BMS250 wk2 derm pt2 skin microbio PDF

Microbiology of Skin Infections BMS250 Learning Outcomes Describe the pathophysiology and clinical features of the infectious disorders of the skin, hair and nails (HSV, HPV, HZV, fungal..) Describe the basic etiology and pathogenesis of common fungal skin infections (tineas) and r...

Microbiology of Skin Infections BMS250 Learning Outcomes Describe the pathophysiology and clinical features of the infectious disorders of the skin, hair and nails (HSV, HPV, HZV, fungal..) Describe the basic etiology and pathogenesis of common fungal skin infections (tineas) and relevant microbiology Describe the basic etiology and pathogenesis of common viral skin infections (HSV, Varicella, HPV) and relevant microbiology Describe the basic etiology and pathogenesis of exanthematous skin diseases (measles, rubella, erythema infectiosum, Parvovirus B19, HHV6) and relevant microbiology Describe the basic etiologies and pathogenesis of gram-positive bacterial skin diseases associated with toxin production (Staph and Strep) Differentiate the pathogenesis of bacterial skin diseases caused by exfoliative toxins and superantigenic toxins Describe the basic etiology and pathogenesis of gram-negative bacterial skin diseases (pseudamonas) and relevant microbiology Introduction Normal skin, epidermis, is colonized after birth by commensal bacteria Coagulase-negative Staphylococci (Staph epidermidis) Then fungi, other bacteria and viruses join in to develop the skin microbiome Staphylococcal Skin Infections Most common superficial purulent skin infections (pyodermas) - Carriers of staph aureus as part of their normal microbiota 30% of healthy patients are colonized with Staph aureus Contributing factors that lead to infection: & Immunosuppressive disorders, diabetes, atopic dermatitis, preexisting tissue injury (surgical sites, burns) J Staph epidermidis – mostly commensal Staph aureus- commensal and aggressive/ D pathogenic Produces toxins that damage tissues & evade immune defenses G MRSA- methicillin resistance staph aureus - ↳ Resistant to beta-lactam antibiotics Risk factors: hospitalization or contact w healthcare settings, invasive devices ie catheters, crowed living, frequent antibiotic use FYI: Clinical Presentations (Staph) Impetigo Ecthyma Carbuncle Folliculitis Staph Soft Tissue Infection (SSTI) Risk factors continued: Defective neutrophil function or number Cancer, chemotherapy Genetics Lack of IL-17 Pathogenesis: Pore-forming toxins ! lyse neutrophils and macrophages - Alpha-toxin, gamma-toxin and other toxins target different components of cells including complement receptors and CXCRs Phenol-soluble modulins ! lyse leukocytes and erythrocytes - Exfoliative toxins (made by certain strains only or the bacteriophages that colonize the bacteria) ! serine proteases that target the desmosomal cadherin ! intraepithelial bullae (if in skin) OR staphylococcal- scalded-skin syndrome (if systemic exposure) To Severe skin peeling  D Activate Tcells in a nonspecific & exaggerated way Bind to immune system proteins (HLA-2 and TCRs) causing a massive immune response Staph Superantigens - Toxins produced by staph aureus Superantigens Examples: Toxic shock syndrome toxin 1 (TSST-1), enterotoxins (A, B, C, …), SE-like superantigen (serotype H, I, …) – at least 24 different kinds identified - Nonspecifically activate T-cells via HLA-2 on APC’s and Beta-subunit of TCR ! CD4+ T cells activated * E TSST-1 causes high fever, hypotension, scarlet fever-like rash, desquamation of skin, multiorgan dysfunction 31 Can increase severity of atopic dermatitis Staph – Neutrophil Evasion Chemotaxis inhibitory protein (CHIPS) or staphopain A (ScpA) ! block complement receptors and CXCR2 neutrophil- - attracting chemokines - Staph-superantigen-like 5 and 11 ! block P-selecting and - ICAM-1 which normally allow neutrophils to adhere to the - endothelium and enter tissue Neutrophils now cannot enter tissue bc blocked - Catalase, alkyl hydroperoxide reductase and staphyloxanthin ! inhibit ROS-mediated killing of S. aureus Neutralizes - ROS which would normally help attack staph infection Staphylococcal nuclease ! destroys neutrophil