PHARMACEUTICAL MICROBIOLOGY -1 PHT 226 Dr. Rasheeda HamidAbdalla Assistant Professor E-mail rasheedahamed12@hotmail.com

Viral Pathogenesis

OBJECTIVES Viral Pathogenesis & Viral Infections Factors Involved in Viral Pathogenesis Viral pathogenesis at the cellular level Routes of Entry and Dissemination to Secondary sites Typical secondary sites of localization Primary and Secondary Infection Cell Tropism Factors Involved in Termination of The Acute Infection Viral Clearance or Persistence

Viral Pathogenesis It is the process by which a viral infection leads to disease. The consequences of viral infections depend on the interplay between a number of viral and host factors. Viruses may persist for a long time in the host in one of the following forms: -Chronic infections -Latent infections -or Slow infections:

Chronic Infections They usually develop from acute infections and can last for days to months to a lifetime. Recovery from this infection is rare. People may be able to transmit the germ to others. Serious signs may not appear until as long as 20 years after the infection began. For example: hepatitis C, which affects the liver is a chronic viral infection.

Latent Infection virus is present in the body, but it remains dormant, not causing any overt symptoms. People can pass the virus on to others. Latent infections can also be activated, causing symptoms and illness to emerge again. E.g: latent infection is Herpes simplex, which periodically flares up to cause cold sores before going dormant again.

Slow infections- These diseases have a prolonged incubation period (which can be months or years), and a progressive clinical course. e.g: Human immunodeficiency virus

Viral Virulence The ability of a virus to cause disease in an infected host A virulent strain causes significant disease An avirulent or attenuated strain causes no or reduced disease Virulence depends on Dose Virus strain (genetics) Inoculation route - portal of entry Host factors - eg. Age SV in adult neurons goes persistent but is lytic in young

Viral genes that affect virulence may Affect the ability of the virus to replicate Enable the virus to spread within host or between hosts Defeat host defense mechanisms Produce products that are directly toxic

Viral genes that affect virulence

Factors Involved in Viral Pathogenesis Effects of viral infection on cells (Cellular Pathogenesis) Entry into the Host Course of Infection (Primary Replication, Systemic Spread, Secondary Replication) Cell/Tissue Tropism Cell/Tissue Damage Host Immune Response Virus Clearance or Persistence

Viral pathogenesis at the cellular level Cells show variety of different responses to viral infection depending on the -Cell type -Virus. Many viral infections cause no apparent morphologic or functional changes in the cell When changes do occur , several responses can be recognized : 1-Cell death A cell can be directly killed by the virus. in most cases this is due to the inhibition of synthesis of cellular DNA , RNA and protein. -e.g., adenovirus and poliovirus.

e.g. herpesviruses& paramyxoviruses 4-Cytopathic effect ( CPE) : 2-Transformation Some viruses can transform normal cells into malignant cells. Transformation: Is an irreversible genetic process caused by the integration of viral DNA into the host’s DNA. 3-Cell fusion : Infection of cells with certain viruses causes the cells to fuse producing giant multinucleate cells. e.g. herpesviruses& paramyxoviruses 4-Cytopathic effect ( CPE) : CPE is a catch-all term that refers to any visible changes in appearance of an infected cell

Primary and Secondary Infection Some viruses remain localized and cause disease at the primary site of infection Viruses can disseminated through out the body ,and infect cells at secondary sites characteristic for each specific virus type , thus causing the disease typically associated with that species . The presence of virus in the blood is termed viremia

Routes of Entry and Dissemination to Secondary sites Common routes by which viruses enter the body are essentially the same as for bacterial infections through: -Skin - Respiratory tract - Gastrointestinal tract - Urogenital tract

Routes of Entry 1-skin Introduction through the skin usually a break in the surface of the skin from an abrasion or cut , or by inoculation of the agent by an insect , animal bite , or needle 2-Respiratory tract: those viruses that enter the body via the respiratory tract and remain localized produce symptoms that primarily in the respiratory passages causing common cold (Rhinoviruses) -other inhaled viruses spread systemically after the primary infection , and produce a characteristic disease due to the infection of cells at secondary sites for example measles and chicken pox.

