Host Defense and Microbial Pathogenesis

Lecture 1

Prepared and presented by Marc Imhotep Cray, M.D.

neutrophil. “Granulocytic Phagocytes,” by Frank R. DeLeo and William M. Nauseef. Scanning electron micrograph of Staphylococcus aureus bound to the surface of a human

By the end of this lecture you should be able to: 1. Describe the general mechanisms by which hosts resist colonization by pathogenic microbes 2. Discuss the ways in which the normal flora contributes to the balance between health and disease. 3. Explain the concept, components and mechanisms of bacterial virulence and pathogenicity Describe the stages in bacterial infection. List and discuss the majorfeatures of the seven species of bacteria most often involved in multiple systemic infectious diseases.

Marc Imhotep Cray, M.D.



Host Defense and Pathogenesis Notes



Bacterial Diseases eNotes



Bloch KC. Ch. 4 Infectious Diseases, Pgs. 61-69 In: Hammer GD and McPhee Eds. JS. Pathophysiology of Disease: An Introduction to Clinical Medicine, 7th Ed. New York: McGraw-Hill Education, 2014 (On Thumb drive.)




Infectious diseases is one of the leading causes of death in both developed and developing countries  Worldwide, more persons succumb to microbial infections than to cancer and heart disease combined  Infections cause significant morbidity and mortality, especially in individuals who are most vulnerable to illness:  the very young,  the elderly,  

the immunocompromised, and the disenfranchised  Pathogenesis of infectious diseases reflects therelationship among  the human host,  the infectious agent, and  the external environment Marc Imhotep Cray, M.D.

 Infectious

agent can be either

exogenous (i.e., not normally found on or in body) or  endogenous (i.e., one that may be routinely cultured from a specific anatomic site but that does not normally cause disease in host) 

 Infection results…  …when an exogenous agent is introduced into a host from the 

environment or …when an endogenous agent overcomes innate host immunity to cause disease o Host susceptibility plays an important role in either of these settings


 Two

broad systems of defense against pathogensin the human body 1. Innate or nonspecific immunity 

does not depend on previous exposure to the foreign substance

2. Adaptive or specific immunity  Major  

constituents of innate immunity:

Physical barriers (skin and mucous membranes) Soluble factors (complement and cytokines),  Physiologic factors (temperature, pH),and  Cellular defenses (natural killer [NK] cells, neutrophils and macrophage) Marc Imhotep Cray, M.D.

 Macrophages  Function of

release various cytokines in innate immunity

cytokines:

Tumor necrosis factor-α (TNF-α) o Induces the inflammatory response  lnterleukin-1 (IL-1) o Induces fever, which enhances the immune response 



Interleukin-6 (IL-6) Induces the acute-phase response  Interleukin-8 (IL-8) o Chemotactic factor for neutrophils  Interlukin-12 (IL-12) o Activates NK and Th1 cells o




Fundamental relationships involved in the host-agent-environment interaction model  In the host, pathogenetic mechanisms extend from level of populations (eg, person-to-person transmission) to level of cellular and molecular processes (eg, genetic susceptibility) 

The environment includes vectors (insects and other carriers that transmit infectious agents) and zoonotic hosts or reservoirs (animals that harbor Hammer GD and McPhee. Pathophysiology of Disease: An Introduction to Clinical Medicine, 2014 infectious agents and often act to amplify the infectious agent)


Humans are continuously

exposed to microbesbut it is relatively rare for them to cause disease  Testament to effectiveness of host defenses o o

prevent invasion by normal flora defend against non-indigenous pathogens

• Defenses include:  physical barriers  processes specializes immune cells  mechanical  secretory immunity  production of noxious compounds  normal flora Marc Imhotep Cray, M.D.

