Infectious Part 1

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Infectious Diseases

Amelia Co-Fibra MD, FPSP

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UNDERSTANDING PATHOGENESES OF INFECTIOUS AGENTS

1. Enumerate the categories of Infectious agents and their general features

2. Know the different human barriers against infectious agents

3. To enumerate and understand the Transmission & Dissemination of microbes

4. To know how microbes cause disease A. VIRAL INJURY B. BACTERIAL INJURY C. INJURIOUS EFFECTS OF HOST IMMUNITY

COURSE OUTLINE

KNOW DISEASES PRODUCED BY SOME OF THE INFECTIOUS AGENTS◦A. VIRAL INFECTION◦B. BACTERIAL INFECTION◦C. PARASITES◦D. FUNGAL

COURSE OUTLINE

PRIONS VIRUSES BACTERIOPHAGES/ PLASMIDS/ TRANSPOSON BACTERIA CHLAMYDIA / RICKETTSIAE/ MYCOPLASMA FUNGI PROTOZOA HELMINTHS ECTOPARASITES

Categories of Infectious Agents

Classes of Human PathogensTaxonomic Site of Propagation Examples Diseases

Prions Intracellular Prion protein Creutzfeld- Jacob Disease

Viruses Obligate Intracellular Poliovirus Poliomyelitis

Bacteria 1. Obligate Intracellular2. Extracellular3. Facultative intracellular

1. Chlamydia trachomatis2. Strep pneumoniae3. TB

TrachomaPneumoniaTuberculosis

Fungi 1. Extracellular2. Facultative intracellular

1. Candida albicans2. Histoplasma

capsulatum

ThrushHistoplasmosis

Protozoa 1. Extracellular

2. Facultative intracellular3. Obligate intracellular

1. Trypanosoma gambiense

2. T. cruzi3. Leishmania donovani

1. Sleeping sickness

2. Chagas dse3. Kala- azar

Helminths 1. Extracellular2. Intracellular

1. Wuchereria bancrofti2. Trichinella spiralis

1. Filariasis2. Trichinosis

PRIONS

Nucleic acid freeSpontaneous mutation or Inherited Mutation in PrP

Cause Transmissible Spongiform Encephalitis

PathophysiologyPrP found in neurons

Mutation• Conformational change

Abnormal PrP• Resistant to PROTEASES

Neuronal damage

Abnormal PrP promotes transformation of normal PrP to abnormal formsEXPLAINING THE INFECTIOUS NATURE OF THESE DISEASE

Cause Transmissible Spongiform encephalitis◦ Kuru ( Human Cannibalism )◦ Bovine Spongiform Encephalitis ( Mad Cow

Disease )◦ Creutzfeldt-Jacob Disease

(Spontaneous - Sporadic/ Inherited -Familial) Transmitted

From corneal/ organ transplant BSE infected cattle Blood Transfusion

Vacuolization of gray matter but no inflammation

Clinical presentation

Obligate Intracellular 20-300nm May aggregate forming inclusion bodies

◦ CMV – large eosinophilic inclusion Nucleic acid core surrounded by capsid Cause

◦ Transient illness ( colds, influenza)◦ Not eliminated persist w/in cells

Continue to multiply ( HEPATITIS B ) Non-replicating OR Latent ( chickenpox shingles)

◦ May transform host cell tumor / cancer cell( Human papilloma virus )

VIRUSES

Mobile genetic elements that infect bacteria

Indirectly cause human diseases◦ Encodes virulence factor◦ Exchange of these elements between bacteria

Bacteriophages/ plasmids◦ Converts Nonpathogens Pathogens

Plasmids/ Transposons◦ Encode antibiotic resistance◦ Eg. Vancomycin – resistant enterococci

BACTERIOPHAGE, PLASMIDS, TRANSPOSONS

Prokaryotes – have cell membrane◦Gram positive - thick wall surrounding the

cell membrane (stain violet )◦Gram negative - thin cell wall sandwich

between 2 phospholipid bilayer membranes ( stain red )

Lack Nuclei Most synthesize their own DNA/RNA Depend on host for Favorable Environment

◦Intracellular or Extracellular

Bacteria

Divide by binary fusion Mycoplasma

◦ Lack cell wall ◦ Mycoplasma are tiniest living organism◦ Airborne transmission◦ Binds surface epithelial cells in airway

