et al. 2020 ).This seems like a high number, but compared to the millions of existing species (Ha wks worth and Lucking 2017 suggested 3.8 million), this would amount to only 0.0002%.Although novel infectious species are still being identified at a regular pace, the ability to infect an animal host remains an extremely rare fungal property.
Infection is usually understood as host damage from the perspective of human health, but from the perspective of the pathogenic fungus, Homo sapiens is r ar el y the pr eferr ed host.Pathogenicity is a relative feature (Rokas 2022 ); the great majority of fungi with infecting ability have their natural habitat in association with non-human v ertebr ates and behav e non-typical in case of infection.Additionally, the invasive properties and course of the disease are also dependent on a multitude of host factors and on the portal of entry of the agent.The degree of host damage is a component of fungal virulence interplaying with host factors; pathogenicity, i.e. the e volutionaril y determined course of e v ents in the host, is r elativ e to the species' natural life cycle.
For an ecological definition of v ertebr ate pathogenicity, we distinguish those fungi where infection is adv anta geous to the species' surviv al, fr om those wher e infection can be considered as detrimental.In the Darwinian sense, this primary pathogenicity is an intrinsic property of the fungus, designed to increase the species' fitness.Use of the pr eferr ed v ertebr ate host an ywher e in the natural life cycle enhances progeny and dispersal.Ho w ever, e v en when this host is essential for the species, it is indispensable for each individual only when the fungus is transmitted from host to host (host-transmitted pathogens , e .g. Trichophyton concentricum ; Table 1.Definitions used in this paper. Symbiont, fungus having continuous or temporary association with a vertebrate host as its natural lifestyle , co vering the entire spectrum from primary pathogenicity to commensalism.Virulence, degree of host damage upon infection.Pathogenicity, e volutionaril y determined course of e v ents in the host, Ceteris paribus .Pathogen, fungus able to cause disease in v ertebr ate hosts.Primary pathogen, fungus using growth in vertebrate tissue to enhance its survival and/or dispersal in any stage in its life cycle, using a specialized tissue phase if systemic or subcutaneous and being having the ability to escape from the host.Examples: Histoplasma capsulatum with tissue phase and Trichophyton concentricum with cutaneous transmission.Opportunistic pathogen (syn.: secondary pathogen), fungus coincidentally able to survive in vertebrate tissue due to factors that are applied in its natural habitat and able to grow in vertebrate tissue only upon damage of the host functionalities due to e.g.immune or metabolic disor ders, w ounds, or medication.Example: Rhizopus arrhizus.Facultati v e pathogen, fungus for which the host is only one of the niches where it is able to reproduce.Obliga te pa thogen, primary pathogen unable to produce assimilative thallus outside the host.Example: Batrachochytrium dendrobatidis .Commensal, fungus using growth on or in the vertebrate body enhancing survival and/or dispersal in any stage in its life cycle without tissue invasion in the immunocompetent host.Examples: Malassezia furfur and Candida albicans .En vironmental pa thogen, primary pathogen transmitted with an environmental phase after infection, the host not being contagious.Example: Coccidioides immitis .Double life cycle, irr egularl y intermittent growth of an environmental pathogen in a vertebrate host and in its environmental habitat.Example: H. capsulatum .Host-tr ansmitted pa thogen, primary pathogen with host-to-host transmission, the host being contagious.Example: T. concentricum .Saprobe, fungus feeding from non-vertebrate organic debris in the environment.Example: Aspergillus fumigatus .Preferred host, healthy v ertebr ate species wher e the fungus is found under its natur al conditions and wher e it exhibits its lo w est degree of virulence.Example: rodent-associated Emmonsia crescens .Lifestyle, basic way of feeding of a fungus.Str a tegy, factors promoting the preferred lifestyle of the fungus and enhancing maximum progeny, potentially evolve to w ar ds higher degree of adaptation.Fitness, the r elativ e r epr oductiv e success of an individual or genotype.Acquired Immunodeficiency Syndrome-defining fungus, fungal infection in an early stage of development of AIDS.Example: Talaromyces marneffei .Enzootic, animal disease in a particular geogr a phic ar ea.Example: T. marneffei on bamboo rats.