extracellular - traps - Protein A (expressed on surface of S. aureus) ! blocks - antibody-mediated phagocytosis by both neutrophils and - macrophages Blocks antibodies from tagging staph for destruction -  Immune Response Against Staph Stop bacterial growth & Antimicrobial peptides Produced by keratinocytes and other immune cells of skin Bacteriostatic or bactericidal activity - Examples: Beta-defensins 2 and 3, cathelicidin, RNase 7 * Neutrophil recruitment via PRR’s Abscess formation to control spread of infection TLR-2 – peptidoglycan and lipoproteins NOD-2 – muramyl dipeptide (breakdown product of peptidoglycan) - Staph’s pore-forming toxin actually activate caspase-1 and result - in activation of IL-1Beta ! promote neutrophil recruitment - IL-17 (via TH17) cells also adds to neutrophil recruitment Recurrent infections are common! Adaptive immune responses are not fully capable of stopping Staph aureus  Exfoliative Toxins Certain types of Staph aureus make exfoliative toxins (ETs) which cause blistering skin disorders = 3 Bullous impetigo (localized) ET- A = Staphylococcal scalded-skin syndrome (SSSS) – severe and generalized, caused by ET-B Cutaneous tenderness and widespread superficial blistering ETs are serine proteases binding to cell-adhesion * =** molecule desmoglein-1 ! loss of cell-cell adhesion between stratum spinosum and granulosum - Very thin-walled, flaccid blister that’s easily disturbed - Maybe useful pathogenic strategy to spread beneath the layer of skin Streptococcal Skin Infections Group A Streptococcus (GAS) (such as Strep pyogens) Common cause of superficial purulent skin infections Local problems: impetigo, ecthyma, intertrigo… Invasive infections: erysipelas, cellulitis, necrotizing fasciitis (deep tissue necrosis ! sepsis, shock, multiorgan failure, [death) J FYI: common cause of strep throat/ scarlet fever/ bacteria pharyngitis FYI: other GAS infections: lymphangitis, bacteremia, septic arthritis, osteomyelitis, pneumonia, meningitis, streptococcal toxic shock syndrome Immunologic-mediated disease can be triggered or follow GAS infections: C Guttate psoriasis, acute rheumatic fever, rheumatic heart disease, glomerulonephritis ] ↳ These can be triggered by having a group A strep infection FYI: Clinical Presentations Blistering dactylitis Intertrigo (axilla) Acute lymphangitis Strep Pathogenesis Risk Factors: causing symptoms. - - Colonization: GAS can live on the skin and in the throat without Environmental Factors: Crowding, poor hygiene, and poverty increase the risk of infections. Pre-existing Conditions: Tissue damage or inflammation (e.g., burns, eczema, fungal infections). Blunt trauma can lead to severe infections like necrotizing fasciitis. Other Strep Species [0 3 Non-GAS species (e.g., Strep agalactiae) infect areas with poor blood flow (e.g., ischemia or venous stasis). · GAS Variants Over 200 subtypes of GAS are identified by the M-protein. Types D and E are linked to skin infections. - Strep – M-Protein M-Protein: Multifunctional protein ! inhibits immune defenses Binds to regulators of complement system resulting in decreased activation of classical and alternative pathways ↑ Inhibits antibody-mediated phagocytosis by binding to the - Fc region of the IgG - Induced inflammation via TLR-2 on monocytes ! * [increase IL-6, IL-1Beta and TNF alpha secretion J Invades by binding to the fibronectin (part of extracellular matrix) and CD46 on keratinocytes Strep Pore-Forming Toxins Streptolysin O Produces large pores in host-cell membrane resulting in apoptosis of neutrophils, macrophages and epithelial e - cells - Streptolysin S Cytolytic against neutrophils, lymphocytes, erythrocytes and platelets Increases inflammation i te m Contributes to vascular injury and tissue necrosis - Strep – Superantigens and Neutrophil Evasion Streptococcal Pyrogenic Exotoxins Strep pyrogenic exotoxin serotype A, C, G to M, mitogenic exotoxin SMEZn. - Overactivates them Non-specifically activate T=cells Contribute to streptococcal toxic shock syndrome, scarlet - fever, erysipelas and invasive presentations - S Neutrophil Evasion Produces own antioxidants that inhibit the ROS mediated -is killing - Glutathione