1. VIROLOGIA
Viral Pathogenesis

2. Viral Pathogenesis refers to the series of events that occur during viral infection of a host.
It is the sum of the effects on the host of the virus replication and of the host immune responses

3. Views of viral pathogenesis

4. POSSIBLE OUTCOMES OF VIRAL INFECTIONS
Acute Infection
Persistent infection
Chronic
Latent
Transformation
Symptomatic infections
Inapparent infection

5. Determinants of viral pathogenesis Determinants of viral disease
IS A DISEASE THE OUTCOME OF ALL VIRAL INFECTIONS?
The outcome of a viral infection depends from the the characteristics of the virus-host interactions and from the host defense response
Determinants of viral pathogenesis
Determinants of viral disease

7. Determinants of viral disease: nature of the disease
IS A DISEASE THE OUTCOME OF ALL VIRAL INFECTIONS?
The hallmarks of virus-host interactions
Determinants of viral disease: nature of the disease
type of target tissues (replication sites);
pathways of viral entry;
viral spread to the replication sites;
viral tropism;
cells permissivity to virus replication;
virulence of viral strain.

8. Determinants of viral disease: severity of the disease
IS A DISEASE THE OUTCOME OF ALL VIRAL INFECTIONS?
The hallmarks of virus-host interactions
Determinants of viral disease: severity of the disease
cytopathogenic attitude of the virus;
immunopathology;
initial inoculum of the virus;
compromised host;
host genetic background;
age.

9. Determinants of viral disease: severity of the disease
IS A DISEASE THE OUTCOME OF ALL VIRAL INFECTIONS?
The hallmarks of virus-host interactions
Determinants of viral disease: severity of the disease
The host immune conditions:
competence of the immune system;
previous exposure to the virus (immunity)

10. The process by which viruses cause disease
VIRAL PATHOGENESIS
The process by which viruses cause disease
Viral entry
Viral spread
Tissue invasion
Tropism
Virus shedding and
transmission
The host defense
Disease

11. Viral pathogenesis: time course of typical infection

12. Sites of virus entry into the host

13. Different routes of viral entry into the host

14. Incubation periods of some common viral infections

15. Virus infection and spread into the host
PRIMARY REPLICATION
PENETRATION
LOCALIZED INFECTION influenza, enteric viruses
PRIMARY VIREMIA
TARGET TISSUES Sensistivity and permissivity
SECONDARY REPLICATION
SECONDARY VIREMIA
DISSEMINATE INFECTION exhantema viruses, polio

17. Entry, dissemination and shedding of blood-borne viruses
Infections can be localized, or can spread beyond the initial site of replication (a disseminate infection)
With many organs involved the infection becomes systemic

18. Sites of virus entry in the respiratory tract

19. Enterovirus pathogenesis

20. Rabies pathogenesis

21. Varicella-zoster (VZV) infection and spread
VZV enters via conjunctiva and upper respiratory tract
Replication occurs in regional lymph nodes
Primary viremia via infected T cells
Replication in visceral organs (liver, spleen, etc.)
Secondary viremia and subseqeunt acute infection of skin -”chicken pox” rash
Latency establish in sensory ganglia of PNS
Reactivation results in “shingles”-postherpetic neuralgia

22. Viral pathogenesis is the sum of the effects on the host due to virus replication and the immune response
Direct effects of primary infection by cytolityc viruses
(e.g. virus-induced lysis of neurons in CNS by poliovirus)
Indirect effects of noncytolytic viruses
(e.g. conseguence of the immune response)
CD8+ T cell-mediated (HIV, HBV, Coxackievirus B)
CD4+ T cell-mediated
Th1 (measle, HSV)
Th2 (RSV)
Antibody-mediated (HBV, rubella)
Immunosuppression (HIV, CMV, measle, influenza)