Table 1 ), and m uc h less so in the pathogens with a double life cycle (environmental pathogens, e.g.Coccidioides immitis ; Table 1 ), returning to the environment after infection (Car pour on et al. 2022 ).The adv anta ge of infection for the environmental pathogens is underlined by their production of specialized forms in animal tissue, as observed in the dimorphic pathogens in Ajellomycetaceae ( Blastomyces , Histoplasma , e.a.): the tissue phases are more pronounced in species that are more prevalent in infection (Jiang et al. 2018 ).When residence in animal tissue is part of the natural life cycle, the fungus must be able to escape from the host after infection for survival and dispersal-although this hypothesis has not been pr ov en in most cases.Transmission is theoretically regarded as a prime criterion of pathogenicity.Note that damage to the host may vary from severe to absent and is therefore not included in the definition.
In contrast, an opportunistic fungus has a preferred habitat outside the v ertebr ate body.We define an opportunistic pathogen (or secondary pathogen) here as a fungus where infection is not part of its natural life cycle (Table 1 ).It ma y ha v e pr operties needed for survival in its natural habitat, which coincidentally also enhance resistance to phagocytosis, exemplified by extremophilic, surface-colonizing fungi that contain melanin (Gostincar et al. 2018 ), a component r equir ed for mitigation of effects of irradiation (Cordero and Casadevall 2017 ) and also promoting resistance to phagocytosis (Liu et al. 2014 ).When inoculated into an animal, the individual isolate aims to survive, but e v en when successful and overcoming the host's immune response, residence in the host is detrimental to the species as it diminishes pr ogen y and fitness.When the pr opa gule would hav e landed in a pr eferr ed habitat, it could have produced a much higher offspring.Such infections are often chronic, and the etiologic agent is likely to die with the host, and thus the infecting individual is lost for the fungal population.
Giv en the abov e fundamental differ ence between primary pathogenicity and opportunism, we may conclude that for the former the infection is strateg ic, while ecolog ical strateg ies of opportunistic species do not include v ertebr ates, and the infection is detrimental e v en if the infecting fungus survives.For opportunists, the individual benefit is not in line with the benefit for the species .T his distinction is not alwa ys unambiguous , as numerous pathogens infect non-optimal hosts, and then behave in a more opportunistic fashion.

Examples of primary pathogenic fungi
One of the best examples of a pathogenic fungus is Batrac hoc hytrium dendrobatidis , the Chytrid fungus capable of infecting a large number of frog species all over the globe (Castro Monzon et al. 2020 ) and a major driver of frog decline (Skerratt et al. 2007 ).Pathogens living in association with their pr eferr ed host ar e likel y able to infect healthy individuals and provoke a defined course of disease, which is usually mild.Ho w ever, severe infection and host decline are usually observed in hosts that are immunologicall y naïv e to the fungus, while pathogens mostly remain innocuous when living in prolonged association with their preferred host.The balance is r estor ed in the aftermath of the epidemic, leading to the co-existence of host and low-virulence pathogen (Hollanders et al. 2023 ) and co-evolution of resistant hosts (Mutnale et al. 2018 ).Similar observ ations wer e made with Pseudog ymnoascus destructans, the fungus causing de v astating white-nose disease in bats in the United States, while the same fungal lineage resided in Europe without causing significant disease (Zukal et al. 2016 ).This suggests that a close relationship between pathogen and host r equir es ada ptation to incr easing r esistance and decr easing virulence to a particular optim um, the tr ansmission-virulence tr adeoff (Kun et al. 2023 ).Host-to-host transmitted pathogens, such as anthropophilic dermatophytes , ha ve their assimilative thallus in host tissue, and thus need the host not only for distribution and survival, but also for growth.Due to their dependence on the animal, there is more evolutionary pressure to w ar ds the decrease of virulence to reestablish coexistence.As an example, the most successful dermatophyte, Trichophyton rubrum, often causes nearly asymptomatic tinea pedis .T he ultimate host-pathogen interaction equilibrium (Kirchner and Roy 2002 ) needs to be r eac hed before the host is driven to extinction.In line with this, the dimorphic pathogens Histoplasma capsulatum and C. immitis mainly cause infection in healthy individuals entering endemic foci when they ar e imm unologicall y naïv e .Virulence , i.e .the degree of damage to the host, differs widely between pathogenic species.Extinction of the host leads to extinction of the pathogen, and therefore this can be regarded as an inefficient, primitive strategy.In ada pted fungi suc h as Emmonsia crescens commonl y causing adiaspir omycosis, the r odent or armadillo hosts (Borman et al. 2018, Hughes and Borman 2018, Nav as-Suar ez et al. 2021 ) seem to experience limited harm, which supports the hypothesis that mitigation of virulence increases the species' survival in the long run.Similarl y, Talarom yces marneffei in bamboo rats (Cao et al. 2011 ) and H. capsulatum in bats (Gugnani and Denning 2023 ) are likely to be long-established environmental pathogens.This particularly holds true for the latter species, which has accumulated enormous diversity in anonymous markers over time (Rodrigues et al. 2020 ).