peroxidase, superoxide dismutase, etc. Nuclease A and DNase Sda1 breakdown the neutrophil extracellular traps  Immune Response Against Strep Antimicrobial peptides Produced by keratinocytes and other immune cells of skin Examples: Beta-defensins 1 and 3, cathelicidin Neutrophil recruitment TLR-2 – peptidoglycan and lipoproteins NOD-2 – muramyl dipeptide (breakdown product of peptidoglycan) Type 1 IFN response me Strong immune response TLR-9 activation via bacterial DNA ! promotes oxidative burst Adaptive responses of T cells and B cells are helpful, however, given the diversity of M-proteins ! immunity against 1 type * doesn’t offer protection against the others Superantigenic Toxins Staph aureus or Group A Strep Exert effects without being processed by antigen presenting cells Do bind to the HLA-2 but to the outer walls Recognition is not restricted to specifics of the HLA-2 or the TRC Thus, greater response from T-cells (compared to typical antigens) Generate increased number of T-cells with CLA (skin homing) ! leading to cutaneous 0 manifestations is Cytokine storm- lead to massive release of cytokines: TNF-alpha, IL-1, IL-6 Capillary leak syndrome and other systemic problems (i.e., toxic shock syndrome) Binds to MHC-II outside of the antigen binding groove & directly crosslinks the MHC-II molecule & the Vbeta chain of TCR - polyclonal Tcell activation * S  Pseudomonas Aeruginosa - Intro Ubiquitous Gram-negative rod, present in aqueous environments fu 3 Sweet, grape-like odor and blue-green colour · Oxidase-positive, non-lactose fermenting, obligate aerobic bacteria with a single flagellum Likes warmth (prefers 42 degrees Celsius or 107.6 F) - Primary cutaneous infections: Green nail syndrome, toe web infection, folliculitis, hot-foot syndrome, external otitis, perichondritis FYI infections: Nosocomial and ventilator pneumonia, cystic fibrosis infections, UTI in catheters, secondary skin infxn in burns, diabetes, surgical sites Bacteremia and ecthyma gangrenosum in hospitalized immunocompromised patients FYI: Clinical Presentations (P) Hot Foot Syndrome Green nail syndrome Ecthyma gangrenosum Pseudomonas Aeruginosa Can’t get into the skin, unless there is already damage of some kind: Maceration, dermatophyte infection, catheter, trauma, burn Alkaline protease, protease IV and elastase ! used to degrade skin structures and parts of immune system - - After contacting the host ! releases exoenzymes L ExoS ! TLR’s ! TNF-alpha production Triggers inflammation ExoT ! binds adenosine diphosphate ribosyltransferase Disrupts cellular processes ExoU ! damages cell membranes ExoY ! binds adenylate cyclase Disrupts energy signalling Exotoxin A ! interferes with protein synthesis ! cell death Procyanin ! pro-inflammatory and oxidative effects LPS ! activates TLR4 ! septic shock mediator Quorum sensing ! intercellular signaling to coordinate gene transcription and possible biofilm formation P. Aeruginosa Pathogenic Features With prolonged colonization: Overproduces alginate (mucoid substance), which scavengers - free -muc radicals, impairs phagocytosis, inhibits neutrophil chemotaxis, inhibits complement activation - Allows biofilm production (polysaccharide rich substance that facilitates plasmid transfers and provides protection against - antibiotics and antimicrobial peptides) - Wound infections, osteomyelitis, catheter-infections, lung infection with cystic fibrosis, endocarditis Antibiotic resistance mechanisms: Multidrug efflux pumps (pump it out), beta-lactamases (breakdown the antibiotic), downregulation of porins on the outer membrane (then antibiotic can’t get in) P. Aeruginosa – Pathogenesis 1 Green Nail Syndrome Occurs with prolonged submersion in fresh water (esp. with soap/ detergents) Esp if have nail disorders (i.e., psoriasis) Toe Web Infection Persistently wet feet in tight-fitting shoes and/or warm, humid weather Secondary to tinea pedis (fungal infection) - Folliculitis and Hot-Foot Syndrome Recreational use of hot tubs, whirlpools, sometimes pools Water heated to above 38C (since P. aeruginosa likes heat) - P. Aeruginosa – Pathogenesis 2 External Otitis (EO) Swimming (prolonged excess moisture exposure in ear