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1、1,主要致病性真菌,浅部真菌感染（致病性真菌感染和条件致病性真菌感染）深部真菌感染（致病性真菌感染和条件致病性真菌感染）,2,浅部感染真菌,表面感染真菌皮肤癣真菌皮下组织真菌感染,3,4,表面感染真菌,位置：寄居于人体皮肤和毛干的最表层。因不接触组织细胞，很少引起宿主细胞反应统称：角层癣菌 代表：秕糠马拉癣菌(Malassezia furfur)症状：由于此菌能产生对黑色素细胞有抑制作用的二羧酸，使花斑癣局部色素减退，如汗渍斑点，俗称汗斑。诱发因素为高温多汗,5,Malassezia furfur,Tinea versicolor on skin surface (sweat stain)Th
2、e lesions are small hypopigmented or hyperpigmented maculesMost common site : back, underarm, upper arm, chest, neck Most common in adolescent and young adult males Associated with increased sweating,6,Pityriasis versicolor showing hyperpigmented lesions in a Caucasian and hyphopigmented lesions in
3、an Australian Aborigine,7,Culture of Malassezia furfur on Dixons agar (contains glycerol mono-oleate),8,Piedraia hortae (何德毛结节菌),It usually affected the scalp hairThe nodules are darker in color, harder, and more firmly attached to the hairsBlack Piedra,9,Piedraia hortae forms a hard superficial pig
4、mented nodule around the hair shaft (在毛干上形成硬的黑色结节，如沙粒状),10,Fungal otitis externa,Fungal infection of the external auditory canalCaused by several species of Aspergillus (most often A.niger), but Candida albicans is also capable of infecting this siteThe major symptoms are itching and feeling of full
5、ness in ear,11,12,皮肤癣真菌,引起皮肤浅部感染皮肤癣是人类最多见的真菌病统称：皮肤癣菌，大约40多个种，分属于3个属嗜角质蛋白，37不能生长，侵犯部位：角化的表皮，毛发，指（趾）甲病理变化：由真菌增殖及代谢产物刺激宿 主引起,13,致病性,指（趾）甲 皮肤 毛发毛癣菌属 + + +表皮癣菌属 + + -小孢子癣菌属 - + +,一种皮肤癣菌可在不同部位引起病变相同部位的病变也可由不同的皮肤癣菌引起,14,15,Tinea pedis caused by T. rubrum. Sub-clinical infection (left) showing mild macerati
6、on under the little toe and more severe infection (right) showing extensive maceration of all toe web spaces,Tinea is transmitted via the feet by desquamated skin scales in substrates like carpet and matting.,16,手足癣治疗原则,水疱型温和搽剂和霜剂角化过度型先角质剥脱剂，再用抗真菌霜剂浸渍糜烂型粉剂收干，抗继发感染，再温和抗真菌,17,Tinea Unguium,usually cau
7、sed by Trichophyton sp,18,甲癣治疗原则,局部治疗甲涂剂系统治疗伊曲康唑，特比萘芬等联合治疗配合拔甲或削甲治疗,19,Tinea Corporis:caused by M. canis, following contact with infectious kittens,20,Tinea Cruris (Jock itch):Infection of the groin, mainly seen in men,21,Tinea Capitis (scalp ringworm),Tinea favosa,发内孢子,22,Tinea Capitis (scalp ringw
8、orm),Tinea alba,发外孢子,23,Tinea Capitis (scalp ringworm),脓癣,24,头癣治疗原则,剪发洗发搽药服药消毒,25,Candidiasis of skin, mucous membranes and nails,Predisposing factorsInfancy, pregnancy, old ageDisorders of immune function, e.g., leukemia, corticosteroid therapyChemotherapy, e.g., immunosuppressive, antibioticEndocr
9、ine disease, e.g., diabetes mellitusCarcinoma,26,念珠菌性间擦疹,好发部位：腋窝、乳房下、腹股沟、会阴，多见于婴儿及肥胖者。,27,Cutaneous candidiasis : including Interdigital candidiasis, diaper candidiasis, paronychia and onychomycosisVulvovaginal candidiasis and balanitis,Interdigital candidiasis,Candidia onychomycosis and paronychia,
10、28,Oropharyngeal candidiasis : including thrush, glossitis, stomatitis and angular cheilitis,Oral thrush,29,皮下组织真菌感染,主要有孢子丝菌和着色真菌申克孢子丝菌，属腐生性真菌，常因外伤接触带菌的花草等引起感染。此菌可引起孢子丝菌下疳。此菌也可引起深部感染。是一种二相性真菌。着色真菌感染发生在暴露部位，称着色真菌病。我国主要有卡氏枝孢霉和裴氏着色芽生菌。,30,Sporotrichosis,此菌可经微小损伤侵入皮肤，然后沿淋巴管分布，引起亚急性或慢性肉芽肿，使淋巴管形成链状硬结，称为孢子