Differ ent fr om the mec hanism of Batrac hoc hytrium , host-to-host tr ansmission is v ery r ar e among fungi.Primary pathogenic as well as opportunistic fungi ar e mostl y acquir ed fr om sources outside the host species , i.e .the en vironment, and in the case of humans often other mammals.In humans, contagious fungal infections are limited to the anthropophilic dermatophytes .T he anthr opophilic dermatophytes hav e become extr emel y successful globall y (Havlic k ov a et al. 2008 ) by transmission via skin flakes loaded with fungal cells, but from an evolutionary point of view, this is a dead end.Sexuality is lost because the lar ge, elabor ate fruitbody can only be produced in the environment, as is characteristic for geophilic Arthroderma species which just use terrestrial animals for dispersal via fur colonization.Host shifts to anthr opophil y hav e taken place r epeatedl y fr om domesticated animals since the early days of animal husbandry.Four out of six anthr opophilic dermatophytes hav e an identifiable, closel y r elated zoophilic counterpart (Zhan et al. 2018 ).The process of dermatophyte adaptation has been described in the Microsporum canis complex (Zhou et al. 2023 ), a well-delimited group of species containing a species on cats ( M. canis ) and one restricted to humans ( Microsporum ferrugineum ) (Fig. 1 ).Cat-human infection by the original zoophilic species is common, often leading to inflammatory tinea capitis on the scalp.Transmission from an infected human r equir es lo w er virulence and less inflammation, which is beneficial for the fungus, and thus can be regarded as a new strategy.The pr eferr ed host of M. canis is the cat, whereas that of M. ferrugineum is the human.The anthropophilic dermatophyte T. rubrum ma y ha v e e volv ed at an earlier sta ge to w ar ds its nearly commensal lifestyle, with no direct ancestral zoophile being identifiable.
Inter estingl y, H. sapiens is pr obabl y the onl y v ertebr ate carrying a large number of host-specific dermatophytes .T he response to hairs of animal fur did not provoke significant differences in a panel of species of dermatophytes (Tang et al. 2023 ), but a transition from fur colonization to immunologically active naked skin, e v en though both environments share keratin being the essential nutritional source of dermatophytes, is a significant step .W ith domestication, mankind has created its own adapted pathogens (Tang et al. 2021 ), and this suggests that the dermatophyte host shifts take place within a r elativ el y short timeframe (Tang et al. 2022 ).Tinea capitis is likely to be an initial phase in the host shift (Kandemir et al. 2020, Zhou et al. 2023 ), but this often highly inflammatory type of infection ob viousl y is inefficient for host-tohost transmission, and further adaptation is required.