9

Skin:

physical barrier and other antimicrobial properties  acidic pH (5-6)  contains lactic acid, fatty acids (in sweat)  normal skin flora (compete with pathogens)

Filtration Tears:

of inhaled air: turbinate bones

lysozyme target peptidoglycan structure of gram-

positive cell walls bacteria: skin, GI tract (compete with potential pathogens)

Commensal

Acidity: stomach, vagina Marc Imhotep Cray, M.D.

10

Flushing:

flow of fluid over mucosal surfaces removes bacteria that are not specifically attached 

urine flow in urogenital tract gut contents in GI tract acid in stomach, pancreatic enzymes, bile, Paneth cells (secrete defensins and lysozymes),peristalsis  tears over cornea 

Mucociliary action:  



in respiratory tract

surface covered in layer ofmucous prevents bacterial attachment ciliated epithelia push mucous upwards towards throat o smokers, Kartagener’s syndrome Mucociliary paralysis

Antimicrobial substances found in mucus:Lysozyme, immunoglobulin A (IgA) antibodies, and iron-binding proteins


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     

Filtration of particles in upper airways (nose hairs and mucus) Mucociliary apparatus Cough reflex Mucus (lysozyme, sIgA antibodies, and iron-binding proteins) Alveolar macrophages (cytokines) Some bacteria that specifically target mucociliary apparatus:



Bordetella pertussis Haemophilus influenzae  Pseudomonas aeruginosa  Mycoplasma pneumoniae 


Secretory

immunoglobulin A (sIgA): Major role in mucosal immunity, prevents colonization Functions: 

protection from proteolysis inhibits bacterial attachment to mucosal epithelia  agglutinates bacteria  binds (inactivates) toxins  present in colostrum so protects suckling infants from infection 

Does

not activate complement or opsonize bacteriaso relatively unimportant in systemic infection


13

Lysozyme (in saliva, tears, other mucosal fluids) 

cleaves peptidoglycans, disrupts bacterial walls

Lactoferrin, transferrin (in 

bind free iron so inaccessible for bacteria

HCl 

(in the stomach)

sodium carbonate and achlorhydria neutralize

Bile 

body secretions, serum)

salts and fatty acids (on skin)

detergent effect disrupts bacterial cell walls


14

Hammer GD and McPhee. Pathophysiology of Disease: An Introduction to Clinical Medicine, 2014

  

During earliest stage of initial infection, nonspecific mediators(complement, phagocytes) predominate Adaptive immunity (production of antibody, stimulation of lymphocytes) requires clonal expansion after recognition of specific antigens Once immunity toward a specific agent is induced, immune response remains primed so that response to reinfection is much more rapid


Commensal

micro-organisms



Human body normally harbors numerous species of bacteria, viruses, fungi, and protozoa, referred to as the human microbiota  The great majority of these arecommensals, defined as organisms that live symbiotically on (or) within the hu man host but rarely cause disease Exclude colonization  competing for ecological niches 

competing for essential nutrients

Produce anti-microbial compounds  bacteriocins, volatile fatty acids Contribute to immunity  induce low levels of circulatory & secretory antibodies which cross react with pathogens Marc Imhotep Cray, M.D.

16

Skin: Staphylococcus epidermidis, micrococci, corynebacteria Oral: streptococci, lactobacilli, staphylococci, corynebacteria,

bacteriodes Nasal

cavity: S. epidermidis, S. aureus, corynebacteria

Urogenital:

staphylococci, corynebacteria, E. coli, Lactobacillus

acidophilus GI tract: E. coli,


entercocci, bacteriodes, lactobacilli

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 Commensal bacteria secrete

toll-like receptor (TLR) ligands, which bind to TLR on surface of normal intestinal tissue 

allows neutrophils and macrophages to recognize conserved bacterial structures such as lipopolysaccharide (LPS)

 This

interaction stimulates basal signaling, which protects against cellular injury



Disruption of TLR signaling or antibiotic associated eradication of commensal bacteria result in compromised ability of intestinal epithelium to withstand injury and repair cell damage (illust. next slide)