Chlamydia ◦ Lack metabolic capabilities (ATP)

Chlamydia & Rickettsia Obligate intracellular organism◦ Mulitply in vacuoles inside the cell

CHLAMYDIA, RICKETTSIAE, MYCOPLASMA

FUNGI PROTOZOA

Eukaryotes – thick chitin walls & ergosterol membrane

Most exhibit Thermal Dimorphism

HEALTHY PERSONS◦ Dermatophytes – skin◦ Subcutaneous tissue abscess &

granulomas IMMUNOCOMPROMISED

◦ Deep fungal infxn invade tissues

AIDS◦ Lethal Pneumonia by

Opportunistic Pneumocystis carinii

Single-celled eukaryotes

Trichomonas vaginalis Intestinal protozoa Blood borne protozoa

◦ Plasmodium spp

HELMINTHS ECTOPARASITES

Multicellular organism Life cycle Roundworms-

Nematodes◦ ASCARIS◦ FILARIA/ TRICHINELLA

Flatworms- Cestodes◦ Tapeworms

Flukes – Trematode◦ Schistosoma

Arthropods◦ Lice◦ Ticks◦ Bedbugs

Live on the skin May be vectors for

other pathogens◦ Lyme disease by ticks

TRANSMISSION & DISSEMINATION OF MICROBES

A. ROUTES OF ENTRY B. SPREAD & DISSEMINATIONC. RELEASE OF MICROBESD. SEXUALLY TRANSMITTED INFECTION

HOST BARRIERS TO INFECTION & ROUTES

OF ENTRY

Barrier – inhibit growth of microbes except normal flora

Pathogens

1. KERATINIZED SKIN2. LOW SKIN pH 5.53. FATTY ACID

1. DERMATOPHYTES infect stratum corneum

2. SCHISTOSOMA LARVAE penetrate the skin- enzyme collagenase dissolve matrix

3. INSECT/ANIMAL BITES4. NEEDLE STICKS5. BREAK in the skin

1. Acidic gastric pH2. Viscous mucous3. Lytic pancreatic enzymes/ bile4. Mucosal antimicrobial peptides -

Defensin5. Normal flora6. Secreted IgA- produced by plama cells in

MALT ( M cells ) transport of antigens to

MALT and for binding/uptake of gut pathogens

GIT- Barrier

Local Defenses Weaken Low gastric acidity Antibiotics Stalled peristalsis

Organism develop strategies to overcome defenses Nonenveloped viruses may resist digestive

enzymes - HAV, Rotavirus Cyst form – Protozoans

GIT-Infection

Barriers Pathogens1. Mucociliary Blanket in

Upper airway2. Mucus from goblet –

Large particles3. Alveolar

macrophages/pmns – Smaller particles < 5 um

1. Impair cilia activity 2. Escape macrophages

(TB)3. Immunosuppression Elaborate Toxins- Hemophilus,

BordetellaChronic SmokersAspiration of Gastric contents

RESPIRATORY

Respiratory Pathogens Influenza Virus

◦ (+) Hemagglutinin proteins on surface bind sialic acid on epithelium of host engulf by cell virus replicate inside cell

◦ (+) Neuramidase Cleaves sialic acid – Allow viral release from cell Lowers the viscosity of the mucus facilitates viral

transit

Staphyloccoci ( Secondary Infection )◦ Gain access to host cell after viral infxn cause

loss of ciliated epithelium

BARRIERS PATHOGEN

1. Regular flushing of urinary tract

2. Vagina is protected by Low pH – breakdown of Glycogen in epithelium by Lactobacilli

Pathogens invade-Short urethra in females-Obstruction/ Reflux

-STD Develop mechanism for attaching to vagina/ cervix-Enter breaks in mucosa

UROGENITAL

Spread & Dissemination of

Microbes

1. Proliferate Locally at the site◦Adhere & Proliferate in/on Epithelial Cells

HPV , Dematophytes◦Confined to Lumen of Hallow Viscera

Cholera

Spread & Dissemination of Microbes

2. Penetrate the epithelial barrier Spread via Hematogenous or Lymphatic or Nerve◦ Invasiveness Due to:

Motility Secrete Lytic enzymes- Hyaluronidase

Degrades extracellular matrix between cells Strep & Staph

◦ Initial spread Follow tissue Planes of Least Resistance Regional LN Blood Stream Distant organs Abscess Regional LNs Bacteremia Colonize

distant organs

HEMATOGENOUS SPREADFREE - Polio, HBV, fungi, protozoa W/in WBC – HSV, HIV, TBW/in RBC - Plasmodium

