‘Sheris Medical Microbiology, Se> Chapter 42. Pathogenesis of Fungal Infection Pathogenesis of Fungal Infection: Introduction ‘We all have regular contact with fungi. They are so widely distributed in our environment that thousands of fungal spores are inhaled or ingest everyday. ‘ther species are so well adapted to lumans that they ate common member ofthe noma flor, Despite this ubiquity, liically apparent systemic fungal infections are uncommon, even among persons living within the geographic habitat of the more pathogenic species. However, progressive systemie fungal infections pose some of the mest dificult diagnostic and therapeutic problems in infectious disease, particularly among immunocompromised patints to whom ‘hey are a major threat, The purpose of this chapter is o give an overview of the pathogenesis and immunology of fungal infections. Details relating to specifi fungi are given in Chapters 44,45, and 46, General Aspects of Fungal Disease Epidemiology Fungal infections are aquied ftom the envionment or may be endogenous inte few instances whee they ae members ofthe normal flora (gue 42 Inhalaon of nfestious conta generated fiom mold growing inthe environment is conumon mechani Some ofthese molds ate wigutus, wheres oters are rested to geogrphic areas whose climate favors thet growth, Inthe ate ase, disease canbe acquired only inthe endemic area, Some envionment fii produce deat after hey are acideatally injected past he skin bari. The pathogenic fungi represen only ny pereniage of tone found inthe envionment. Endogenous infections ae rected to afew yeasts, primarily Cand albicans, These yeas have the abity to colonize by adering to host calls an, given the opportuni, invade despe ucts. environmental conidia ae inhaled or njostod Endogenous yeasts may invade igre. Systemic disease Bone Meningitis seanFungi system view: Localized disease (lef) is produced by local rauma or the superficial invasion of flora resident on the oropharyngeal (thrush), gistointestnal, or vaginal mucosa, Systemic disease (right) begin with inblation of conidia followed by dissemination to other sits, Pathogenesis ‘Compared with bacterial, viral, and parasitic discase, less is known shout the pathogenic mechanisms and virulence factors involved in fungal infection. ‘Analogies to bacterial diseases come the closest because ofthe apparent importance of adherence to mucosal surfaces, invasiveness, extrecelllarprodues, and ‘neration with phagocytes (Figure 42-2). In general, the prineiples discussed in Chapter 22 apply to fungal infections. Mos fingi are opportuniss,prodcing serious diteate only in individuals with impaired host defense systems. Only few fungi are able to cause disease in previously healthy persons, Pangal pathogenesis is similar to bacteria. ‘Most fungi are opportuniss x 5 Immunity to fimgal infections. A. Pathogenic fungi are able to survive and multiply slowly in non-activated macrophages. B. When macrophages ar activated by eytokines from TEcells the growth is restricted andthe Fungi digested, Adherence ‘A numberof fungal species, particularly the yeasts, are able to colonize the mucosal surfaces ofthe gestrointstnal and female genital tracts. I has been shown experimentally thatthe ability to adhere to buccal or vaginal epithelial ell is associated with colonization and virulence. Within the genus Candida, the species ‘hat adhere best to epithelial cells are those mos frequently isolated from clinical infections. Adherence usually requires a surface adhesin om the microbe and 8 receptor onthe epithelial ell. Inthe ease of C albicans, mannoprotein components extending from the cell wal have been implicated asthe adhesin and Abconectin, and components of the extracellular matrix as the receptors). few binding mediators have been identified for other fungi, usualy a surface smannoprotein. = Candida adherence Adkerenceis mediated by fangaladhesins and host cell receptors “Mannoprotcin is an adhesin, and fibronectin a receptor Invasion Passing an initial surface baries—skin, mucous membrane, or respiratory cpthelium—is an important step for most successful pathogens. Some fungi are ttoduced through mechanical breaks. For example, Spororixschencki infetion typically follows a thom prick or some other obvious trauma. Fungi that initially infec the Tang must produce conidia small enough tobe inhaled past the upper airway defenses. For example, arthroconidia of Coceidioidesimmits to 6 jm) can remain suspended in sr fora