11、丝菌下疳。,31,ChromomycosisInfections occur in exposed areas, skin lesions become dark, so called chromomycosisRepresentive species: Cladosporium carrianii, Fonsecaea pedrosoi, etc.Are saprophytic fungi, usually enters the body by trauma,32,经外伤侵入丘疹结节结节融合成疣状或菜花状斑痕形成影响淋巴回流肢体象皮肿,33,Chromomycosis,Chronic ver
12、rucous chromoblastomycosis of the hand due to Cladophialophora carrionii,34,Mycetoma 足分枝菌病,是由多种放线菌或真菌引起的一种慢性化脓性肉芽肿性疾病，主要感染足部，以肿胀、窦道和颗粒为特征。 caused by fungi are called eumycetoma (40%)Actinomycetoma is caused by actinomycetes (60%)It is characterized by the formation of abscess, which contain large ag
13、gregates of fungal or actinomycete filaments known as grains,35,EumycetomaDark grainsMadurella mycetomatisLeptosphaeria senegalensisExophiala jeanselmeiPale grainsFusarium sp.Acremonium sp.Scedosporium apiospermum,ActinomycetomaWhite-yellow grainsActinomadura maduraeNocardia brasiliensisYellow-brown
14、 grainsStreptomyces somaliensisRed-pink grainsActinomycetoma pellettieri,36,深部真菌感染,引起深部感染的真菌包括两大类：致病性真菌与条件致病性真菌致病性真菌主要有组织胞浆菌、球孢子菌、副球孢子菌和芽生菌，这些真菌均属二相性。多见于美洲，我国极少见。它们侵袭深部组织和内脏以及全身，引起慢性肉芽肿样炎症、溃疡和坏死。条件致病性真菌包括有：念珠菌、隐球菌、曲霉菌与毛霉菌、肺孢子菌等。,37,Characteristics of systemic dimorphic mycoses,Are uncommon, often oc
15、curs in endemic areas Most infections are asymptomatic or self-limitingin immune-compromised hosts, infections are often fatalThe pattern of infection are similarRoute of acquisition is inhalation Pulmonary infectionDisseminated infection (Blood, Bone marrow, Brain and CSF, Joint),38,Coccidioidomyco
16、sis,Coccidiodes immitis is considered to be the most virulent of fungal pathogens.Restricted to hot, semi-arid areas of SW USA and Mexico.Grows in the soil, but inhalation of a single spore can initiate infection.,In infected tissues, C. immitis appears as a mixture of endospores and spherules.,Coni
17、dia,Spherules,39,Coccidioidomycosis:,Encounter: Mycelium found in dry, dusty soil. Contact by inhalation of arthroconidiaSpread: Most commonly an asymptomatic self limited pulmonary disease, but may spread via the blood to skin, soft tissues, bones, joints and meninges.Immune Response: T-cell mediat
18、ed (Th-1)Evasion of Defenses: Resistant to killing by phagocytes- protein rich, hydrophobic outer wall- alkaline halo associated with urease E. Damage: secreted proteinases break down collagen, elastin hemoglobin, IgG & IgA,40,1. Ethnicity: Filipinos, African Americans, Native Americans at higher ri
19、sk2.Age: Extremes more susceptible3.Sex: Males more susceptible4.Pregnancy: 3rd trimester5.Immunosuppression,F. Diagnosis,1.Exam: Suppurative or granulomatous inflammation2.Histopathology: spherules or endospores seen in sputum, exudates or tissue3.Culture: danger, highly infectious!4.Serology: Comp
20、lement fixation assay (in cerebrospinal fluid), particle agglutination assay,G. Treatment,Amphotericin B followed by an azole,E. Risk Factors,Coccidioidomycosis:,41,Histoplasmosis,(also called cave disease),Caused by the dimorphic fungus Histoplasma capsulatum,Tuberculated macroconidia, grown at 25C