Routes of Entry (cont’d) 3-Gastrointestinal tract Viruses infecting via the GI tract follow characteristic “fecal-oral” transmission pattern ,those viruses that remain localized in the cells of the GI tract may cause symptoms such as diarrheal disease, for example ,enteric adenoviruses or rotaviruses Many viral infections that remain localized in the GI tract are asymptomatic Some viruses that infect via the GI tract enter the lymphatic system and the blood, then can cause symptomatic disease unrelated to the GI for example ,in the liver (hepatitis A) or the CNS (poliovirus)

4-Genital tract Viruses infecting by this route are transmitted primarily during sexual contact . Spread of the virus can affect non-genital tissues, such as CNS ,where herpes virus may cause meningitis or encephalitis .

Typical secondary sites of localization A-skin: Viremia can result in a rash due to infection of cells in the epithelium .This type of rash contains infectious virus. B-Central Nervous system The most common route by which viruses infect the CNS is one whereby virus-carried by the blood-infects endothelial cells of the cerebral vessels , and ultimately is released into the brain itself

Alternatively ,virus can be released from endothelial cells into the cerebrospinal fluid at the choroid plexus . A less common ,but important route of viral spread is the axonal migration of virus from peripheral nerve endings directly into the CNS (Rabies virus)

C-fetus -The fetus represents a special ,but very important ,site for secondary localization of virus infections. -virus from the maternal circulation infects cells of the placenta ,thereby gaining access to the fetal circulation and to all of the tissues of the developing fetus - Neonatal infection can also occur during birth when the fetus comes in contact with infected genital secretions of the mother.

Cell Tropism Viral affinity for specific body tissues (tropism) is determined by Cell receptors for virus. Cell transcription factors that recognize viral promoters and enhancer sequences. Ability of the cell to support virus replication. Physical barriers. Local temperature, pH, and oxygen tension enzymes and non-specific factors in body secretions. Digestive enzymes and bile in the gastrointestinal tract that may inactivate some viruses.

Cell Damage Viruses may replicate widely throughout the body without any disease symptoms if they do not cause significant cell damage or death. Retroviruses do not generally cause cell death, being released from the cell by budding rather than by cell lysis, and cause persistent infections. Conversely, Picornaviruses cause lysis and death of the cells in which they replicate, leading to fever and increased mucus secretion .in the case of Rhinoviruses, paralysis or death (usually due to respiratory failure) for Poliovirus.

Factors Involved in Termination of The Acute Infection In a typical uncomplicated ,acute infection ,virus is totally eliminated from the host in two to three weeks .This outcome is primarily a function of the host’s immune system , with involvement of both -cell-mediated and - humoral responses . The relative importance of these two responses depends upon the virus and the nature of the disease

A- Cell mediated responses The earliest immune system responses to virus infection are a generalized inflammatory response ,accompanied by nonspecific killing of infected cells by natural killer cells . This latter activity is enhanced by interferon and other cytokines and begins well before the virus –specific immune response. Later, cytolysis by virus specific cytotoxic T lymphocytes that recognize virus peptides displayed on the cell surface ,also eliminates infected cells These cellular responses are especially significant in that they help to limit the spread of the infection by killing infected cells before they have released progeny virus

B-Humoral response Circulating antibodies may be directed against any of the virus protein Humoral antibodies also take part in killing infected cells by two mechanism 1-antibody –dependent , cell –mediated cytotoxicity 2-complement –mediated lysis

Viral Clearance or Persistence The majority of viral infections are cleared but certain viruses may cause persistent infections. There are 2 types of chronic persistent infections. True Latency - the virus remains completely latent following primary infection e.g. HSV, VZV. Its genome may be integrated into the cellular genome or exists as episomes. Persistence - the virus replicates continuously in the body at a very low level e.g. HIV, HBV, CMV, EBV.

Mechanisms of Viral Persistence Antigenic variation Immune tolerance, causing a reduced response to an antigen, may be due to genetic factors, pre-natal infection, molecular mimicry Restricted gene expression Down-regulation of MHC class I expression, resulting in lack of recognition of infected cells e.g. Adenoviruses Down-regulation of accessory molecules involved in immune recognition e.g. by EBV. Infection of immune privilege sites within the body e.g. HSV in sensory ganglia in the CNS Direct infection of the cells of the immune system itself e.g. Herpes viruses, Retroviruses (HIV) - often resulting in immunosuppression

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