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Lecture 5 011608 - MMG 461 MOLECULAR PATHOGENESIS Lecture 5...

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Unformatted text preview: MMG 461: MOLECULAR PATHOGENESIS Lecture 5: The infectious cycle I Entry, colonization and the role of normal flora CGArvidson January 16, 2008 The goals of a pathogen are the same as any organism: q Find a niche q Multiply q Find a new niche TYPICAL INFECTIOUS CYCLE q Entry of the pathogen q Colonization q Multiplication q Damage to the host – Disease (not required) q Exit – Transmission to new host (hopefully) TYPICAL INFECTIOUS CYCLE q Entry of the pathogen – – – Reservoir (source of the infection) Mechanisms of transmission (Host) defenses RESERVOIRS of INFECTION q Environment – Contaminated food – Fomites q Infected persons – Sick people – carriers q Infected animals – zoonoses q Self – Opportunistic infections ROUTES OF TRANSMISSION q Airborne or respiratory q Oral-Fecal q Direct inoculation – – Arthropod vector Needle stick q Direct contact q Congenital – Transplacental – Birth HOST DEFENSES AGAINST COLONIZATION – the non-specific or innate immune system q q q q q q q q q Skin Coughing Nasal hairs cilia Enzymes in saliva and tears Low pH of stomach, female genital tract Sweeping away by liquid currents (ie. mucous) Lack of nutrients (ie. sequestration of iron) phagocytes Most pathogens have evolved systems to overcome one or more of these defenses AIRBORNE/RESPIRATORY ROUTE Host defenses – Mucous coating the surface of the URT q – – – – contains lysozyme Ciliated cells of the URT secretory immune system and secretory IgA alveolar macrophages normal microbiota Examples – strep throat, measles, tuberculosis, infectious mononucleosis, the common cold, influenza ORAL-FECAL ROUTE (GI tract) Host defenses – – – – – intact intestinal mucosal epithelium secretory immune system and secretory IgA bile, acid, and digestive enzymes peristalsis normal microbiota Examples – Food and water-borne diseases such as: cholera, typhoid fever, bacterial gastroenteritis, dysentery, poliomyelitis, hepatitis A DIRECT INOCULATION Host defenses – intact skin barrier Examples – most staph infections – deep wound infections (tetanus, gangrene) – diseases spread by insect vectors (malaria, plague, typhus, arboviral diseases) – diseases occasionally spread by transfusion (hepatitis, HIV) – many zoonotic infections DIRECT CONTACT Host defenses – intact epithelial surface – mucosal secretory immune system Examples – skin diseases such as impetigo, athlete’s foot – sexually transmitted diseases, conjunctivitis, trachoma, herpes CONGENITAL ROUTE Host defenses – placenta Examples – Transplacental: congenital rubella, syphilis – transmitted at birth: any STD, herpes, group B strep TYPICAL INFECTIOUS CYCLE q Entry of the pathogen q Colonization – Adhesins – Competition with normal microbiota q Multiplication q Damage to the host – disease q Exit – Transmission to new host (hopefully) COLONIZATION q Establishment of a bacterial “colony” in a given host q Requires attachment of a microorganism to host cells/tissues – necessary, but not sufficient for disease by some microbes Adhesins: attachment factors on the invading organism Receptors: factors on host cells recognized and bound by adhesins Adhesin-receptor interactions frequently determine host range and tissue tropism ADHESINS Examples of bacterial adhesins: – E. coli Pap Pili q bind a digalactoside abundant in the urinary tract – Streptococcal F protein q binds to host cell fibronectin – Mycoplasma pneumoniae membrane protein q binds to host cell glycoproteins via sialic acid residues – Neisseria pili q bind specific receptors found only on human cells – Vibrio cholerae pili q Expression coordinately regulated with cholera toxin production NORMAL MICROBIOTA q Normal/indigenous microbiota – Microbes found in healthy people – Present but not in the process of causing disease q Commensalism – literally “to eat at the same table” – Commensal organisms live together, sharing some nutrients, but peacefully co-existing, with neither coming to harm. – Can even be mutualistic. NORMAL MICROBIOTA q Transient – q Carriage – – q Present in some healthy people for a short time, without causing disease, eventually cleared Asymptomatic: colonized with pathogen, but no (overt) disease symptoms Persistance/latency: pathogen remains in the body following disease, but symptoms gone. Newborns begin life sterile, but are colonized soon after birth. – First colonized by mother’s flora during normal (vaginal) birth. Good Bugs – Bad Bugs q Once a person is colonized, it is difficult for new