Hammer GD and McPhee. Pathophysiology of Disease: An Introduction to Clinical Medicine, 2014




Complement system is composed of a series of plasma protein and cell membrane receptors that are important mediators of host defenses and inflammation  Most of biologically significant effects of complement system are mediated by third component (C3) and terminal components (C5–9) o To carry out their host defense and inflammatory functions, C3 and C5–9 must first be activated



Two pathways of complementactivation have been recognized and have been termed classic and alternative pathways  classic pathway is activated by antigen–antibody complexes or antibodycoated particles, and  alternative pathway is activated by mechanismsindependent of antibodies, usually by interaction with bacterial surface components




Inherited disorders of complement are associated with anincreased risk of bacterial infection



Specific infections seen in complement-deficient patients relate to biologic functions of missing component  For example, patients with adeficiency of C3 or of a component in either of two pathways necessary for activation of C3 typicallyhave increased susceptibility to infections with encapsulated bacteria such as Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae, and Klebsiella pneumoniae  In contrast, patients with deficiencies of C5 –9 have normal resistance to encapsulated bacteria because C3b-mediated opsonization is intact (illust. next slide)


H a m m e r G D a n d M c P h e e .



classic pathway is activated by antigen–antibody complexes or antibody-coated particles



alternative pathway is activated by mechanisms independent of antibodies, usually by interaction with bacterial surface components

P a th o p ysh i o lo g y o f D sie a es: A n I n rto u d tci o n t o C lin ic a lM e d ic in e, 2 0 1 4


" Pathogenesis - the

course of the infectious process

"Virulence"

factors or "pathogenicity" factors  Microbes which can cause disease are thought to carry out process by utilizing one or more properties called virulence factors or pathogenicity factors

IMPORTANT TO NOTE:  THE STUDY OF MICROBIAL VIRULENCE FACTORS IS A MAJOR EMPHASIS IN MICROBIOLOGY AND INFECTIOUS DISEASE RESEARCH 

UNDERSTANDING MOLECULAR MECHANISMS BY WHICH PATHOGENS EXERT THEIR VIRULENCE PROPERTIES LEADS TO NEW ANTIBIOTICS AND VACCINES


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Bacteria carry a variety of virulence factors that facilitate pathogenesis: These include:  factors that help them evade the immune system  factors that facilitate adhesion  factors that facilitate spread through 

tissues invasion of host cells  a variety of different toxins that are toxic to host 


fimbriae -

adherence to host tissues

toxins -

secreted or membrane-bound proteins, cause tissue damage or inhibit tissue function

capsules -

surface polysaccharides, protect against host immune

defenses endotoxin -

lipopolysaccharide (LPS), component of membranes elicits immune/inflammatory responses

siderophores -


scavenge iron and promote uptake into bacteria

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Factors

that help bacteria evade the host immune system



Structural components likecapsules prevent phagocytosis A variety of proteins, such as listeriolysin O, facilitate intracellular survival in phagosomes  Enzymes involved in destruction of immune molecules include IgA proteases and leukocidins  Antigenic variation and phase variation result in a change of surface 



antigens effectivelyallowing bacteria to hide from preformed antibody Intracellular invasion allows bacteria toevade humoral immune response




Factors that facilitate adhesion, invasion, and spread include:  flagella  pili  cell-wall associated proteins  slime layers and  enzymes including hyaluronidase, mucinase, and urease




Two general types of bacterial toxins are common 1. LPS, which is extremely toxic to animals, has been called the endotoxin of gram-negative bacteria because it is an integral part of cell wall and is released only when cells are lysed  When LPS is split into lipid A and polysaccharide, all of toxicity is associated with lipid A component  Endotoxin stimulates inflammatory cytokines including tumor necrosis factor alpha (TNF-α) and interleukin-1 (IL-1) 2. Many different exotoxins can be produced that affect a variety of cellular processes including inhibition of protein synthesis; others have adenylate cyclase activity or function as superantigens 

