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I INFECTION/ PATHOGENESIS Dr M Ballal KMC-IC Manipal •infectious diseases are the predominant cause of illness and death • 20th century -- improvements in living conditions, sanitation and medical intervention • these advances - concentrated in wealthy countries leaving out the majority of the world . • William H Stewart ,a Surgeon General of USA-1969 “ it is time to close the book on infectious diseases” Year 1977 Agent Ebola virus Legionella spp Campylobacter jejeuni E coli 0157 Borrelia burgdorferi H.Pylori HIV HCV Bartonella henselae Human HSV 8 Ehrlichia phagocytophilum Australian bat lyssa virus Influenza virus H5N1 Nipah virus SARS Corona virus Diseases Ebola hemarrahgic disease Legionnaire’s disease gastroenteritis Hemorrahgic colitis,HUS Lyme disease Gastric/duodenal ulcer AIDS Non A non B hepatitis Cat scratch fever Kaposi’s sarcoma ehrlichiosis Human rabies Avian influenza in humans Respiaratory illness and meningoenchepahlitis Severe acute respiratory syndrome 1982 1983 1989 1993 1994 1996 1997 1999 2003 TRIAD OF INFECTIOUS DISEASES • AFFECTED HOST • INFECTIOUS AGENT • ENVIRONMENT • Pathogenicity Virulence - ability to cause disease degree of pathogenicity • Many properties that determine a microbe’s pathogenicity or virulence are unclear or unknown • But, when a microbe overpowers the hosts defenses, disease results! Two main arms of host defense – innate and acquired and any imbalance in the two arms gives rise to infection Bacterial infections are caused by two mechanisms toxin production invasion and inflammation Epidemic: unusual occurrence in a community or a region of disease e.g.- cholera or chicken pox Endemic: constant presence of a disease or infection or infectious agent within a given population or geographical area e.g.- typhoid, hepatitis A • Sporadic: scattered out)- cases occur irregularly or haphazardly from time to time e.g.- meningococcal meningitis, tetanus, herpes zoster • Pandemic: an epidemic affecting a large population covering a large area ( section of a nation, entire nation, continent, or world) e.g.- cholera El Tor- 1962 • Carrier : is a person who harbors the pathogenic organism without suffering from it a) healthy carrier: harbors the pathogen but never suffered form the disease b) convalescent carrier: recovered from the disease but continues to harbor the pathogen Temporary carrier: carries for less than 6 months Chronic carrier: for years or rest of his life Paradoxical carrier: acquires the organism from other carrier Contact carrier: acquires from the patient Carrier in animals: source of infections to man The infection may be acquired by contact with animal bite, or ingestion of milk or meat. some animals are asymptomatic serve as reservoirs e.g.: bovine TB, Bubonic plague, salmonella food poisoning viral- rabies protozoal – leshmaniasis, helminthic- hydatid disease fungal- trichophyton STAGES OF INFECTIOUS DISEASES • INCUBATION PERIOD: time between the acquisition of the organism and beginning of the symptoms • PRODROME PERIOD: non specific symptoms like fever, malaise, loss of apettite. • SPECIFIC ILLNESS PERIOD: during which overt characteristics signs and symptoms of the disease occur • RECOVERY PERIOD: illness disappears and patient is back to health Major bacterial diseases transmitted by tick in USA • • • • • Lyme’s disease Rocky mountain spotted fever Ehrlichiosis Relapsing fever Tularemia • VERTICAL TRANSMISSION Transplacental - treponema pallidum CMV within birthcanal / at birth- Streptococcal agalactiae Hepatitis B N.gonorrhoea C. albicans – oral thrush breast milk: staphylococcus aureus CMV 4 important portals of entry: Respiratory tract: strep. Pneumoniae N.meningitidis EBV H.capsulatum Gastrointestinal tract: S. dysentriae Hepatitis A polio virus Skin: clostridium tetani Rickettsia rickettsii rabies plasmodium Genital tract: N.gonorrhoea T.pallidum C.albicans human papilloma virus Transmitted by water, food, and insect vectors. .Adherence to cell surfaces: 1. pilli- N.gonorrhoea E .coli } urinary tract epithelium 2. glycocalyx- viridian streptococci- endothelium of heart walls Invasion, Inflammation and Intracellular survival: invasiveness is an ability of an organism to penetrate a tissue after adhering to a cell surface. some bacteria can invade the tissues in absence of physical injury e.g. N meningitidis in nasal epithelium ,Salmonella in intestinal epithelium Invasion: The organisms are endocytosed by the epithelial cells transported within vacuoles and released into the sub mucosal space from where they invade the underlined tissues • Enzymes secreted by invasive bacteria play a role in pathogenesis e.g.: collagenase, hyaluronidase coagulase IgA protease leucocidins The other virulence factors contributing to invasiveness: • Antiophagocytic factors 1. Capsule: Streptococcus pneumoniae, N meningitidis Opsonisation 2. M protein of Group A streptococci and A protein of Staphylococcus aureus binding to IgG prevents activation of complement Portals of Entry • 1. Mucus Membranes • 2. Skin • 3. Parenteral 1. Mucus Membranes • A. Respiratory Tract – microbes inhaled into mouth or nose in droplets of moisture or dust particles – Easiest and most frequently traveled portal of entry Common Diseases contracted via the Respiratory Tract • • • • • • • • Common cold Flu Tuberculosis Whooping cough Pneumonia Measles Strep Throat Diphtheria Mucus Membranes • B. Gastrointestinal Tract – microbes gain entrance thru contaminated food & water or fingers & hands – most microbes that enter the G.I. Tract are destroyed by HCL & enzymes of stomach or bile & enzymes of small intestine Common diseases contracted via the G.I. Tract • Salmonellosis – Salmonella sp. • Shigellosis – Shigella sp. • Cholera – Vibrio cholorea • Ulcers – Helicobacter pylori • Botulism – Clostridium botulinum Mucus Membranes of the Genitourinary System - STD’s Gonorrhea Neisseria gonorrhoeae Syphilis Treponema pallidum Chlamydia Chlamydia trachomatis HIV Herpes Simplex II Mucus Membranes • D. Conjunctiva – – mucus membranes that cover the eyeball and lines the eyelid • Trachoma – Chlamydia trachomatis 2nd Portal of Entry: Skin • Skin - the largest organ of the body. When unbroken is an effective barrier for most microorganisms. • Some microbes can gain entrance thru openings in the skin: hair follicles and sweat glands 3rd Portal of Entry: Parentarel • Microorganisms are deposited into the tissues below the skin or mucus membranes • Punctures • injections • bites • scratches • surgery • splitting of skin due to swelling or dryness Preferred Portal of Entry • Just because a pathogen enters your body it does not mean it’s going to cause disease. • pathogens - preferred portal of entry Preferred Portal of Entry • Streptococcus pneumoniae – if inhaled can cause pneumonia – if enters the G.I. Tract, no disease • Salmonella typhi – if enters the G.I. Tract can cause Typhoid Fever – if on skin, no disease How do Bacterial Pathogens penetrate Host Defenses? 1. Adherence - almost all pathogens have a means to attach to host tissue Binding Sites adhesins ligands Adhesins and ligands are usually on Fimbriae • Neisseria gonorrhoeae • ETEC (Entertoxigenic E. coli) • Bordetello pertussis 2. Capsules K. pneumoniae • Prevent phagocytosis • attachment • Streptococcus pneumoniae • Klebsiella pneumoniae • Haemophilus influenzae • Bacillus anthracis • Streptococcus mutans • Yersinia pestis 3. Enzymes • Many pathogens secrete enzymes that contribute to their pathogenicity A. Leukocidins • Attack certain types of WBC’s • 1. Kills WBC’s which prevents phagocytosis • 2. Releases & ruptures lysosomes – lysosomes - contain powerful hydrolytic enzymes which then cause more tissue damage B. Hemolysins - cause the lysis of RBC’s Streptococci 1. Alpha Hemolytic Streptococci - secrete hemolysins that cause the incomplete lysis or RBC’s 2. Beta Hemolytic Streptococci - secrete hemolysins that cause the complete lysis of RBC’s 3. Gamma Hemolytic Streptococci - do not secrete any hemolysins C. Coagulase - cause blood to coagulate • Blood clots protect bacteria from phagocytosis from WBC’s and other host defenses • Staphylococci - are often coagulase positive – boils – abscesses D. Kinases - enzymes that dissolve blood clots • 1. Streptokinase - Streptococci • 2. Staphylokinase - Staphylococci • Helps to spread bacteria - Bacteremia • Streptokinase - used to dissolve blood clots in the Heart (Heart Attacks due to obstructed coronary blood vessels) E. Hyaluronidase • Breaks down Hyaluronic acid (found in connective tissues) • “Spreading Factor” • mixed with a drug to help spread the drug thru a body tissue F. Collagenase • Breaks down collagen (found in many connective tissues) • Clostridium perfringens - Gas Gangrene – uses this to spread thru muscle