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CSU, Stanislaus

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Lecture 5

Spread and Replication Reading: pg. 157 –165

Surface vs. systemic infection (fig. 15.1, pg. 157, fig. 15.2, fig. 15.3, pg. 158)
Replication rates (fig. 15.6, pg. 159)
Mechanisms of spread
- Spread to lymph and blood (fig. 15.7, pg. 160)
- Spread from blood
- Spread via nerves (fig. 15.9, pg. 161)
- Spread via cerebrospinal fluid
- Spread via other routes
Genetic determinants of spread
Other factors
Molecular basis (fig. 15.11, pg. 164)
Host factors (fig. 15.12, pg. 165

Parasite Survival Strategies, etc Reading: pg. 167 – 180

Strategies to evade innate defenses
- Killing or avoiding being killed by phagocytes (fig. 16.1, pg. 168)
- Interfering with ciliary action
- Interfering with complement’s alternative pathway (fig. 16.2, pg. 169)
- Producing iron binding molecules
- Blocking interferons
Strategies to evade adaptive defenses
Immunosuppression
Persistent infections
Reactivation

Pathologic consequences of infection Reading: pg. 183 – 197

General scheme (fig. 17.1, pg. 183)
Pathology caused directly by microorganism
- Direct tissue damage (fig. 17.2, pg. 184)
- Exotoxins of importance (fig. 17.3, pg. 185)
Pathologic activation of natural immune mechanisms (fig. 17.6, pg. 188)
Pathologic consequences of the immune response
- Hypersensitivity (fig. 17.8, pg. 191)
- Cell-mediated responses (fig. 17.11, pg. 193)
Skin rashes (fig. 17.12, pg. 194)
Viruses and cancer (fig. 17.13, pg. 195, fig. 17.14, pg. 195)

Pathology of Infection
(p. 157-197)

Spread and replication

Parasite survival Strategies

Pathologic consequences of infection

Spread and Replication: Surface vs. systemic infection

p Determining factors

n Temperature – temperature-sensitive microbes

p Rhinoviruses

p Mycobacterium leprae

n Site of budding

p Influenza and parainfluenza viruses (fig.15.2)

Spread and Replication: Surface vs. systemic infection

p Many microbes have to invade deeper tissue

n fail to spread and multiply at site of initial infection

p Measles and typhoid

n route of infection is different from site of replication and shedding.

p Mumps - infect via respiratory route; multiply in salivary glands

p hepatitis A - infect via alimentary route; multiply in liver

Spread and Replication: Replication rates

p Varies from 20 min to weeks in vitro

p Microbes multiply faster in vitro than in vivo

Spread and Replication: Mechanisms of spread

p Spread to lymph and blood

n microbes encounter a variety of defenses:

p Tissue fluids with antimicrobial substances (antibody, complement)

p Local macrophages (subcutaneous and submucosal)

p Physical barrier of local tissue structure – prevents spreading

p Lymphatic system – where phagocytes and other defenses awaits (fig. 15.7)

Spread and Replication: Mechanisms of spread

p Spread from blood

n Viremia and bacteremia

n Microbes may be:

p free – exposed to immune defenses

p Associated with circulating cells - protect and carry them around body

§ Epstein-Barr virus and rubella, and intracellular bacteria (Listeria, Brucella) – protected inside lymphocytes or monocytes

§ Malaria - erythrocytes

n Microbes invade only certain organs and tissues:

p Specific receptors for microbe

p Random localization

p Accumulation of circulating microbes in areas with local inflammation

n Microbe shed from body surface or into bloodstream

Spread and Replication: Mechanisms of spread

p Spread from nerves

n Viruses reach CNS via axons

n Few host defenses to control viral spread

n Fig. 15.9: routes of invasion of the CNS

n Uncommon route of spread to CNS

p olfactory nerves

§ Amoeba in freshwater pools - causes meningoencephalitis in swimmers

p Viruses and bacteria in nasopharynx

§ Meningococci, poliovirus

p Spread from cerebrospinal fluid

n After crossing blood-cerebrospinal barrier microbes can:

p invade neural tissues – echovirus, mumps virus

p Multiply locally and infect ependymal and meningeal cells – N. meningitidis, H. influenzae

p Spread via other routes

n organ to organ via pleural or peritoneal cavity

n Infections of:

p peritoneal cavity - injury or disease of abdominal organs

p Pleural cavity – chest wounds or lung infections

Spread and Replication: Genetic determinants of spread

p host genetic determinants

n Affect susceptibility to pathogens

n Example: Sickle cell gene

p Wildtype

p Sickle cell gene - nucleotide change in DNA

§ Sickle cell trait (heterozygous form)

§ confers resistance to severe forms of malaria

§ selected for in malarial regions of world

p Microbial genetic determinants

n Virulence factors:

p encoded by microbial genes

p Includes adhesion, penetration into cells, antiphagocytic activity, toxin production, interactions with immune system

n Genetic changes due to:

p High mutation rates of surface antigens

p Acquisition of genetic elements

n Molecular basis of microbial pathogenicity (fig. 15.11)

Spread and Replication:

p Molecular basis

p Other factors

n brain can influence immune responses via

p Shared chemical messengers with endocrine and immune system

n Host factors (fig. 15.12)

p Host factors

Parasite survival strategies

Strategies to evade innate defenses

p Killing or avoiding being killed by phagocytes

p Interfering with ciliary action

n Impairment or destruction of ciliary cells

p Interfere with complement’s alternative pathway

p Producing iron binding molecules

n Siderophores

n Take iron away from host iron-complexing proteins

p Blocking interferons

n block actions of interferons (IFNa, IFNb)

Strategies to evade adaptive defenses

p More sophisticated

n Lymphocytes (B and T cells) – recognize shape or amino acid peptides

p Capsules

§ recognized by B cell à production of antibodies, opsonization and phagocytosis

p Peptides

§ presented on macrophage surface à detected by T cells à cytotoxic and other defenses

p Cause a rapid “hit-and-run” infection

n rhinoviruses, rotaviruses

p Concealment of antigens from host

n Remain inside cells – latent viruses (HSV)

n Colonizing privileged sites

p Hydatid cysts

§ form by Echinococcus granulosus (tapeworm)

§ Liver, lung, brain

p Integration into host DNA (retroviruses)

n Mimicry – microbe mimics host antigens

n host produces autoantibodies à autoimmunity

p Group A beta-hemolytic streptococci – mimic cardiac muscle à rheumatic heart disease

n Microbes cover surfaces with host molecules

p Antigenic variation

n Mechanisms involved

p Mutation

§ antigenic drift

p Recombination

§ exchanged of genetic information

p Gene switching

§ switch from use of one gene to another

Immunosuppression

p Temporary or long-lasting

p Immunosuppresssive effects

n actual infection of immune cells à impair cell function or cell death

n release immunosuppressive molecules

Staphylococci toxins – potent T cell mitogens

p Interference with signaling between immune cells

n Fake molecules or fake cell receptors for host molecules

p Glycoprotein C (Herpes simplex virus) –interferes with complement activation

n Other proteins:

p interfere with apoptosis

p induce apoptosis

p Interference with local expression of immune response in tissues

n Destruction of IgA by protease

n Inactivation of complement proteins

n Production of Fc receptor molecules (Fig 16.8)

p Persistent infections

n several forms:

p Infectious (hep B)

p Low infectivity (adenoviruses)

p Non-infectious (latent, HSV)

n Latent infections can be:

p Associated with chronic diseases, cancers

p Reactivated

Reactivation

p Two stages in reactivation

n Stage A: resumption of viral activity

p HSV - triggered by sensory stimuli, fevers or hormones

n Stage B: Spread and replication of reactivated virus

p HSV – travels down axon to mucosal surface, infect and spread forming a vesicle filled with viruses

p Can be controlled by immune system

§ Cold sores – due to poor lymphocyte response

§ Zoster – due to declining cell-mediated responses

Pathologic consequences of infection

p General scheme

p Symptoms of disease caused by:

n Microbe

n Toxins

n Induction of immune response

Direct tissue damage

Exotoxins

p A-B toxins - consist of two parts

p A portion = Toxic or active enzyme

p B portion = Binding component - Binds to specific host cell receptors

n Example: Diphtheria toxin

p Exotoxins inactivated à toxoid (vaccine) à diphtheria, tetanus

p Pathologic activation of natural immune mechanisms

n Overactivity cause damage to host tissues

p Endotoxins

§ Activation of immune response and clotting pathway (fig. 17.6)

p Increased levels of TNF and activation of complement

Hypersensitivity

p lead to tissue damage due to over-stimulation or prolonged response of adaptive immunity

Pathology of Infection (p. 157-197)

Spread and replication

Parasite survival Strategies

Pathologic consequences of infection

Spread and Replication: Surface vs. systemic infection

p Determining factors

n Temperature – temperature-sensitive microbes

p Rhinoviruses

p Mycobacterium leprae

n Site of budding

p Influenza and parainfluenza viruses (fig.15.2)

Spread and Replication: Surface vs. systemic infection

p Many microbes have to invade deeper tissue

n fail to spread and multiply at site of initial infection

p Measles and typhoid

n route of infection is different from site of replication and shedding.

p Mumps - infect via respiratory route; multiply in salivary glands

p hepatitis A - infect via alimentary route; multiply in liver

Spread and Replication: Replication rates

p Varies from 20 min to weeks in vitro

p Microbes multiply faster in vitro than in vivo

Spread and Replication: Mechanisms of spread

p Spread to lymph and blood

n microbes encounter a variety of defenses:

p Tissue fluids with antimicrobial substances (antibody, complement)

p Local macrophages (subcutaneous and submucosal)

p Physical barrier of local tissue structure – prevents spreading

p Lymphatic system – where phagocytes and other defenses awaits (fig. 15.7)

Spread and Replication: Mechanisms of spread

p Spread from blood

n Viremia and bacteremia

n Microbes may be:

p free – exposed to immune defenses

p Associated with circulating cells - protect and carry them around body

§ Epstein-Barr virus and rubella, and intracellular bacteria (Listeria, Brucella) – protected inside lymphocytes or monocytes

§ Malaria - erythrocytes

n Microbes invade only certain organs and tissues:

p Specific receptors for microbe

p Random localization

p Accumulation of circulating microbes in areas with local inflammation

n Microbe shed from body surface or into bloodstream

Spread and Replication: Mechanisms of spread

p Spread from nerves

n Viruses reach CNS via axons

n Few host defenses to control viral spread

n Fig. 15.9: routes of invasion of the CNS

n Uncommon route of spread to CNS

p olfactory nerves

§ Amoeba in freshwater pools - causes meningoencephalitis in swimmers

p Viruses and bacteria in nasopharynx

§ Meningococci, poliovirus

p Spread from cerebrospinal fluid

n After crossing blood-cerebrospinal barrier microbes can:

p invade neural tissues – echovirus, mumps virus

p Multiply locally and infect ependymal and meningeal cells – N. meningitidis, H. influenzae

p Spread via other routes

n organ to organ via pleural or peritoneal cavity

n Infections of:

p peritoneal cavity - injury or disease of abdominal organs

p Pleural cavity – chest wounds or lung infections

Spread and Replication: Genetic determinants of spread

p host genetic determinants

n Affect susceptibility to pathogens

n Example: Sickle cell gene

p Wildtype

p Sickle cell gene - nucleotide change in DNA

§ Sickle cell trait (heterozygous form)

§ confers resistance to severe forms of malaria

§ selected for in malarial regions of world

p Microbial genetic determinants

n Virulence factors:

p encoded by microbial genes

p Includes adhesion, penetration into cells, antiphagocytic activity, toxin production, interactions with immune system

n Genetic changes due to:

p High mutation rates of surface antigens

p Acquisition of genetic elements

n Molecular basis of microbial pathogenicity (fig. 15.11)

Spread and Replication:

p Molecular basis

p Other factors

Pathology of Infection
(p. 157-197)