Some toxins are neurotoxins or cytotoxins


Endotoxin 

LPS found in outer membrane of gram-negative bacteria (both cocci and rods) ENDOTOXIN: Edema Nitric oxide DIC/Death Outer membrane TNF-α O-antigen Le T and Bhushan V. Microbiology. In:First Aid for the USMLE Step 1 2015 eXtremely heat stable IL-1 Neutrophil chemotaxis


These promote evasion of host immune response:  Protein A 



IgA protease 



Binds Fc region of IgG Prevents opsonization and phagocytosis expressed by S. aureus Enzyme that cleaves IgA Secreted by S. pneumoniae, H. influenzae type B, and Neisseria (SHiN) in order to colonize respiratory mucosa

M protein 

Helps prevent phagocytosis Expressed by group A streptococci Shares similar  possibly underlies epitopes to human cellular proteins (molecular mimicry) autoimmune response seen in acute rheumatic fever



Type III secretion system 

Also known as “injectisome” Needle-like protein appendage facilitating direct delivery of toxins from certain gram-negative bacteria (e.g.,Pseudomonas, Salmonella, Shigella, E. coli ) to eukaryotic host cell


    

Entry: skin is a major barrier but can be breached by bites or wounds, entry usually via mucosal surfaces Colonization: attachment to mucosal surfaces Proliferation: acquisition of nutrients Invasion: entry into host tissue/cells; local, systemic Avoidance of immune system o resistance to complement and antibody killing o

survival in phagocytes (resistance to enzyme degradation, reactive oxygen species, escape)  Overcoming iron limitation  Transmission


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Scope

of the Problem:  Viruses, bacteria, protozoa, fungi, and parasites  Enormous


diversity

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Viruses Bacteria Single-celled eukaryotes (animal-like cells):  Parasitic

protozoa  Fungi/yeast Higher eukaryotes:  Parasitic intestinal  Tissue


worms

worms

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Microbes

1

are everywhere and in high numbers

gram of human feces contains about 1 trillion bacteria


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“Avirulent” “Virulent”

or “nonpathogenic” - harmless

or “pathogenic” - capable of causing disease

Normal

flora - microbes that colonize the body and usually do not cause disease.

Opportunistic

pathogens - microbes that normally do not cause disease, but may under certain circumstances.

Frank

pathogens - microbes that always cause disease.

Other -

diseases caused mostly by ingestion of preformed toxins or when toxins are produced from bacteria during infection


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Le T and Bhushan V. Microbiology. In:First Aid for the USMLE Step 1 2015


Clinical Bacteriology Gram-positive lab algorithm



A 54-year-old man develops a pyogenic infection along the suture line after knee surgery. The laboratory gives a preliminary report of a beta-hemolytic, catalase-positive, coagulase-positive, Gram-positive coccus. The most likely causative agent is (A) Moraxella catarrhalis (B) Staphylococcus aureus (C) Staphylococcus epidermidis (D) Streptococcus agalactiae (E) Streptococcus pyogenes


Clinical Bacteriology



Microbes cannot think;

MISSION: SURVIVE AND MULTIPLY TO ENSURE SURVIVAL OF THE SPECIES.

they simply exploit the human environment solely for growth and survival


40

Invade Concept  Staph

of Site-Pathogen Combinations

infection: invasion through compromised skin

 Tuberculosis: inhalation  Strep

into lung

infection: streptococci bind to throat epithelial cells

 Urinary

tract infection: E. coli enter at urethral orifice

 Gastritis: stomach lining acceptable to Helicobacter pylori


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1) Initial Invasion (Infection) Subtle

Infiltration in quiet of night and often with camouflage  Streptococcus pyogenes  Streptococcus pneumoniae and Neisseria meningitidis

Massive

invasion to overwhelm the opposition  Some invaders can escape stomach acid (e.g., E. coli, Salmonella)