21、,Intracellular yeast at 37C,Histoplasmosis is characterized by intracellular growth of the pathogen in macrophages and a granulomatous reaction in tissue. These granulomatous foci may reactivate and cause dissemination of fungi to other tissues.,42,Histoplasmosis,A. Encounter. H. capsulatum grows in
22、 soil, especially soil contaminated by guano. Inhalation of conidia from the environment is source of infection. This is more likely in endemic areas. In U.S. these include the Atlantic Ocean to N. Dakota (500,000 cases/year in U.S.), except New England & Florida. Most cases occur in Ohio Valley and
23、 Mississippi Valley),43,More Histoplasmosis,90% of cases are asymptomatic, but in rare cases flu like respiratory symptoms occurDisseminated histoplasmosis occurs in 1:200 cases and is diagnosed frequently in patients with AIDS living in the central U.S. In these cases, the organism spreads via bloo
24、d from the lung to involve bone marrow, adrenal glands, heart valves and CNS4.Spread can also be associated with underlying lung disease (e.g., emphysema).,B. Spread,C. Immune Response,Cell-mediated responses are of primary importanceActivated macrophage can kill yeast cells,D. Evasion of Defenses,S
25、urvival in macrophages elevates pH of phagosomesYeast cells absorb iron (siderophore) and calcium from hostAlteration of cell surface,44,Histoplasmosis,D. Damage,Lung-bronchial obstruction and inflammatory sequelaeDisseminated histoplasmosis-fulminant disease that may result in toxic shockCNS-fatal
26、if untreated.,45,Even More Histoplasmosis,F. Treatment,Amphotericin still mainstay of therapy vs. disseminated and severe pulmonary histoplasmosis. Ketoconasole or itraconasole is effective as therapy for self-limited disease (used in AIDS).,Ocular Histoplasmosis,A small fraction of individuals form
27、 scar tissue in the retina many years after the original histoplasmosis infection. Live organisms cannot be recovered from these specimens. The scarring can obscure the macula and lead to loss of central vision. The first signs are small “histo spots”. Advanced disease is treated with laser photocoa
28、gulation to limit the proliferation of blood vessels.,46,Blastomycosis,Granulomatous mycotic infection that predominantly involves lungs and skin; but can spread to other organs. Most prevalent in males 40-60 years of age and children.,Blastomyces dermatitidis,Dimorphic organism originates in the so
29、il and infection ensues by inhalation of spores. Converts to yeast in animal hosts or at 37o in vitro.,47,Blastomycosis,Encounter: Most cases are in southern, central, and southeastern USA. Infection is by inhalation of spores.Spread: The pulmonary infection is either self -limited or progressive. D
30、issemination often occurs to the skin and to the bone - 80% of patients have large skin lesions; a large number also have granulomatous pulmonary lesions.Risk Factors: Occupational contact with soil; owning a dog. Living in endemic area.Evasion of Defenses: Escapes phagocytosis by neutrophils and mo