tissue G. Necrotizing Factor - causes death (necrosis) to tissue cells “Flesh Eating Bacteria” Necrotizing fasciitis Summary of How Bacterial Pathogens Penetrate Host Defenses • 1. Adherence • 2. Capsule • 3. Enzymes – A. leukocidins – B. Hemolysins – C. Coagulase – D. Kinases – E. Hyaluronidase – F. Collagenase – G. Necrotizing Factor 4. Toxins • Poisonous substances produced by microorganisms • toxins - primary factor - pathogenicity • 220 known bacterial toxins – 40% cause disease by damaging the Eukaryotic cell membrane • Toxemia – Toxins in the bloodstream 2 Types of Toxins • 1. Exotoxins – secreted outside the bacterial cell • 2. Endotoxins – part of the outer cell wall of Gram (-) bacteria Exotoxins • Mostly seen in Gram (+) Bacteria • Most gene that code for exotoxins are located on plasmids or phages 3 Types of Exotoxins • 1. Cytotoxins – kill cells • 2. Neurotoxins – interfere with normal nerve impulses • 3. Enterotoxins – effect cells lining the G.I. Tract Response to Toxins • If exposed to exotoxins: antibodies against the toxin (antitoxins) • Exotoxins inactivated ( heat, formalin or phenol) no longer cause disease, but stimulate the production of antitoxin – altered exotoxins - Toxoids • Toxoids - injected to stimulate the production of antitoxins and provide immunity Example: DPT Vaccine • D - Diphtheria – Corynebacterium diphtheriae • P - Pertussis – Bordetello pertussis • T - Tetanus – Clostridium tetani DPT - Diphtheria Toxoid Pertussis Antigen Tetanus Toxoid • • • • • • • D P T M M R Polio – Salk – Sabin • Hib • HBV • • • • • • • • • • Type of Vaccines Toxoid Antigen Toxoid Attenuated Attenuated Attenuated IPV – Inactivated Polio virus (Killed) 1953 OPV – Oral Polio vaccine (attenuated) 1964 Conjugated vaccine Recombinant vaccine (antigen) yeast – Capsid produced by genetically engineered yeast • Chicken Pox • Attenuated Diseases caused by Neurotoxins • Botulism – Clostridium botulinum • Gram (+), anaerobic, spore-forming rod, found in soil – works at the neuromuscular junction – prevents impulse from nerve cell to muscle cell – results in muscle paralysis • Clostridium tetani Tetanus (Lock Jaw) • Gram (+), spore-forming, anaerobic rod • neurotoxin acts on nerves, resulting in the inhibition of muscle relaxation • tetanospasmin - “spasms” or “Lock Jaw” Diseases caused by Enterotoxins • Cholera – Vibrio cholerae – Gram (-) comma shaped rods Cholera toxin • Converts ATP into cAMP • causes cells to excrete Cl- ions and inhibits absorption of Na+ ions • Electrolyte imbalance • H2O leaves by osmosis • H2O Loss (Diarrhea) Severe cases, 12 - 20 liters of liquid lost in a day • Untreated cases - Mortality Rate about 50% • Mortality may be reduced to about 1% – administering fluids and electrolytes EHEC (Enterohemorrhagic E. coli) • E. coli (0157:H7) • enterotoxin causes a hemolytic inflammation of the intestines • results in bloody diarrhea – Toxin • • • • • alters the 60S ribosomal subunit inhibits Protein Synthesis Results in cell death lining of intestine is “shed” Bloody Diarrhea (Dysentary) Endotoxins - part of the Gram (-) Bacterial cell wall • LPS (Lipopolysaccharides) – O Antigen – Lipid A • Lipid A - Toxin portion of the LPS – responsible for Fever that is associated with many Gram (-) Bacterial infections – Gram (-) cells are “digested” endotoxins are released - fever – Antibiotics Interactions between hosts and infectious agents • Commensalism-commensal : if an infectious agent and its host exists together and each is neither rewarded nor damaged • Symbiosis/ mutualism: if the infectious agent derives benefit from the host but causes no harm to the host it is termed saprobe If the host and the infectious agent benefit from the encounter - symbiosis or mutualism • Parasitism : if the host is damaged by the infectious agent with or without benefit to the infectious agent the process is called parasitism and the infectious agent is - parasite • Colonizing flora: when microbes exist on body surfaces either external or internal ( upper respiratory/ GIT) are called as colonizing flora. The relationship of colonizing flora to the host may be commensal, saprobe, or parasitic. • Pathogen: organism that has demonstrated the ability to cause infections. • Potential pathogen – opportunistic agent RELATIONSHIPS OF THE INFECTIOUS AGENTS AND THEIR HOSTS AT THE CELLULAR LEVEL RELATIONSHIP INFECTIOUS AGENTS FREELIVING MOST BACTERIA, FUNGI, PARASITES