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2) Establishing a "Beach Head“ (Colonization) Ensuring the

availability of food and water (scavenging of

nutrients) Establishing a good defense (armor;

barriers) against an offensive

(immune) attack

3) Taking the Offensive (Invasion/Spread) Moving out from initial

site to more distant sites that offer more

territory and more opportunities for survival and expansion

4) Expand to Neighboring Environments 

Infect other individuals


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Viruses

take over our cells and use them as "factories" to make new virus particles:  Budding - slow release; eventually stresses and kills the cell  Lysis -

rapid, complete destruction of cell by explosion

 Latent

infection - more protracted, insidious infection that may or may not lead to destruction of infected cell or may lead to cancer


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viral infections


45

 Bacteria exploit a wide


spectrum of parasitic strategies

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Seven important species of bacteria are involved in so many different systems they are presented your eNotes under the heading‘‘Major Recurring Species’’ These species are: 1. Chlamydia trachomatis 2. Escherichia coli 3. Haemophilus influenzae 4. Pseudomonas aeruginosa 5. Staphylococcus aureus 6. Streptococcus pneumoniae 7. Streptococcus pyogenes Marc Imhotep Cray, M.D.

Note: To reinforce your pharmacology primary drugs for treatment for specific organism are provided where there is drug resistance, or where Tx involves something besides or in addition to antibiotics, or is reasonably straightforward, but are not recommended initial therapy for disease prior to identification of the bacterial agent.

bacterial infections


Features: 1. Small, non–Gram-staining, obligate intracellular pathogen (OIP). 2. Found only in humans; transmitted as elementary bodies by direct contact (birth, sex, or on feet of flies tracking from one eye to next). Diseases: 1. Causes disease by intracellular replication that elicits (except in neonates) a granulomatous response, which, if untreated, leads to symptoms depending on the body locale, such as fallopian tube blockage, leading to infertility or ectopic pregnancy.


Milner DA. Ed. Diagnostic pathology. Infectious Diseases. Philadelphia: Elsevier, 2015


cont. 2. The three major serovar groups each cause a different spectrum of disease; multiple serotypes of each allow reinfection

a. Chl. trachomatis serovars D–K in the United States causeconjunctivitis, genitourinary tract infection, and neonatal pneumonia b. Chl. trachomatis serovars A–C cause trachoma c. Chl. trachomatis serovars L1, L2, and L3 cause lymphogranuloma venereum 3. Lab ID ( laboratory identification): cell culture required to grow so diagnosis is commonly by immunofluorescence or genetic probes.

4. Treatment: commonly doxycycline, a macrolide, or fluoroquinolone (FQ)


Features: 1. Motile, lactose-fermenting, member of the Enterobacteriaceae. 2. Colonic normal flora (nonpathogenic strains) of human and animals. May colonize lower end of urethra and vagina Transmitted during birth or via fecal–oral route. Diseases: 1. E. coli causes urinary track infections (UTIs), neonatal sepsis and meningitis, and diarrheal diseases.


cont. 2. Disease results when normal flora strains enter normally sterile sites or when organism acquires virulence factors a. All strains haveendotoxin and constitutively produce commonpili that adhere to colon cells b. Like other Enterobacteriaceae, E. coli easily receives (or donates) genetic elements from other enterobacteria. 3. Lab ID a. Grows on bile-containing media like Hektoen. b. Ferments lactose and is identified by a panel of metabolic tests. 4. Treatment: treated (except for uncomplicated UTIs) according to drug susceptibility results.