3. Viral Propagation◦ A). Propagate from Cell to Cell by replication◦ B). Propagate By Fusion or Transport within

Nerves – Rabies, VZV 4. Placental – Fetal Route

◦ Bacterial / Mycoplasma Placentitis Premature delivery

◦ Maldevelopment - Rubella Severe in Early trimester

◦ Syphilis affect mother late in 2nd Trimester◦ Passage to birth canal- Gonococcal, Chlamydia◦ Maternal Milk – CMV, HBV, HTLV-1

Maternal transmission ◦ HIV – Major cause of AIDS in children◦ HBV – Can later cause Chronic Hepatitis & Liver

Notes:

RELEASE OF MICROBES FROM THE

BODYImportant in the Transmission

Release of Microbes from the Body

Release depends on the Location1.Skin shedding2.Coughing3.Sneezing4.Voiding – urine/ feces5.Insect vector

Respiratory◦ Viruses & Bacteria ◦ Infectious only when lesions are open to AIRWAYS

Fecal-oral◦ Water-borne viruses

HAV, HEV, Polio, Rotaviruses Saliva

◦ EBV, CMV, Mumps Larval penetration

◦ Hookworms, Schistosomiasis

Transmission- Person to Person

Sexual / Prolonged Intimate or Mucosal Contact◦ Viruses - HPV, HSV, HBV, HIV◦ Bacteria – Syphilis, Gonorrhea, Chlamydia◦ Protozoan – Trichomonas ◦ Candida

Blood & Blood products/ Needle pricks, etc◦ HBV, HCV, HIV

Transmission- Person to Person

Direct Contact or Consumption of Animal products

Indirectly via an Invertebrate vectors◦ Insects, Ticks, Mites

Transmission – Animals to HumanZOONOTIC INFECTIONS

SEXUALLY TRANSMITTED

INFECTONS

Sexually Transmitted InfectionSTransmitted through Sexual Contact Chlamydia & Neisseria – Usually by sexual

intercourseShigella & Entamoeba – Occasionally

spread by sexHigh Risk Groups for STI1. Adolescent2. Men with Men3. Illegal drug user

Organism tend to be short lived outside the host

Usually dependent on Direct person to person spread

Initial site of infection – urethra, vagina, rectum, oropharynx

Most are Asymptomatic carriers

STI increases the Risk for additional STI’s - CoinfectionRisk factors are the same for all STI’sBiologic interaction between them

Increase the spread of infxnGonococcal cervicitis local tissue damage

Increased chance of HIV infxn STI Vertical Spread

C. trachomatis – conjunctivitis Neonatal Herpes simplex –

visceral&CNS disease

Syphilis – miscarriage

HOST DEFENSES AGAINST INFECTIONS

VIRULENCE◦Ability of microbe to infect , colonize,

damage host tissues HOST RESISTANCE

◦Ability of host defense mechanisms to eradicate infection – Innate & Adaptive Immune Defenses

Outcome of Infection – Determined

INNATE DEFENCES◦ Physical Barriers◦ Macrophages◦ NK cells◦ Plasma Proteins – Complement , Cytokines, Acute

phase reactants Adaptive Immune response

◦ Are stimulated by exposure to microbes◦ Increase in magnitude, speed & effectiveness with

successive exposure◦ Mediated by T & B lymphocytes and their products

Immune Defenses

HOW MICROORGANISMS

CAUSE DISEASE1. DIRECT LY CAUSE CELL

DEATH2. TOXIN / ENZYME

RELEASE3. INDUCE CELLULAR

RESPONSES

MECHANISMS OF VIRAL INJURY

Predilection of virus to infect certain cells and not others.