organisms to colonize. – a good thing - resident microbiota can prevent disease by outcompeting an incoming pathogen q Indigenous microbiota can cause disease, and are extremely well positioned to do so, if the host is compromised. – opportunistic infections “Normal” flora in the wrong place = disease NORMAL MICROBIOTA q The species making up the normal microbiota can vary greatly between individuals, depending on – – – – – q Geographic environment Diet Age Hormonal state Physiogical differences The microbial community of a given individual is in a constant state of flux BENEFITS OF THE NORMAL MICROBIOTA – Priming of the immune system q Low levels of antibodies against the normal microbiota can prevent disease should the organism enter another site in the body where it could cause disease – Keeping out the bad guys q q q Incoming pathogens must compete with the resident microbiota, and are usually greatly outnumbered Some resident microbes produce antimicrobials (bacteriocins) that keep out other microbes Normal microbiota may alter the environment such that it is less hospitable for incoming pathogens STERILE SITES OF THE BODY q q q q q q q q q q q q q Stomach Lower respiratory tract Kidneys Digestive glands, pancreas, gall bladder Central nervous system and meninges Skeleton Skeletal muscles Cardiovascular system (blood) Hematopoietic-lymphoreticular system Pleura Peritoneum Urinary system, bladder, urethra Male genital system SKIN q Resident – – – – q Transient – frequently washed off – – – – q Staphylococcus epidermidis Proprionibacterium acnes Micrococcus Propionibacterium Corynebacterium Staphylococcus aureus Streptococcus pyogenes Clostridium perfringes few G- too dry EYES and EARS q Eyes – Coagulase-negative Staphylococci – A few members of naspharynx flora q α-hemolytic streptococci q commensal Neisseria and Haemophilus q Ears – – – Coagulase-negative Staphylococci A few members of skin flora S. pneumoniae, P. aeruginosa, enterics RESPIRATORY TRACT q Upper – external nares q q skin flora such as coagulase negative Staph., Strep, may also find P. aeruginosa – nasopharynx and oropharynx q q q q q q q q q q staphylococci & micrococci Peptostreptococcus Actinomyces Fusobacterium α-hemolytic streptococci Enterococci commensal Neisseria and Haemophilus diphtheroids (Corynebacterium) Enterobacteriaceae Lower – protected by mucociliary blanket, only transiently inhaled organisms encountered in lung GASTROINTESTINAL TRACT q Mouth - heavily colonized, varies from site to site – – – – – – – – q α-streptococci Streptococcus mutans Neisseria sp. Diptheroids (aerobic Corynebacterium) S. aureus and S. epidermidis Lactobacilli spirochetes Mycoplasma Lots of anaerobes in gums – Bacteroides, Fusobacterium, Clostridium, Peptostreptococcus q Esophagus – Mostly transients from mouth and URT GASTROINTESTINAL TRACT q Stomach – sterile if acid + enzymes (fast) – Occaisionally, up to 103 cfu/ml acid-resistant gram-positives q q q q q q q Streptococcus Staphylococcus Lactobacillus Peptostreptococcus Fusobacterium Helicobacter Small intestine – – – flora scarce, increasing with distance from stomach Mostly anaerobes Enterococci, peptostreptococci, Porphyromonas, Prevotella GASTROINTESTINAL TRACT q large intestine/colon – 99.9% anaerobes – Feces 20% by weight = bacteria – – – – – – – – – Bifidobacterium Eubacterium Bacteroides Fusobacterium Clostridium Lactobacillus Streptococci enterococci Enterobacteriaceae MALE UROGENITAL TRACT Generally sterile, except for last 1-2 cm q anterior urethra – – – coagulase-negative Staphylococci Streptococci Lactobacillus FEMALE UROGENITAL TRACT q Urinary tract usually sterile q Vaginal tract: varies with hormone levels q Pre-menarche and post-menopause: scanty flora, usually derived from skin and colon – Staph, strep, enterococci, enterobacteriaceae q with estrogen production: deposition of glycogen in vaginal epithelial cells supports growth of lactobacilli and production of lactic acid, leads to acid pH and facilitates colonization by other microbes – Coagulase-negative Staphylococci, Streptococci (gp B), Gardnerella, Mycoplasma, Ureaplasma, Mobiluncus, Clostridium, Enterococcus q Cervix and uterus usually sterile Good Bugs q Probiotics – A live microbial supplement which benefits the host by improving its intestinal microbial balance, presumably by affecting the composition of the intestinal microbiota q Prebiotics – non-digestible dietary supplements that modify the balance of the intestinal microbiota, stimulating the growth and/or activity of beneficial organisms and suppressing potentially deleterious bacteria ...
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