31、nocytes by shedding its surface antigen after infectionDamage: Consequence of the immune response to the organismskin lesions, respiratory infiltrates.Diagnosis: based on clinical findings and microscopic detection of organisms in tissue specimens,48,Amphotericin B is the drug of choice for rapidly
32、progressive blastomycosisItraconazole or Ketoconazole for less severe cases,Immune response,1. Alveolar macrophage provide a first line of defense.2.T-cell stimulated PMNs kill Blastomyces cells by oxidative mechanisms.Conidia are more sensitive to killing by PMNs because yeast are too big.TH-1 resp
33、onse is of primary importance,Blastomycosis,Treatment,49,Opportunistic fungal infections,Opportunistic mycoses are fungal infections that do not normally cause disease in healthy people, but do cause disease in people with weakened immune defenses (immunocompromised people). Weakened immune function
34、 may occur due to inherited immunodeficiency diseases, drugs that suppress the immune system (cancer chemotherapy, corticosteroids, drugs to prevent organ transplant rejection), radiation therapy, infections (e.g., HIV), cancer, diabetes, advanced age and malnutrition.The most common infections are:
35、 Candidiasis Cryptococcosis Aspergillosis Pneumocystis carinii pneumonia (PCP) Penicillosis marneffei,50,白假丝酵母菌(Candida albicans),形态：圆形或卵圆形单细胞真菌，革兰阳性繁殖：出芽繁殖，形成假菌丝，在组织易形成芽生孢子培养：普通琼脂、血琼脂与沙保培养基 需氧。室温或 37甚至42生长良好 菌落灰白色或奶油色，表面光滑，带有浓厚的酵母气味。 有大量向下生长的营养假菌丝，呈类酵母型。 在玉米粉培养基上可长出厚膜孢子,属于假丝酵母菌属，俗称白念，为酵母型真菌，是条件致病菌
36、可引起皮肤、黏膜和内脏的急性或慢性炎症，即念珠菌病，是最常见的深部感染真菌病，口腔念珠菌病是艾滋病患者最先出现的继发性感染。生物学特性,51,假菌丝和厚膜孢子,52,Systemic involvement,Urinary tract infectionPulmonary candidiasis Endocarditis MeningitisCandidaemia(septicaemia) Infancy, old age, pregnancy, prolong antibiotic, HIV/AIDS, diabetes,53,微生物检查：,1、直接镜检：同时见出芽的念珠菌与假菌丝 2、分离
37、培养与鉴定：假菌丝，芽生孢子 芽管形成试验/厚膜孢子形成试验 3、白色念珠菌细胞壁甘露聚糖抗原/ELISA 特异性高但敏感性低 4、动物试验：小鼠,54,Cryptococcus neoformans,属于隐球菌属，为酵母型真菌 传染源是鸽子，人因吸入鸽粪污染的空气而感染 主要引起肺和脑的急性、亚急性或慢性感染。生物学特性,圆形，有肥厚荚膜（一般厚度是直径的两倍 ）染色：一般染色法不易着色，墨汁负染，胞内有较大的反光颗粒。出芽繁殖，不形成假菌丝（酵母型菌落）培养特性：沙保或血琼脂培养基，2537生化特性：分解尿素荚膜多糖抗原：AD 和AD 5个血清型，我国约70%属A型,55,56,致病性,外
38、源性感染，肺是主要入侵途径，也属于人体正常菌群，引起条件性感染原发感染通常在肺部，多数症状不明显，自愈；有的引起支气管肺炎；严重者呈暴发性感染并迅速死亡部分患者经血行传播至中枢神经及其它组织，引起肉芽肿性炎症，主要导致慢性脑膜炎致病物质：荚膜,57,微生物学检查,负染色镜检抗原检查： 检查患者血清和脑脊液中新隐荚膜抗原分离鉴定 尿素酶或酚氧化酶动物试验： 小鼠,58,曲霉Aspergillus 烟曲霉 支气管哮喘或肺部感染 毛霉Mucor 腐生菌 脑、肺、胃肠道卡氏肺孢菌Pneumocystis carinii 免疫缺陷病人 肺炎,59,Aspergillus,Aspergillus is a
39、 filamentous, cosmopolitan and ubiquitous fungus found in nature. It is commonly isolated from soil, plant debris, and indoor air environment. It is the second most commonly recovered fungus in opportunistic mycoses following Candida.,60,morphology,It is a filamentous fungiHyphae are septate and hya
40、line. Consisting of a Vesicle The morphology and color of the conidiophore vary from one species to another.,61,62,Aspergillus flavus,Aspergillus niger,Aspergillus fumigatus,63,足细胞分生孢子梗顶囊杆状小梗串状分生孢子（分生孢子头）,64,Species,The genus Aspergillus includes over 185 species. Around 20 species have so far been