Batrac hoc hytrium dendrobatidis , the frog pathogen of which the environmental part of the life cycle consists of just waterborne zoospores, occurs on a wide variety of frog species (Mutnale et al. 2018 ).Other fungi have been described with a very wide ecological amplitude.Sigler ( 2005 ) reported E. crescens from a large number of small animal species, but r ar el y on lar ger hosts; the terr estrial r odents ar e likel y to be pr eferr ed hosts (Fig. 1 ; Borman et al. 2009 ).Some close r elativ es of Emmonsia in Emergom yces hav e thus far mainly been found in humans (Jiang et al. 2018 , Friedman andSchwartz 2019 ), and seem to have a narrow amplitude with host r estriction.Envir onmental pathogens can also be restricted by factors in their environmental habitat, such as Coccidioides species in desert soil (Fisher et al. 2002 ).Other enzootic and endemic fungi can be limited in their expansion by factors such as the distribution of the pr eferr ed host (Hrycyk et al. 2018 ) or climate (Gorris et al. 2019 ).
Fr equentl y mentioned factors promoting infection are (i) adhesion (Hogan et al. 1996 ) 2005 ), and (vii) dimorphism and cell shape in tissue (Klein and Tebbets 2007 ).While factors (1 −4) ar e gener al and also a ppl y to envir onmental, often extr eme habitats, factors (5 −8) ar e mor e effective under conditions of tissue inv asion.Enhancing e v asion of the host's immune response is indispensable for fungi with an inv asiv e str ategy.In contr ast, opportunists lac k a str ategy that includes tissue invasion; instead, they tolerate extreme environmental conditions that may coincidentally be effective in tolerating the immune response.
Primary pathogens are largely able to evade phagocytosis by macr opha ges and neutrophils, the infection being resolved later by acquired cellular immunity (Horwath et al. 2015 , Fig. 2 ).Biologicall y activ e pr oteases, beta-glucan and mannans fr om fungi stimulate innate immune cells, such as dendritic cells, resulting in the production of cytokines (Interleukin-6, IL-12, and IL-23) and proinflammatory mediators (Bartemes and Kita 2018 ), and subsequently T h1-, T h2-, and T h17-type CD4 T-cells pro vide protection.For effective control of the pathogen, the correct balance is to w ar ds T h1 and T h17 cells and the pr oduction of interfer on gamma-stim ulating pha goc ytosis (Sey edmousavi et al. 2014 ).Talaromyces marneffei is in the endemic areas of bamboo rats in Southeast Asia e v en an AIDS-defining fungus (Maniar et al. 2005 ).In AIDS, the T-helper cells are affected, and therefore patients are less able to control fungal infections that are normally controlled by CD4 + immunity; hence the primary pathogens tend to be AIDS-associated (Almeida 2008, Brown et al. 2014, Devi et al. 2020, Myint et al. 2020, Qin et al. 2020 ; Centers of Disease Control List of AIDS-defining illnesses).In recent years, T. marneffei has been emerging in non-AIDS populations (Bai et al. 2021 ), which suggests that the fungus goes through a process of adaptation; possibly the human becomes a pr eferr ed host for this fungus.It should be noted that well-adapted pathogens show low virulence to their pr eferr ed host, but may cause se v er e infections in non-optimal hosts, which makes the distinction of pathogenic versus opportunistic behavior less clear.In addition, infections tend to take a more serious course when the host is imm unocompr omised.The prime control mechanism is delayed, via the acquired, ada ptiv e arm of immunity (Schaffner 1989 ).The infection kinetics show an initial increase, followed by near-resolution, the fungus residing in dormanc y (Bro wn et al. 2013, Crum 2022 ) and is reactivated with T-cell impairment, e.g. in the Human Immunodeficiency Virus-positive population.

Examples of opportunistic fungi
Defining primary pathogenicity as beneficial for the species, opportunism in contrast is an infection that may be successful for an individual fungal strain, i.e. the strain is able to survive, but is detrimental to the long-term survival of the species .T he infecting strain is lost for a prolonged period or for e v er for the fungal population, which means suboptimal reproduction and lo w er than maximum fitness of the species.Vertebrate hosts are an unfavored environment where the fungus struggles to surviv e. Normall y the infection is quic kl y r esolv ed by inflammation and phagocytosis via macrophages and neutrophils (Loh and Lam 2023 ).With sufficient and a ppr opriate extr emotoler ance, ho w e v er, Figure 2. Dia gr am pr eferr ed habitats (striped areas) of some fungal examples.Aspergillus fumigatus on human and plant debris (facultative pathogen), Emmonsia crescens with pr eferr ed r odent hosts; Microsporum canis with pr eferr ed feline host but also infecting humans; Microsporum ferrugineum with pr eferr ed human host; Sporothrix sc henc kii in plant debris but also infecting cats and humans; Fonsecaea pedrosoi , pr obabl y in environmental debris but also successfully infecting humans; and Fusarium oxysporum considered as cross-Kingdom pathogen.