canal), aggressive cleaning, ear-occluding devices (earphone, hearing aids), skin conditions (i.e., psoriasis) interfere with external ear canal’s self-cleaning mechanism P. aeruginosa is involved in 50% of EO cases (Staph aureus is next most common) Malignant EO ! P. aeruginosa invades the soft tissue and can lead r &toemem necrosis of cartilage, mastoid, and/or temporal bone Bacteremia and Ecthyma Gangrenosum Hospitalized patients with neutropenia, hematological malignancy or low CD4+ count ( female, adults > children Most commonly caused by T. rubric and Epidermophyton floccosum Tinea Pedis and Tinea Mannum Dermatophytosis of feet (pedis) or palmar and interdigital areas of hands (mannum) Transmission: Communal baths, showers and pools Occlusive footwear 53 Pedis ! the fungal is present ubiquitously, so internal environment and footwear are driving factors Mannum ! direct contact with infected human, animal, soil or autoinoculation Can be secondary infection, hand used to pick and scratch at other infected body parts i.e., infected toenails Most commonly caused by T. rubric, T. interdigitale and Epidermophyton floccosum FYI Clinical Features Tinea Pedis and Tinea Mannum W Measles Highly contagious, single-stranded, enveloped RNA virus of the Paramyxoviridae family Koplik spots, fever, cough, coryza, conjunctivitis with possible severe complications of pneumonia and encephalomyelitis Person-person transmission; contact or airborne respiratory - droplets (airborne for up to 2 hours) - Enters via respiratory mucosa or conjunctiva, replicates and spreads to lymph nodes and later bloodstream - Humoral (controls replication) and cell-mediated immunity (eliminated infected cells) is important ↳ Transient immunosuppression ! (1) delayed-type hypersensitivity (2) increased risk of bacterial infections * Morbilliform eruption (rash) lasts 3-5 days * - - Rubella Enveloped positive-stranded RNA virus of the Togaviridae family Transmission: direct or droplets from nasopharynx Lifelong immunity in most 9] Shed virus (infectious) 5-7 days prior to rash and for up to 14 days after rash onset Congenitally infected infant can shed for up to 12 months (urine, blood, nasopharyngeal secretions) Clinical overview: Rash 2-3 days Enlarged cervical, suboccipital and postauricular lymph nodes High risk of fetal malformation with congenital infection esp. in first trimester [ Erythema Infectiosum - Parvovirus B19 3 Overview: 5th disease or “slapped cheeks” disease; cheek rash is followed by erythematous, lacy eruptions on trunk and extremities (immune complex - deposition) 5 3 Symmetric polyarthritis (small joints) in adults Papular purpuric gloves-and-socks syndrome: pruritic erythema, edema and petechiae of hands and feet with fever and oral erosions (adolescents) Transmission: close contact, school outbreaks in winter and spring are common; FYI: 15-60% of children 5-19yo have antibodies, while >90% of elderly have antibodies Parvovirus B19 is part of Parvoviridae, no envelope, single-stranded DNA virus Requires a specific cell receptor (group P antigen) to infect the cell, if cell lacks it, cannot get infected Transient aplastic crisis – can infect and destroy erythroid progenitor - cells - Group P antigen acts receptors; without it – ParvoB19 can’t get in Fetal death is possible, if infects erythroblasts in fetus resulting in hemolysis and anemia Human Herpesvirus 6 (HHV-6) Overview: Exanthem subitum/ roseola infantum, 6th disease Febrile seizures often without rash in children (FYI: rash only present in 23% of cases) “Rose” – coloured macules and papules Chronic infection with latent stage and possibility to reactivate (true of ALL herpesviruses) Herpesviridae family, double-stranded DNA Infects wide range of cells: monocytes, macrophages, NK cells, neuronal - cells, CD4+ T-cells - In 1% of population, it integrates its DNA with that of the host Salivary glands: area of replication ! transmission via saliva Incubation 5-15 days - Reactivates during immunosuppression, i.e., during/after stem cell - transplantation - Herpes Simplex Virus - Intro DNA virus, Herpesviridae family, common to have intermittent reactivation Initially infects skin or mucosa, then