considerable ime and can reach the terminal bronchioles to iaitate pulmonary cocciioidomyeosis, Spacali, uma ‘Traumatic injection is linked to trauma ‘Small conidia may pass airway defenses “Triggered by temperature and possibly other cues, dimorphic fungi ftom the environment undergo a metabolic shit similar to the hest shock response and completely change thet morphology and growh toa more invasive form Invasion directly across mucosal bariets by the endogenous Yeast C albicans is Similarly associated wih a morphologi change, the formation of hyphae. The triggering mechanisms of his ehange ae unknown, but the new form i able to penetrate and spread. Extracellular enzymes (ep, protease, elastases) are associated wih the edvancing edge ofthe hyphal form of Candida and withthe snvasve forms of many of the dimorphic and other pathogenic fungi. Alihough these enzymes must costribute to some aspect of invasion or spread, their precise role i unknown for any fungus, Invasion aross mucosal bariers may involve enzymes Injury ‘None ofthe extracellular products of opportunistic fang or dimorphic pathogens has been shown to injure the host directly during infection in a manner snalogous to bacterial toxins, Although the presence of necrosis and infarction inthe sues of patients with invasion by fung suchas Aypergillu suggest & toxie effect, direct evidence is lacking, A numberof fungi do produce exotoxins called mycotexins, inthe environment but notin viva. The structural components ofthe ell do not cause effects similar o those ofthe endotoxin of Gram-negative bacteria, althoug mannan is know to eiculate widely inthe body: The ecculating products of Cryptococcus neoformans have been shown to dovn-reglate immune funetions. The injury eaused by Fungal infections seemsto be duc primarily to the destructive aspects of delayed-ype hypersensitivity (DTH) responses as a resul of the inability ofthe immune system to clear the fungus, In thie respect, fungal infections resemble tuberculosis more than anyother diese, += DI; DTH ia tubereulosie [No clastic exotorns are produced in vivo Injury is duc to inflammatory and immunologic responses Immunity Innate Immunity ‘There considerable evidence that healthy persons have a igh level of inate immunity to most fungal infections. This is particularly trae of opportunistic ‘molds. Ths resistance is mediated by the professional phagocytes (neutrophils, macrophages, and dendritic cells), the complement system, and pattern cognition receptors. For fang, the most important receptors include aTetin-ike structure on phagocytes (dctin-I) that binds glucan, and Toll-like receptors (TLR2, TERS), In most instances, neutrophils and alveolar macrophages are able to kill he conidia of Fungi i they reach the tissues, A small numberof species, all of which ae dimorphic, are able io praduce mild to severe diese in otherwise healthy persons, Invitro studies have shown these fungi tobe more resistant ‘o killing by phagocytes than the opportunist possibly because ofa change in surface structures subject to patter recognition. C albicans is able to bind ‘complement components in a way tat interferes with phagocytosis, ‘Most fungi are rally killed by neutrophils imumits, one of the est-studied species, hasbeen shown to contain a component i the wall ofits conidial (infective) phase that is antiphagocytic. As the layphae convert othe sphere (iss) phase, they slso become resistant to phagocyte killing beease oftheir size and Surface characterises, Some fungi produce substances such as melanin, hich interfere with oxidative kiln by phagocytes. The tissue yeast form of Histoplasma capsulatum multiplies within ‘acrophages by interfering with Iysosomal killing mechanism in a manner similar o that of some bacteria. These mechanisms of avoiding phagocytic killing appear to allow many éimorphie fungi to multiply sufficiently to produce an infection tat can be controlled only by the immune response. ‘Tissue phases of dimorphic fungi resis phagocytic Killing Adaptive Immune Response ‘A recurrent theme with fungal infections is the importance of an intact immune response in preventing infection and progression of disease. Most fungi are ‘incapable of producing even a mild infection in immunocompetent individuals. A small numberof species are able ta eause clinically spparent infection tht usually resolves once there i ime for activation of normal irumune responses, In most instances in Which it has been investigated, the actions of