the fungus may effectiv el y r esist, and experience later augmented action via T-cell response.Infection kinetics with the main response by the innate arm of immunity either shows r a pid r esolution or, if unsuccessful, gr adual incr ease (Sc haffner 1989 ) leading to c hr onic infection.Antigen r ecognition via antigen-pr esenting cells may lead to an ina ppr opriate Th2-cell r esponse with low levels of IFN-γ and high le v els IL-4 and IL-10 and insufficient clearance (Seyedmousavi et al. 2014 ).
A high diversity of factors enhancing an infection has been reported from a wide diversity of fungi.The most de v astating infections have been observed with Mucorales .Patients with severe infections inv ariabl y hav e significant underl ying diseases, suc h as diabetes, acute myeloid leukemia (AML) or COVID-19 infection, are subjected to immune-lo w ering therap y, or a combination of these factors (Rudr am urthy et al. 2021 ).Se v er e, often fatal infections have also been reported from black yeasts and relatives, classified in the ascomycetous order Chaetothyriales (Quan et al. 2020 ).In the past, as with the latter fungi often no un-derlying disease or immunoincompetence was found in affected patients, se v er al a gents wer e rightfull y attributed to the highest biosafety category (BSL-3) in use for fungi.For example, Mitchell et al. ( 1990 ) reported fatal dissemination by Cladophialophora devriesii , and Tintelnot et al. ( 1995 ) by its close r elativ e Cladophialophora arxii .Numer ous enigmatic se v er e infections wer e r eported fr om Exophiala species.Dissemination led to a c hr onic, finall y often fatal disease.Exophiala dermatitidis was r epeatedl y r esponsible for disseminated phaeohyphomycosis (Matsumoto et al. 1993 ), often in healthy-appearing adolescents (Hiruma et al. 1993 ) and then sometimes showing neur otr opism (Shimazono et al. 1963, Alabaz et al. 2009, Chang et al. 2009 ).Exophiala spinifera sho w ed a similar clinical ability (Dai et al. 1987, Rajendran et al. 2003, Wang et al. 2015 ), also with some juv enile pr eponder ance, but with a slight osteotr opic r ather than neur otr opic tendency (Li et al. 2011 ).Of particular interest is Cladophialophora bantiana , with about 150 published cer ebr al cases (Horré and de Hoog 1999 , Kantarcioglu et al. 2017 ), mostly in apparently healthy individuals (Garg et al. 2007, George et al. 2008, Schweizer et al. 2019, Miossec et al. 2020 ).
Ho w e v er, de v elopments during the last two decades have shed doubt on whether BSL-3 classification was justified for black fungi.Matos et al. ( 2002 ) found that the supposed pathogen Exophiala dermatitidis to be an abundant and consistent colonizer of the walls in public steam baths and thus would be massiv el y inhaled in countries where no infectious cases by the fungus were known.Similarl y, the fungus a ppear ed to hav e a pr eponder ance in some specific domestic habitats, such as dishwashers (Zalar et al. 2011 ), r ail way sleepers (Dö gen et al. 2013, Gümral et al. 2014 ) and other environments that are rich in hydrocarbons (Isola et al. 2013 ).Analyzing the large number of published cases by de Hoog et al. ( 2020), the majority of infections occurred in patients with underlying diseases among which were AML (Myoken et al. 2003 ) and solid organ transplant (Tanuskova et al. 2017 ).An explanation of the unexplained fatal cases came with the discovery of inherited CARD9-related immunodeficiency (Lanternier et al. 2015 ).P articularl y homozygous CARD9 mutations led to Th17 impairment whic h incr eases susceptibility to Candida , dermatophytes and melanized fungi (Song et al. 2021 ).Despite the se v er e infections caused by members of Chaetothyriales , these fungi exhibit ancestral connections with ants (Quan et al. 2020 ) and lichens (Cometto et al. 2023 ) but show no trace of v ertebr ate association.Even the neurotropic species Cladophialophora bantiana seems less dangerous than supposed, as it has a possible environmental habitat in sugar-rich plant tissue (Costa et al. 2023 ).