local nerve endings and transports into the ganglia where it becomes latent until - - reactivation - HSV-1 (oral) and HSV-2 (genital), both can infect either body part Most adult population is seropositive for HSV-1 acquired during childhood * [ Most primary infection are asymptomatic, and most transmission occurs during asymptomatic shedding 3 * More serious problems: eye, CNS and neonatal infections OR severe and disseminated disease (with immunosuppression) Herpes Simplex Virus - Pathogenesis Recurrence depends on immune function/ competence Mutations in IFN, TLR2 have been associated within - increased rates of lesions or human simplex encephalitis - Dendritic cells and CD8+ T cells will localize to sites of reactivation to contain the virus and will stay there for - weeks after clearance - Humoral immunity helps to reduce viral titers at inoculation sites, and to protect neonate from herpes (via breastfeeding), but lack of antibodies doesn’t - increase - clinical severity of the HSV disease  ↑ Varicella Herpes Zoster Virus - Intro Varicella-Zoster virus (VZV) is from Herpesvirus Family Chicken pox (initial clinical presentation) * and shingles (reactivation) - Highly contagious [ 3 Chicken pox: rash begins on face and scalps, spreads to trunk, few spots on extremities: scattered lesions, rose-coloured macules to papules then vesicles ! papules and crusts; pruritic (all types of lesions are present at same time) SX worse with age and lack of immune competence me Latent within sensory and autonomic neurons Shingles: reactivation and multiplication of VZV ! unilateral dermatomal PAIN and rash Postherpetic neuralgia – chronic and debilitating Varicella Herpes Zoster Virus – Pathophysiology Pathogenesis: Enters via mucosa of respiratory tract and oropharynx ! tonsillar T-cells ! disseminated via blood and lymph: replicated within reticuloendothelial system 10-14 days after infection ! larger viremia (post-replication): systemic symptoms and skin lesions (as VZV overpowers host defenses) Enters sensory nerves and transported into sensory ganglia Density correlates with density of skin lesions (trigeminal nerve, spinal sensory ganglia T1-L2) Latency persists for life (Latency-Associated Transcript is expressed by virus in latency) Circulates in lymphocytes T-cell mediated immunity is required for successful end to clinical infection, and maintenance of the clinical latency (protection again reactivation and other strains)  Varicella Herpes Zoster Virus - Reactivation When T-cell mediated immunity falls and virus is allowed to reactivate: Spreads within ganglion, causes necrosis and inflammation (amplifies nociceptor’s response) ! = * severe neuropathic pain Destruction of the neurons (atrophy, axon and myelin loss with fibrosis) may be part of the persistent neuropathic pain Damaged primary sensory nerves can become spontaneously active Spreads antidromically via sensory nerve and released from endings into the skin ! zoster vesicles Technically, can spread to other nerves, meninges, CSF and spinal column ! rare complication such as transverse myelitis and meningoencephalitis Human Papillomavirus - Intro DNA virus of the Papillomaviruses, nonenveloped, double stranded DNA virus >150 HPV types Low risk Causes warts High risk – for malignancy, include E6 and E7 proteins with oncogenic - effects - Infects keratinocytes Initial invasion is made easier by damage to skin/ impairment of barrier function Replication begins and continues as the viral particles are transported from surface towards the basal epidermal keratinocytes, where the virus will establish a permanent replication factory - Important viral protein include E6 and E7, which allow viral genome - amplification - Shed with dead keratinocytes from skin surface Human Papillomavirus - Pathogenesis Common warts: HPV-2, 27, 57 and HPV-4 and HPV-1 * Butcher’s warts – in those who constantly deal with wet meat ! HPV-7 is the common - cause - References Kang S, Amagai M, Bruckner AL, eds, et al. Fitzpatrick's Dermatology. 9th ed. McGraw Hill; 2019. https://accessmedicine-mhmedical- com.ccnm.idm.oclc.org/book.aspx?bookid=2570 Chapter 150, 152, 154, 160, 163, 164, 165, 167