Tropism Determined : ◦ HOST CELL RECEPTOR- MAJOR DETERMINANT◦ CELLULAR TRANSCRIPTION FACTORS

That Recognize Viral Enhancer & Promoter Sequences Allow Viral replication inside the cell

◦ ANATOMIC BARRIER◦ LOCAL TEMPERATURE◦ pH◦ HOST DEFENSE

Tissue Tropism

1. Binding to host cell surface proteins◦ Viruses possess specific cell-surface PROTEINS◦ Viruses may use Normal Cellular Receptors of Host◦ Host Proteases are Needed For Binding

Host Proteases Cleaves & Activates Influenza Hemagglutinin

2. Translocation into cytosol 3. Replication via virus specific enzymes

Viruses Enter Host

(+) Hemagglutinin proteins on surface bind sialic acid on epithelium of host engulf by cell virus replicate inside cell(+) Neuramidase – lowers the viscosity of the mucus facilitates viral transit

Direct Cytopathic effects

• Viral killing of one cell type cause the death of the other cells• A

trophy of the muscles

Antiviral Immune responses

• Immune system kill infected cells

Transformation of infected cells into benign of malignant tumor cells

Mechanism of Viral injury

Preventing synthesis of host macro-molecules : DNA, RNA, CHON

• Polio virus

Produce Degradative enzymes & Toxic proteins

• HSV

• HIV

Cytopathic Effects - Virus Kill Cell Directly

Inducing Host immune response to virus – infected cells ◦ Host (CTL) Lymphocytes attack virus-infected cells

FAS Ligand on CTL binds FAS receptor in liver cells Eg. Hepatitis B virus

Virus Damage Cell involved in Host Antimicrobial Defense Secondary Infections

Viral killing of one cell type cause the death of the other cells◦ Motor denervation atrophy of the muscles

Antiviral Immune responses

1. ABORTIVE2. LATENT3. PERSISTENT

Viral Infection can be:

BACTERIAL INJURY TO HOST TISSUES

1. Bacterial Virulence2. ADHERE TO HOST CELLS ENTRY 3. DELIVER TOXINS4. Virulence of Intracellular Bacteria

Bacterial Virulence

Virulence of Intracellular microbe

Bacterial Toxins

Mechanism of Bacterial Injury

Virulence genes Plasmids & Bacteriophage

◦ Mobile genetic elements ◦ Spread between bacteria◦ Encode virulence factors – Abtic resistance, toxins

Quorum sensing◦ Induce expression of virulence factor as their

concentration in tissues increases◦ Eg. Staph aureus - abscess

Biofilm formation◦ Live in viscous layer of extracellular material◦ Enhance adherance & Inaccesible◦ IV catheters, Artificial joints

Bacterial Virulence

AdhesinsStrep. Pyogenes

• Have a Broad range of Host cell specificty

• Bind host cell or extracellular matrix

Gram (-) PiliE. coli

N. gonorrhea

• Tip of pili determine binding specificity

• Binds Uroepithelial cell

Bacterial Adherence

•Contain protein F & Lipoteichoic acid – bind fibronectin on epith. cells & matrix• M protein prevents phagocytosis

Gram (+) Fibrillae covering- Strep.

pyogenes

Bacterial Adherence

Infect either◦Epithelial cells – Shigella, Invasive E. coli◦Macrophages – Mycobacteria◦Both – S. typhi

Escape immune system- TB Facilitate spread Interact w/ cell

◦ Inhibit host CHON synthesis – Shigella & E.coli

◦Blocks fusion of acidic lysosome to form phagosome – M.TB

Virulence of Facultative Intracellular Bacteria

Bacteria coated w/ antibodies or

Complement C3b opsonization

( Alternate pathway – M. TB )

M. TB binds CR3 complement Receptor

on Macrophages

Endocytosed into macrophage- Escape host

immune- Facilitate spread

Some Mechanisms of Bacterial Entry to Cell

Gram (-) use complex secretion system

Needle like structures

Pores inject proteins

Cause rearrangemen

t of host cytoskeleton

Facilitate entry• Eg. Listeria

monocytogenes

Some Mechanisms of Bacterial Entry to Cell

Inhibit host protein synthesis Replicate rapidly Lyze host cell w/in 6 hours

Blocks fusion of lysosome with phagosome allow bacteria to replicate unchecked w/in macrophages