Features: 1. Gram-negative, fastidious, pleomorphic rod (short to almost filamentous rods from cultures coccobacillary in cerebrospinal fluid [CSF]) 2. Part of normal flora (NF) of upper respiratory tract  NF strains generally do not have a capsule and are called nontypeable; encapsulated virulent strains are stereotyped by lab  all are transmitted via respiratory droplets by direct contact Diseases: 1. Ottis media may be caused by any strain with or without capsule


cont. 2. Virulent strains with type b capsule cause meningitis or epiglottitis in unvaccinated children generally younger than 2 years of age. H. influenzae type d causes exacerbations of chronic bronchitisin patients with chronic obstructive pulmonary disease (COPD) 3. Lab ID: fastidious—does not grow on blood agar (BA) butgrows on chocolate agar (chocolate agar positive) or near Staph. aureus on BA (satellite colonies); or with X (hematin) and (nicotinamide supplementation nutrient agar adenine dinucleotide [NAD]) factor on V

4. Treatment: treated with cefpodoxime or ceftriaxone (for life-threatening infections) or amoxicillin-clavulanate Marc Imhotep Cray, M.D.

Features: 1. Gram-negative rod with polar flagella 2. Oxidase positive (not an Enterobacteriaceae) and obligate aerobe (nonfermentative) 3. Pigments: fluorescein, a fluorescent pigment, and pyocyanin, a blue-green pigment Bluegreen pus is a classic sign of Ps. aeruginosa cellulitis in burn patients 4. Ubiquitous and widely distributed in/on plants, soil, and water Rapid growth even in distilled or tap water (i.e., sink drains, faucet aerators, cut flowers)


cont. Diseases: 1. Pseudomonas is afrequent cause of n osocomial infections, with pneumonias in cystic fibrosis, burn, and neutropenic patients; cellulitis in burn patients; eye and ear infections 2. Pathogenesis: a. Exopolysaccharide layer (capsule) increases adherence to tracheal epithelium and mucin. alsoinhibits phagocytic uptake  Pili aid in adherence b. In tissues or blood, endotoxin inflammation or (ADP)-ribosyl shock exotoxin A is antriggers c. Pseudomonas adenosine diphosphate transferase (similar to diphtheria toxin) thatinactivates EF-2 (elongation factor) halting protein synthesis primarily in liver and resulting in liver necrosis d. Phospholipase-C damages all membranes, causing tissue necrosis; elastase and other proteolytic enzymes damage elastin, immunoglobulin A and G (IgA, IgG), complement components, and collagen Marc Imhotep Cray, M.D.

cont. 3. Lab ID: iridescent sheen on beta hemolysis around colonies grown on blood agar; fruity odor 4. Treatment: drug resistance; do susceptibility tests. a. Pseudomonas has a high inherent resistance and also acquires resistance (e.g., beta-lactamases, decreased carbapenem entrance due to porin loss, DNA gyrase mutations (FQ), and aminoglycosideinactivating enzymes 

pump rids ofilantibiotics b. AntiEfflux pseudom ona l peitnic lins , meropenem, imipenem, third-generation and fourth-generation cephalosporins, or tobramycin is generally used; combinations are often used in severe disease in immunocompromised (IC) patients Marc Imhotep Cray, M.D.

Features: 1. Catalase-positive, coagulase-positive, beta-hemolytic, Gram-positive coccus found in grapelike clusters 2. Colonizes mucosa (15% of adults are carriers) Transmitted by direct contact and fomites Diseases: 1. Causes skin and surgical infections, endocarditis, toxic shock syndrome, septicemias, scalded skin syndrome, food poisoning, infective arthritis, osteomyelitis, postinfluenza pneumonia, and pneumonia in very young cystic fibrosis (CF) patients


2. Pathogenesis: a. Hemolysins and other cytolytic toxins b. Coagulase bi nds t o prothrombin , triggering fibrin polymerization around Staph. aureus, slowing clearance c. Fibrinogen-binding cl umping fac tor allows S. aureus to bind to normal heart tissue to damage d. Protein A on its surface binds the Fc portion of antibody, reducing opsonization e. Teichoic a cids (lipoteichoic and cell-wall–bound) play a role in adherence and, when cell wall is breaking up,lipoteichoic acids with peptidoglycan trigger shock via same pathways as endotoxin 3. Lab ID: positive catalase and coagulase tests; beta-hemolytic ferments mannitol (mannitol agar positive) Marc Imhotep Cray, M.D.