neutrophils and ‘Tryl-mediated immune responses have been found wo be of primary importance in tis resolution. Progressive, debilitating o life-threatening disease with these gents is commonly associated with depressed or absent cellular immune responses, and the course of any fuga disease is worse in immunocompromised than previously healthy persons. ‘Teell-mediated responses of primary importance Progressive fungal diseases occur in the immunocompromised Humoral Immunity Antibodies canbe detected at some time during the couse of almost all fungal infections, but for most ther litle evidence thatthe contribute to immunity. ‘The only encapsulated fungus, Cryptococcus neoformans, is an example ofa fungus against which antibody plays a roe in controling infection. Although the polysaccharide capsule of C neoformans has antiphapocytie properties similar o those of encapsulated bacterial pathogens, itis less antigenic. Anicapsular Antibody plays a role in resolving eryptococcalinfetion, but Ty responses ate sill dortnant. Antibody aso plays @ role in contol of C albicans infections by cnancing fungus-phagocyte interactions, and ths is probably tru fr other yeasts. In some other fungal infections, the lack of protective eect of antibody is striking. In eoveiioidomyeosis, for example, high tiers of Cimmitis-specifi antibodies ae associated with dissemination and a worsening clinical course Opsonizing antibody is efTetve in some yeast infections Considerable clinical disease have neutropenia, defeets in neutrophil funtion, or depressed Tj] immune reactions, These ean result fom factors suchas steroid treatment, leukemia, Hodgkin's disease, and acquitedimmunodeficieney syndrome. In other cases, an immunologic deficit ean usually be demonstrated by absence of delayedtype hypersensitivity responses or Ty-stimulated cytokines speifi othe fungus in question. Inthe late case, itis possible that hyporesponsiveness i due at east, ‘in part to activation of suppressor cells or continued ceculation of fungal antigen, Celular immunity ‘Systemic disease associated with deficiencies in neutrophils and T-cell-mediate immunity Although no all fungi hae ben stud to the same degree, unified picture emerging frm clinical and experimental animal studies is ilustated in Egute 442.2 Whenhypacor yeast esl ofthe fungus reach dep Ussue sie, they are ether killed by neutrophils or resist desuction by one of the aliphagoeyte ‘mechanisms desribed cari. Surviving cells continue fo gow stow of they are dimorphic, convert thet east, hyphal, or sperale sue pass. The frowth ofthese invasive forms maybe slowed but nt killed by macrophages, which nges! them A feature ofthe fang pathogens is resist the killing ‘mechasiams of the macrophage and conte to maulpy In healthy persons, ie extent of infection issn, and any symptoms are caused bythe alantary response. Phagacls king ‘Pangi that escape neutrophils grow slowly in macrophages [Everything awaits th specific adaptive immune response tothe invader. In fungal infections it isthe interaction between dendritic cells and macrophages that favors prodiction of interleukin 12(IL-12) and interferon XX (INF~1 leading the CD4 cells to differentiate to Ty cells tat has the dominant effect. The ‘uring point comes when local macrophages containing mulkplying fungi are activated by cytokine mediators produced by T lymphocytes that have interacted with the Tuga antigen. The activated macrophages are then able to rest the growth ofthe fungus, ad the infection is controlled. Defects that distur this «eyele lead to progressive disease. To the extent that they are known, the specifies ofthese reactions ae discussed in the folowing chapters =: Tell esponses, Growth is restricted when macrophages activated by cytokinesImmune defects lead to progressive disease McGraw Hill Copyright © McGraw-Hill Global Education Holdings, LLC. Allights reserved ‘Your IP addzess is 172.16.105.117 ‘Access Provided by: Universidad Autonoma de Bucaramanga ‘Silverchair Fungi system view: Localized disease (lef) is produced by Toca rauma of the superficial invasion of flora resident on the oropharyngeal thrush), gastrointestinal, or vaginal mucosa, Systemie disease (righ) begins with inalation of conidi followed by dissemination to othe sites, Immunity to fungal infections. A. Pathogenic fungi are able to survive and multiply slowly in non-activated macrophages. B, When macrophages ar ativated by cytokines from cells the grow s restricted andthe fungi digested.