VIROLOGIA Viral Pathogenesis

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

Views of viral pathogenesis

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

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

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.

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.

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)

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

Viral pathogenesis: time course of typical infection

Sites of virus entry into the host

Different routes of viral entry into the host

Incubation periods of some common viral infections

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

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

Sites of virus entry in the respiratory tract

Enterovirus pathogenesis

Rabies pathogenesis

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

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)

Measles virus infection and spread

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

General patterns of infection

General patterns of infection

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

The course of typical acute infection

Some persistent viral infections of humans

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)

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

HSV-1 primary infection of a sensory ganglion

HSV-1 latency and reactivation

Epstein-Barr virus primary and persistent infection

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)

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

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.

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

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

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.

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

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

Cytopathic Effects: an overview HSV-1

Syncitia formation RSV Measle virus

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

Mechanisms of viral transformation and oncogenesis 1 2

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

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

Integration of intrinsic defense with the innate and adaptive immune response

Intrinsic defense responses

Apoptosis as a defense against viral infection

PATHOGENESIS OF A VIRAL DISEASE The kinetics of host defense mechanisms

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.

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

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.

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).

EPIDEMIOLOGY OF VIRAL DISEASES Classification of disease by incidence

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

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

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

Viral infections are transmitted among hosts in specific ways

Acute viral infections with seasonal variation in incidence

Effect of humidity on transmission of influenza virus

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

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