4. Treatment: drug resistance a.

do susceptibility tests

In the 1950s, Staph. aureus acquired a plasmid conferring resistance to many early antibiotics such as tetracyclines and penicillins  A new group of penicillins (methicillin and nafcillin) were developed to target new resistant strains These strains are known in the United States asmethicillinsensitive Staph. aureus (MSSA)

b. In ] 1980s, some MSSA strains developed a new cell wall synthetic enzyme (PBP) made by the mecA gene, which allows bacterium to build peptidoglycan in presence of methicillin or nafcillin these strains are known asmethicillin-resistant Staph. aureus (MRSA) c. Now, there are vancomycin-intermediate Staph. aureus (VISA) with thick cell walls that bind high levels of vancomycin and vancomycin-resistant Staph. aureus (VRSA) with even higher resistance similar to vancomycin resistant enterococci (VRE)


Features: 1. Gram-positive, alpha-hemolytic, lancet-shaped diplococcus 2. Oropharyngeal mucosal colonist/opportunist Diseases: 1. Otitis, sinusitis, pinkeye; pneumonia or meningitis in nonvaccinated young, old or alcoholics 2. Pathogenesis: a. Colonizes with help of protein adhesins and an IgA protease; reduces numbers of competing NF by production of large amounts of hydrogen peroxide b. Thick polysaccharide capsule reduces effectiveness of complement and antibodies, decreasing phagocytic uptake more than 80 different capsular polysaccharide types. c. Hemolyzes cells throughpneumolysin and partially reduces hemoglobin to green pigment (alpha-hemolysis) Marc Imhotep Cray, M.D.

3. Lab ID Streptococcus pneumoniae a. Alpha-hemolytic and lysed by bile and inhibited by optochin b. Capsules are typed by quellung reaction (apparent capsular swelling when mixed with the specific matching antibody) 4. Treatment: penicillin resistance due to decreased binding to penicillinbinding proteins mandates testing 5. Prevention a. A 7-valent polysaccharide-protein conjugate vaccine (T-cell dependent) for infants b. A 23-valent polysaccharide vaccine for patients 65 years or older, asplenics, diabetics, human immunodeficiency virus (HIV) positive, COPD, and so forth Marc Imhotep Cray, M.D.

Features: 1. GAS is beta-hemolytic, Gram positive, catalase negative, coccus in chains 2. Also known as GAS because it interactswith Lancefield antibodies for Group A cell wall carbohydrates(the basis for the rapid antigen test) 3. Inhibited by bacitracin and produces L-pyrrolidone arylamidase (PYR test positive) 4. Colonizes skin and upper respiratory tract mucosa Survives on hard surfaces; spread by fomites, respiratory droplets, and direct contact  Because GAS is not particularly invasive, it requires colonization and skin trauma to infect


(Group A strep [GAS]) cont. Diseases: 1. GAS causes pharyng itis, impetigo, erysipelas, cellulitis, necrotizing fasciitis, bacteremia, rheumatic heart disease, poststreptococcal acute glomerulonephritis, and toxic shock syndrome 2. Tissue is damaged by enzymes, including streptolysins and streptokinase A and B, which break down clots, DNase, and hyaluronidase (spreading factor in necrotizing fasciitis) a. Streptolysin S is a beta-hemolysin b. Streptolysin O is an immunogenic, beta-hemolysin  Antibody to Streptolysin O is a marker of recent mucosal infections and (or) rheumatic heart disease (ASO titer) which is culture negative


3. M proteins a. Attach Strep. pyogenes to cytoplasmic membrane. b. Class I M proteins extend through t cell wall to cell surface c. Strains causing rheumatic heart disease have exposed class I M proteins, which are responsible for cross-reactivity with human heart antigens d. M-12 strains are associated with glomerulonephritis