41、reported as causative agents of opportunistic infections in man. Among these, Aspergillus fumigatus is the most commonly isolated species, followed by Aspergillus flavus and Aspergillus niger.,65,Pathogenicity and Clinical Significance,局限性肺曲霉病基础疾病致肺空洞存在 曲霉在此生长，不侵犯组织不播散曲霉肺炎（免疫功能低下）过敏性支气管肺曲霉病（过敏体质）,66
42、,Pathogenicity and Clinical Significance,全身性曲霉病多发生在某些重症疾病晚期原发病灶主要在肺 常由败血症引起全身性感染生前很难得到确诊,67,Pathogenicity and Clinical Significance,黄曲霉毒素与恶性肿瘤，尤其是肝癌的发生密切相关,68,Laboratory diagnosis,The specimen like sputum biopsy, bronchalveolar lavage or transbronchial biopsy depending in the site involved.Direct ex
43、amination of septate hyphae by 10% KOH preparation.血清学诊断或血清学试验检出曲霉细胞壁半乳糖甘露乳糖抗原.,69,Culture : In SDA with antibiotics at 25 and 37c有隔菌丝和分生孢子头.,70,Pneumocystis carinii Pneumonia,71,PCP: Historical Features,1909 - First recognized in lungs of Guinea pigs by Chagas.Similar to Trypanosoma cruzi, yet diff
44、erent.These observations were confirmed by Carini soon after.1912 - Delanoes named it after its discoverer and to reflect its tendency to infect the lungs.,72,PCP: Historical Features,Not initially believed to affect humans.1951 - Vanek described an interstitial pneumonia with Pneumocystis carinii o
45、rganisms in a human.1955 - First reported in immunodeficiency.1957 - First associated with chemotherapy.1982 - AIDS and Pneumocystis carinii association.,73,PCP: ClassificationFungus or Protozoan?,Shares both fungal and protozoan nucleic acids and structural features of each.Does not grow in fungal
46、cultures, and antifungal therapy is ineffective.Found to respond to anti-parasitic therapy.Initially, thought to be a Protozoan.Now believed to be a fungus, probably related to Saccharomyces.,74,卡氏肺孢菌Pneumocystis carinii,生物学性状单细胞型，兼具原虫及酵母菌的特点，其发育过程如下：孢子小滋养体大滋养体（二分裂、出芽或接合生殖）囊前期孢子囊囊内减数分裂形成孢子成熟孢子囊内含8个孢
47、子致病性艾滋病患者最常见的并发症和主要的致死原因微生物学检查采集痰液，染色镜检，若发现滋养体或孢子囊可确诊防治本菌对多种抗真菌药物不敏感，用药首选复方新诺明,75,X-ray of Pneumocystis jirovecii pneumonia,There is increased opacification (whiteness) in the lower lungs on both sides, characteristic of Pneumocystis pneumonia,76,PCP: Transmission,Airborne via human-to-human transmi
48、ssion or environmental.Possibly, exposed almost universally as children and then have reactivation later as immunity decreases.,77,PCP: Transmission,Site of Infection:Primarily in the lungs within the alveoli.Attaches to and damages type I pneumocytes.Results in interstitial inflammation with lympho
49、cytes and macrophages.,78,PCP: Extrapulmonary Infection,Once rare, more common with AIDS.Extrapulmonary sites of infection:Reticuloendothelial system (liver, spleen, bone marrow)Sinuses, middle ear, eye, and dermis around head.,79,Patients at Risk,AIDS at CD4 200.Congenital and acquired defects in c
50、ellular immunity.Organ transplantation recipients.Chemotherapy.Corticosteroids.Malnutrition.Premature birth.,80,Conclusions,Most fungal infections affect our surface not our contentsA few dimorphic fungi can cause systemic infections in otherwise healthy people.Endemic areasContact by inhalationCand