23. Measles virus infection and spread

24. Kinetics of virus replication and immune responses
The kinetics of virus replication and the kinetics of the defensive response both affect the outcome
Slow localized spread
Intermediate spread
Fast disseminate spread

25. General patterns of infection

26. General patterns of infection

27. Acute infection followed by clearance of virus:
productive infection
viremia (circulating virus)
clearance by immune system
example: rhinovirus (common cold)

28. The course of typical acute infection

29. Some persistent viral infections of humans

30. initial productive infection with viremia
Acute infection followed by latent infection and periodic reactivation:
initial productive infection with viremia
viral persistence in non-infectious form
intermittent reactivation with productive infection
example: herpes simplex virus type 1 (HSV-1)

31. HSV-1 latency and reactivation
Productive infection of epithelial cells
Virus infects sensory neurons
Virus travels to sensory ganglion by neuronal retrograde transport
Virus establishes latent infection in sensory ganglion
Limited expression of viral genes, latency associated transcripts (LATs),
viral genome replicates in episomal state
6. Virus may be reactivated by changes in physiological status of the neuron
(neuron damage, immunosuppression, hormonal changes, stress, UV)
7. Changes lead to activation of viral gene expression and productive infection

32. HSV-1 primary infection of a sensory ganglion

33. HSV-1 latency
and reactivation

34. Epstein-Barr virus primary and persistent infection

35. Acute infection followed by chronic infection:
initial productive infection with viremia
virus not cleared completely by immune system
continuous, low-level productive infection
may be "smoldering" infection (productive infection
by small fraction of cells)
example: human immunodeficiency viruses (HIV)

36. HIV initial productive infection of permissive cells viremia
apparent latent infection
evidence for smoldering infection of population of permissive cells
antigenic variants produced during time course of infection:
> 109 new cells infected each day; every possible point mutation occurs between
104 and 105 times per day in an infected individual

37. Slow, chronic infection
seen only with unconventional infectious agents scrapie,
bovine spongiform encephalopathy (mad cow disease)
continuous and slowing increasing production of
infectious agent with time.

38. MECHANISMS OF VIRAL PATHOGENESIS
CELLULAR PATHOGENESIS
HOST IMMUNE RESPONSE
EPIDEMIOLOGY, PREVENTION AND CONTROL

39. MECHANISMS OF VIRAL PATHOGENESIS
CELLULAR PATHOGENESIS
HOST IMMUNE RESPONSE
EPIDEMIOLOGY, PREVENTION AND CONTROL

40. Cellular pathogenesis: patterns of infection
Type Viral production Cell fate
Abortive
Cytolytic death
Persistent
Chronic senescence
Latent
Transforming
DNA viruses immort./transfor.
RNA viruses immort./transfor.

41. MECHANISMS OF CELLULAR PATOGENESIS
Direct effects of cytolityc viruses
Cytopathic effect
Inclusion bodies
Apoptosis
Dysregulation of cell physiology
Indirect effects of non-cytolytic viruses
Host immune response

42. MECHANISMS OF CELLULAR PATOGENESIS
Cytopathic effect(s): Virus(es)
Inibition of host protein synthesis polio, herpes, toga, pox
Host chromosome margination and DNA herpes
degradation
Nuclear shrinking picorna
Proliferation of nuclear membrane herpes
Cell membrane alterations enveloped viruses
Vacuoles in the cytoplasm papova
Syncytia (cell fusion) paramyxo, herpes, HIV
Cell Rounding up and detachment herpes, rabdo, adeno, picorna
Inclusion bodies:
Intranuclear basophils adeno
Virion in the cytoplasm (Negri bodies) rabdo
“Factories” in the cytoplasm (Guarnieri bodies) pox
“Owl eyes” in the nucleus CMV
Perinuclear acidophils reo

43. Cytopathic Effects: an overview
HSV-1

44. Syncitia formation
RSV
Measle virus

45. Inclusion bodies formation
Reovirus replicate in the cytoplasm and generate inclusion bodies containing viral proteins stained by eosin