Candida auris , a m ultidrug-r esistant and halo-thermotoler ant fungus causes fatal infections mostly in hospitalized patients having a weakened immune system.Later, more isolates were obtained from halophilic environments such as indoor swimming pools, sandy beaches and tidal salt marshes, strains having reduced thermotolerance and drug resistance (Eko w ati et al. 2018, Ar or a et al. 2021, Escandón 2022, Akinbobola et al. 2023 ).Therefore, it has been hypothesized that the fungus emerged from its natural halophilic reservoir, adapted to endothermic vertebrates as a result of global warming, and was carried by colonized seabirds (Casade v all et al. 2019 ).Yet, there is no adequate information about the environmental phase of its life cycle or the transmission pathwa ys .T he detection of C .auris in stor ed a pples in India related to the clinical strains of the fungus, suggested that a gricultur al use of fungicides can be a selective force for the drug resistance in C .auris (Yadav et al. 2022 ).The fungus can colonize healthy humans and animals without causing any infection (Sexton et al. 2021, Yadav et al. 2023 ), and during the infection, it is able to escape from the host's innate immune system (Weerasinghe et al. 2023 ).Karyotype differences and limited recombination (Ross andLorenz 2020 , Wang andXu 2022 ) show evidence for the loss of sexuality in C .auris .
The fundamentally different immune balance between primary pathogenic and opportunistic fungi was noted in the classical description of infection kinetics by Schaffner ( 1989 ). Pathogenicity should not only be described with abiotic and hostrelated factors, but also with the fungus having a strategy in which a v ertebr ate host plays a r ole, an ywher e in the lifecycle, enhancing the fitness of the species .T his strategy focuses on the evolutionary success of the species, whereas many of the currently described factors to overcome the host immune system are designed for the survival of the individual.In general, host infection of a pathogen increases progeny in the population, whereas in opportunists it is detrimental to the population due to postponed or absence of transmission, and no new generation being founded.

Examples of fungi between opportunism and primary pathogenicity
In general terms, the host's imm une system r ecognizes the gr adational difference between primary and opportunistic pathogens.The opportunist is usually cleared by inflammation via the innate immune system of macrophages and neutrophils or eosinophils.If the initial response is ineffective, subsequent phagocytosis mediated by CD4 + cells often fails, leading to c hr onic infection.Infections by host-specific primary pathogens on pr eferr ed hosts such as Histoplasma are usually suppressed effectively, but with dela y and pro vided that acquir ed cellular imm unity is functional.Ho w e v er, intermediates between primary and opportunistic pathogenicity are numerous, and this approximate bipartition in imm une r esponse is not al ways ob vious (Fig. 3 ).Se v er al fungi, such as Candida albicans and Malassezia and Pneumocystis species natur all y colonize hosts as intestinal, cutaneous and pulmonary commensals, mostly without causing fulminant disease.Due to their intimate mammal association they are likely to respond to an y br eac h in the host's imm unity.
Cryptococcosis is a disease caused by Cryptococcus neoformans and its r elativ e C. gattii .The infection is acquired through inhalation, leading to pneumonia, and if not pr operl y tr eated it may lead to meningitis which can be fatal (Song et al. 2021 ).Cryptococcus neoformans has mostly been regarded as an opportunist causing infection nearly only in immunocompromised patients .T he fungus is more common in HIV patients rather than those with a competent innate immune system, and studies have identified mechanisms such as capsule formation, melanin production, titan cell formation, and non-lytic exocytosis that interfere with phagocytosis allowing the expulsion of viable cells from macrophages (Wang et al. 2022 ).The latter mechanism is related to brain infection and the crossing of the blood-brain barrier, as the fungus can utilize macr opha as "Trojan horses," allo wing y east cells to migrate into brain tissue (Kronstad et al. 2011, Santiago-Tirado et al. 2017 ).The fungus has been speculated to have gone through an ada ptiv e lea p, fr om nematodes inhabiting a natural niche of bird guano to human infection (Casade v all et al. 2003 ).Its close r elativ e C. gattii fr equentl y causes deep infection in immunocompetent individuals, which suggests that Cryptococcus has shifted from an environmental to a pathogenic lifestyle already long ago.