EXAMPLES STAPH, ENTERIOBACTERIACEAE, CANDIDA, ASPERGILLUS,PROTOZOA , HELMINTHES LEGIONELLA,BRUCELLA, MYCOBACTERIUM TUBERCULOSIS, DIMORPHIC FUNGI RICKETTSIA, EHRILICHIA,TOXOPLASMA GONDII, INFLUENZA VIRUS FACULTATIVELY INTACELLULAR CERTAIN BACTERIA, MYCOBACTERIA AND CERTAIN FUNGI OBLIGATELY INTRACELLULAR CERTAIN BACTERIA,FUNGI AND PROTOZOA, VIRUSES Categories of infectious diseases Communicable disease: an illness that can be transmitted from an external source, animate or inanimate, to a patient Contagious disease: an illness that can be transmitted from patient to patient Iatrogenic infection: an infection that is produced by medical interventions Infectious disease: an illness caused by a replicating or multiplying external agent Nosocomial infection: an infection that is acquired in a health care facility Opportunistic infection: an infection in a patient with compromised defenses by an agent of low virulence that would not produce infection in a normal patient Sub-clinical infection: an infection that produces an immunologic response but no clinical symptoms ,also called asymptomatic infection Obligatory steps for infectious microorganisms step Attachment and entry into the body requirement Evade natural protective and cleansing mechanism phenomenon Entry infection) Local or general spread in the body Evade immediate local defenses Spread multiplication Increase numbers Multiplication Evasion of host defenses Evade immune and other defenses long enough for the full cycle in the host to be completed Microbial answer to the host defenses Shedding from the body Cause damage in the host Leave the body at a site and on a scale that ensures spread to fresh host Not strictly necessary but often occurs transmission Pathology, disease Clinical signs and symptoms of infection • 1. 2. 3. 4. • 1. 2. 3. Four cardinal signs of inflammation (Greek and roman physcians) Dolor- pain Calor – heat Rubor – redness Tumor – swelling the release of vasoactive amines and other chemical mediators will give rise to increased blood flow with venous and capillary congestion is known as calor and rubor Increased permeability of vessels with fluid , blood and proteins escaping in to the extra cellular spaces- dolor and tumor Segmented neutrophils are attracted to area of irritation by chemotatic substances and escape through the permeable vasculature into the extracellular spaces-pus formation Two symptoms of infections: general or systemic local signs • General or systemic: • in the acute phase of infection-high grade and spiking fever chills , flushing and increase in pulse rate • in sub acute or chronic infection- intermittent low grade fever, weight loss or fatigability, toxic reactions to bacterial products produce exematous or hemorrhagic skin reactions or variety of neuromuscular cardio respiratory or gastrointestinal symptoms – initial indicators of an underlying infectious disease • radiographic manifestations of infectious disease include pulmonary infiltrates, fibrous thickening of cavity lining, gas and swelling in the soft tissue, radio opaque masses or accumulation of fluid with in body cavities and organs • Laboratory values suggesting an infectious disease with minimal or early symptoms include an elevation in the ESR, peripheral blood leucoytosis, alteration in plasma proteins, elevation in gamma globulins, presence of certain reactants such as CRP or production of type specific antibodies • Local signs of infection: the cardinal signs of inflammation are the manifestation of local infection localized redness and heat and the production of swelling or tumors mass can be seen either visually if present on the external surfaces or from radiographs or other noninvasive techniques • If nerve endings are irritated or stretched by the expanding mass or by chemical irritants pain may be experienced either in the immediate area or in other sites through complimentary efferent path ways known as referred pain • The presence of a draining sinus and secretion of purulent exudates indications of local inflammatory or infectious process Iceberg concept of infectious disease • It is uncommon for a microbe to cause exactly the same disease in all infected individuals. • The exact clinical picture depends upon infecting dose, route, age, sex, presence of other microbes, nutritional status and genetic background.
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