4. Nonimmunogenic hyaluronic acid capsule—inhibits phagocytic uptake until other surface components are opsonized 5. Strep. pyogenes erythrogenic (SPE) toxins a. SPEs are produced only by strains ofStrep. pyogenes carrying a lysogenic phage b. All SPEs produce a fine, blanching, ‘‘sandpaper’’ rash on arms and upper trunk c. SPE-A and -C are superantigens, nonspecifically activating large numbers of T cells and triggering proinflammatory cytokines and ultimately producingshock and multisystem organ failure

6. Lab ID Pharyng itis: rapid antigen test with culture; all other infections: culture. Marc Imhotep Cray, M.D.

Malaria (several protozoan species

of Plasmodium) - transmitted to humans by bite of female Anopheles mosquitoes 

A major global health problem in tropical developing countries  Plasmodium is a model intracellular parasite - carries out a key part of its life cycle inside human red blood cell  Produces enzymes that breakdown hemoglobin of red blood cell as a key nutrient source  Complex life cycle; partly in humans and partly in mosquitoes 

Phase in humans can be cyclic and thus give rise to relapses over several years  Treatment is difficult and resistance to drug therapy is highly problematic


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Life Cycle: Penetrate skin Immature worms

Heart and lungs

Eggs mature

Coughed up Swallowed

Eggs in soil

Small intestine

Eggs excreted Eggs in feces

Larvae mature Lay eggs


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Viruses

 Size

 Replicate

10-100 times larger

on their own?

 Structure  Metabolic

No Simple (Genetic material + protein coat only)

Functions

 Susceptible to classical Marc Imhotep Cray, M.D.

Bacteria

Yes Complex cell

No

Yes

antibiotics? No

Yes 69

1. “Microbial World”: viruses, bacteria, protozoa, fungi, and other parasites. 2. Microbes are everywhere in the environment; humans are heavily colonized! 3. In humans, there are “avirulent”: (e.g., normal flora which are beneficial) microbes vs. those which are “opportunistic” or “pathogenic.” 4. Sole mission of microbes: Get by and multiply! 5. Viruses “take over” our cells and use them as “factories” to make new viruses 6. Bacteria and parasites have evolved highly ingenious strategies to evade our immune responses and to exploit diverse environments within human body 7. Bacteria and parasites rely on traits (“virulence factors”) to make them “pathogenic”. 8. Studies of microbial“virulence factors” will provide novel insights for developing new antibiotics and vaccines Marc Imhotep Cray, M.D.

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THE END

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Chen EM and Kasturi SS. Deja review, Microbiology and Immunology 2nd Ed . New York: McGraw-Hill, 2010 Kishiyama JL. Ch. 3 Disorders of the Immune System, Pgs. 31-59 and Bloch KC. Ch. 4 Infectious Diseases, Pgs. 61-87 In: Hammer GD and McPhee Eds. JS. Pathophysiology of Disease : An Introduction to Clinical Medicine , 7th Ed. New York: McGraw-Hill Education, 2014 Johnson AG et al. Bacterial Diseases. In: Microbiology and immunology. 4th Ed. Baltimore: Lippincott Williams & Wilkins, 2010 Le T and Bhushan V.First Aid for the USMLE Step 1 2015 , New York: McGraw-Hill, 2015 Milner DA. Ed. Diagnostic pathology. Infectious Diseases. Philadelphia: Elsevier, 2015

eLearning (IVMS Cloud)   

Infectious Disease Microbial biology & Immune System Rural Medicine Global Health (Focus on Ethiopia)

Textbooks:  Ryan KJ and Ray CG Eds. Sherris Medical Microbiology, 5th Ed. New York: McGraw-Hill, 2010 

Carroll KC etal. Jawetz, Melnick, & Adelberg’s Medical Microbiology 27th Ed. New York: McGraw-Hill, 2016


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Host Defense and Microbial Pathogenesis

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