Ancestral species of the infectious Sporothrix clade ar e envir onmental, residing in soil and decomposing plant material; some species also associated with bark beetles (de Beer et al. 2016 ).In the "pathogenic clade" (Zhang et al. 2015 ), Sporothrix sc henc kii is ancestr al; the m ultiple single-source infections affecting humans typicall y originated fr om plant material suc h as mosses (Dixon et al. 1991 ), hay (Dooley et al. 1997 ) or mining wood (Zhang et al. 2015 ).The emergence of Sporothrix brasiliensis in Curitiba since 1990 (Cognialli et al. 2023 ), originating from Rio de Janeiro (Barros et al. 2004 ), is notable.Nearly all infections by this species are cat-transmitted (Yeow et al. 2023 ).It is interesting to look at the disease under a "One Health" perspective, considering that members of the genus affect various mammals (cats , dogs , and humans) incr easingl y fr om S. sc henc kii to S. brasiliensis .Corrêa-Junior et al. ( 2023 ) sho w ed that S. brasiliensi virulence factors in cats and humans are similar, indicating minimal adaptation needed between species.It may be assumed that cats while scr atc hing wood and soil, carry S. brasiliensis yeast cells under their nails, dir ectl y inoculating the inv asiv e form into host tissue (Cabañes 2020 ).Recently, a suitable type of airborne transmission was noted (Bastos et al. 2022 ).T hus , the fungus can no w transmit betw een hosts, with the new host becoming preferred.Cases have been Figure 3. Dia gr am of fungal ecology with pathogenic and opportunistic arms.Host shifts take place particularly between adjacent hosts, while environmental pathogens are canalized by their abiotic habitat and tend to become endemic.Some opportunistic pathogens with environmental lifestyles survive in animal hosts upon accidental inoculation and might evolve to w ar d primary pathogenicity.
described showing that S. brasiliensis becomes particularly fulminant in AIDS patients (Poester et al. 2020 ).Inter estingl y, the onl y patient still alive in the report of Cruz et al. ( 2021 ) presented IgG antibodies against Sporothrix , indicating the presence of immunological memory.Sporothrix brasiliensis shows a primary pathogenic profile, unlike its opportunistic ancestor S. schenckii (Fig. 1 ).The dimorphism of Sporothrix , where tissue invasion leads to the production of yeast cells rather than hyphae , ma y be a factor that has enabled this transition.
Chromoblastomycosis (CBM) is a traumatically inoculated skin infection caused by se v er al members of the black yeast order Chaetothyriales , such as Fonsecaea pedrosoi .Infections should be cleared by inflammatory action of the innate cellular immune system, but insufficient immune response leads to extended acanthotic lesions (Queiroz-Telles et al. 2017 ).In some Phialophora cases, particularly enhanced by genetic immune defects in the Dectin-CARD9 axis (Zhang et al. 2015, Song et al. 2021 ), the in-fection becomes c hr onic due to ina ppr opriate signaling with a Th2 response (Wang et al. 2018 ), as is also fr equentl y observ ed in CBM patients (Sobianski Herman et al. 2024 ).In cutaneous and subcutaneous tissue, the fungus produces large, spherical muriform cells which are resistant to phagocytosis .T his form is not unique to the human host but may r epr esent the fungus' pr e v alent growth type in tissue, either animal or plant (de Hoog et al. 2007, Fornari et al. 2018 ).The muriform cell is likely an adaptation to extreme conditions, coincidentally aiding survival in human tissue.In this scenario, the fungus should be able to escape from the infected host, to include the human host as part of a natur al life cycle.Chr omoblastomycosis is not conta gious, and the shedding of skin material loaded with fungal cells into the environment has as yet not been proven.