46. Mechanisms of viral
transformation and
oncogenesis 1 2

47. MECHANISMS OF VIRAL PATHOGENESIS
CELLULAR PATHOGENESIS
HOST IMMUNE RESPONSE
EPIDEMIOLOGY, PREVENTION AND CONTROL

48. HOST DEFENSES AGAINST VIRAL INFECTIONS
Physical barriers
Chemical barriers
Intrinsic cellular defenses
Innate soluble immune response: cytokines, inflammation, fever, complement
Innate cellular immune response: DC, macrophages
Adaptive soluble immune response: antibodies
Adaptive cellular immune response: NK, CTL

50. Integration of intrinsic defense with the innate and adaptive immune response

51. Intrinsic defense
responses

52. Apoptosis as a defense against viral infection

53. PATHOGENESIS OF A VIRAL DISEASE
The kinetics of host defense mechanisms

54. Immune reactions during the response to viral infections that can cause host cell damage and disease
Interferons and lymphokines: fever, headache,malaise.
Delayed-Type Hypersensitivity, Complement fixation, Immunocomplexes: cell damage and local inflammatory responses.
Inflammation due to the cell-mediated response: severe tissue damages in adults.
Immunocomplexes accumulation in the blood and kidney: glomerulonephritis.

55. MECHANISMS OF VIRAL PATHOGENESIS
CELLULAR PATHOGENESIS
HOST IMMUNE RESPONSE
EPIDEMIOLOGY, PREVENTION AND CONTROL

56. EPIDEMIOLOGY OF VIRAL DISEASES
The study of the occurrence, distribution and control of diseases
Prevalence: the proportion or percentage of individuals in the population having a disease.
Incidence: the total number of cases of disease in a population.
Morbidity: incidence of illness in a population.
Mortality: incidence of death in a population.

57. EPIDEMIOLOGY OF VIRAL DISEASES
The study of the occurrence, distribution and control of diseases
Outbreak: the occurrence of a large number of cases of a disease in a new site and in a short period of time (HAV).
Endemic: disease constantly present, usually in low numbers.
Epidemic: the occurrence of a disease in unusually high numbers due to the introduction of new viral strain in a naive population (Influenza).
Pandemic: a worldwide epidemic due to the introduction of a new virus (HIV, SARS, Influenza).

58. EPIDEMIOLOGY OF VIRAL DISEASES
Classification of disease by incidence

59. EPIDEMIOLOGY OF VIRAL DISEASES
The spread of the Asian influenza pandemic of 1957

60. EPIDEMIOLOGY OF VIRAL DISEASES
Recent outbreaks of emerging and reemerging infectious diseases

61. EPIDEMIOLOGY OF VIRAL DISEASES
Mechanisms of viral transmission:
aerosol, infected things, direct contact, sexual contact, transplant,
blood-transfusion, zoonosis.
Factors influencing viral transmission
Environmental persistence of virions;
Viral replication in body fluids
Risk factors
Age, health, immune status, work, travels, life style
Populations characteristics
Percentage of susceptible serum-negative individuals
Geography/Season
Prevention and control
Quarantine, vector elimination, immunization (natural infection, vaccination), antiviral therapy

63. Viral infections are transmitted among hosts in specific ways

64. Acute viral infections with seasonal variation in incidence

65. Effect of humidity on transmission of influenza virus

66. EPIDEMIOLOGY OF VIRAL DISEASES Prevention and control
Quarantine
Public health measures
Directed against the reservoirs (domestic animals,
wild animal, insect, humans)
Directed against transmission (food, water, air)
Education (STDs)
Immunization
Natural infection
Vaccination
Antiviral therapy

67. EPIDEMIOLOGY OF VIRAL DISEASES Prevention and control
Vaccines:
the proven best defense
against viruses
Antiviral drugs:
small molecules that block
virus replication