Effect of Bacteria inside the cell

Endotoxins

• Component of Bacterial cell

Exotoxins

• Proteins secreted by bacteria

Bacterial Toxins

Lipopolysaccharides◦Large outer cell wall of gram negative

Response of Host◦Beneficial◦Detrimental

ENDOTOXINS

1. Induction of cytokines & chemoattractants

2. Increased expression of co-stimulatory molecules enhance T-cell activation

Lipopolysaccharide- Beneficial Effect Activates immune response

High Levels of LPS• DIC , ARDS, SEPTIC SHOCK via Induction of excessive levels of

cytokines• TNF, IL-1, IL-12

Lipopolysaccharide-Harmful Effect

1. ENZYME - Protease staph.◦Split epidermis from dermis

2. TOXINS – with A-B toxins A subunit – enzymatic activity

INACTIVATES HOST PROTEINS – Cholera/Diptheria

DEGRADES HOST PROTEINS - Botulinum B-subunit – binding receptor & delivers

A subunit to the cell

Exotoxin- Secreted proteins

3. Neurotoxins – Clostridium botulinum & tetani◦Inhibit release of neurotransmitters◦But do not kill neurons

4. Superantigens – staph aureus, strep pyogenes◦Stimulate very large T-lymphos Lead to very high lymphocyte proliferation and cytokine release Capillary leak shock

Exotoxin

INJURIOUS EFFECTS OF HOST IMMUNITY

TB Granulomatous inflammation ( Delayed Hypersensitivity Reaction )◦ Prevents spread of microbe◦ But cause tissue Damage & Fibrosis

HepaB Immune response Liver damage Beta hemolytic Strep

◦ Ab against M protein Cross react w/ cardiac proteins RHD

◦ Ag + ASO (anti streptococcal antibodies) Deposit in renal glomeruli causing Poststreptococcal Glomerulonephritis

Immune response Tissue injury

IMMUNE EVASION BY MICROBES

A. Remaining inaccessible to host immune response

B. Varying or shedding antigensC. Resisting innate immune defensesD. Preventing T-cell activation E. Impairing effective T-cell

antimicrobial responses by specific or non-specific immunosuppression

Mechanism of Immune evasion by Microbes

Propagate in the lumen of ◦ Intestine – Clostridium difficile◦ Gallbladder – Salmonella typi

Shed from luminal surface of epithelial cells◦ CMV- urine, milk◦ Polio – stool

Infect the keratinized skin – Pox virus Infect Host cell – malaria Encyst in tissues – tapeworms Viral Latency – many viral genes are not

expressed

Inaccessible to Host Immune

Low fidelity of Viral RNA polymerases◦HIV

Reassortment of viral genomes◦Influenza virus

Different capsular polysaccharides◦Strep Pneumoniae

Shed antigens w/in minutes of penetrating the skin Preventing recognition by antibodies ◦ Schistosoma mansoni

Varying antigens / Shedding antigens

CAMP Resistance◦ Cationic antimicrobial peptides ( CAMP )

Defensin, Cathelicidins Initial defense against invading microbes

◦ Enabling them to avoid killing by pmns & macropahges

Carbohydrate Capsule◦ Pneumococcus, Meningococcus, Hemophilus

PREVENTI PHAGOCYTOSIS◦ K1 capsule containing sialic acid

E. coli- meningitis Sialic acid will not bind C3b ( alternate

complement pathway)

Resisting Innate Immune Response

Covering them with host proteins◦ Staph aureus covered by A molecules that

bind Fc portion inhibit Phagocytosis Protease

◦ Degrade antibodies ◦ Neisseria, Hemophilus, Streptococcus

Replicating w/in phagocytic cells◦ Mycobacterium, cryptococcus

Some viruses block complement activation◦HERPESVIRUSES, POXVIRUS

Produce homologues of IFN/ IFN receptors ◦INHIBIT THE ACTION OF SECRETED IFN

Produce cytokine mimics◦EBV – homologue of IL 10

( Bind & Inhibit secreted IFN )

Several DNA viruses Bind or Alter Localization of MHC class I proteinsHSV, EBV , CMV

Impairing peptide presentation to CD8 cytotoxic T cell

Decrease Recognition of Infected cells by CD4 , CD8

Express MCH class I homologues - Herpes Virus

Act as Inhibitors of NK cells • B

y engaging Killer Inhibitory receptors

Decrease Recognition of Infected cells

Herpes viruses Target MHC class II molecules for

Degradation & Impairing antigen presentation to CD4 + T helper cells

Decrease Recognition of Infected cells

Infected Lymphocytes Directly compromise

their functionHIV infect & Kill CD4 (+)T

lymphocytes, Macrophages, Dendritic

EBV – infect B lymphocytes

Immunosuppression

Infectious Part 1

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