Aspergillus fumigatus is not on this list.The fungus has its natural habitat in self-heating plant debris (Göttlich 1996 ).It also surviv es successfull y in imm unocompr omised hosts (Fig. 1 ).Despite numerous human infections, mammal-to-mammal transmission is absent, and e v en when this occurs, the fe w ada pted genotypes will soon get lost in the enormous pool of environmental genotypes of the ubiquitous fungus.Azole resistance is an evolutionary driver, but the few human-derived propagules are unlikely to significantly contribute .T he fungus e volv es under azole pr essur e in a gricultur al envir onments (Verweij et al. 2020 ), but remains a strict opportunist.Also, some Fusarium species commonly invade both plants and humans, for which trans-Kingdom has been suggested (Meza-Menchaca et al. 2020 ).There are indications that the mechanisms of plant-and human pathogenicity are similar; in that case, these species might be consider ed facultativ e pathogens with different hosts (Fig. 1 ).

Conclusions and hypotheses
Infectious fungi employ various strategies to infect human hosts.In opportunists, the survival of the species does not depend on the single infecting str ain.Tr ansmission driv es e volution and ada ptation.Without tr ansmission, ther e is no e volution or host shift, maintaining the fungus-human relationship.At the other end of the spectrum, host-to-host pathogens may shift to a similar, imm unologicall y naïv e host, causing an epidemic.Pr obabl y the fungus decreases its virulence subsequently, resulting in genotypes that can coexist with the host.Environmental pathogens are less likely to experience host shifts, as they ar e contr olled by their pr eferr ed host as well as by the properties of their environmental habitat.Among the environmental fungi, a small number of opportunistic fungi are predisposed to survive in mammalian tissue, potentially leading to pathogenic adaptation.This large host lea p fr om the envir onment or inv ertebr ates to mammals involv es surviv al mec hanisms fr om their natur al habitat.
With respect to the fungi described abo ve , several general statements can be made.Many dermatophyte species have adapted to humans, originating from domesticated animals.This corresponds to the concept of primary host-transmitted pathogens with pr eferr ed animal hosts that shift to an adjacent animal host, H. sapiens .This can lead to epidemics, as seen with Trichophyton indotineae (Gupta et al. 2022 ).New epidemics are most likely from host shifts inv olving nearb y animal hosts.Possibly the systemic bamboo rat pathogen T. marneffei shows signs of adaptation, with a change in its clinical profile (Chan et al. 2016 ), although still in patients with impaired cellular immunity.Opportunistic mucoralean fungi, despite increased cases during the COVID-19 pandemic (Singh et al. 2021 ), show no signs of adaptation.Infections r esult fr om the emer gence of susceptible hosts.Also, blac k fungi lac k ada ptation despite fr equent c hr omoblastomycosis in healthy individuals .In this disease , traumatic inoculation is follo w ed b y c hr onic infection due to insufficient clearance of the inoculum.Spor otric hosis seems to be a similar situation: Sporothrix brasiliensis cases have surged since 1990, primarily from direct traumatic inoculations by cat scr atc hes (Sanc hotene et al. 2015 ), but these mainl y concern dir ect tr aumatic inoculations fr om cat scr atc hes whic h hav e dug up the species fr om the soil.Ho w e v er, the catto-human transmission via sneezing (Bastos et al. 2022 ) suggests human tissue as a new habitat for Sporothrix ; this is underlined by disseminated spor otric hosis in HIV patients (Poester et al. 2020 ) and healthy individuals (Fernandes et al. 2018 ), highlighting the role of acquired cellular immunity in controlling this fungus.
Most fungal pathogens on humans have their origin in nonhuman mammals and may follow epidemic patterns and adaptations similar to those of viruses and bacteria.Ho w e v er, knowledge of the natural association of fungi with wild animals is limited.Fu-tur e r esearc h on the natur al origins of epidemics should include fungi.

Figure 1 .
Figure 1.Summary of immune response against primary and opportunistic pathogens, with innate and adaptive arms.