INTERFERONS

Introduction When a virus first enters a susceptible host, that organism is vulnerable to potentially catastrophic damage from the virus’s uncontrolled replication and consequent damage to host tissues and functions. There are a variety of defense mechanisms in cellular organisms, the purpose of which is to slow down and ultimately to eliminate the virus, or other pathogens, from the system.

Host Defense Mechanisms Cells have evolved many mechanisms to defend themselves against infection with viruses and cellular microbes. Prokaryotic cells produce restriction endonucleases to degrade foreign DNA, including that of phages. The cells modify their own DNA so that it is unaffected by the restriction enzymes.

Host Defense Mechanisms The cells of vertebrate animals respond to the presence of dsRNA, which is produced during infection with many viruses by different mechanisms Innate immunity which includes synthesizing cytokines, including interferons, interleukins and tumour necrosis factor These proteins can trigger a range of anti-viral defenses. Adaptive immunity which includes antibodies production

Anti-Viral Immunity in Vertebrates Components of innate immunity that might be encountered after cells have become infected are interferons and natural killer (NK) cells.

Discovery of Interferons It was discovered that allantoic fluid obtained from a chicken embryo infected with influenza virus would prevent the subsequent infection of uninfected chick embryo. Isaacs and Lindenmann reported in 1957 that influenza virus-infected chick cells produced a secreted factor Virus-infected cells secrete a group of glycoproteins that inhibit virus replication, most effectively in the species it was produced and that it is non-specific with respect to the types of viruses it can inhibit.

Interferons (IFNs) Interferons are proteins synthesized and secreted by cells in response to virus infection. They are glycoproteins with molecular weight of 16,000 to 45,000. A potent trigger for interferon production is dsRNA, which is produced, not only by dsRNA viruses, but also by ssRNA viruses as they replicate. The roles of interferons are to protect adjacent cells from infection and to activate T cell-mediated immunity. There are a number of types of interferon that are produced by most cell types when they become infected with viruses. Interferons are small proteins released by macrophages, lymphocytes, and tissue cells infected with a virus

Interferons After secretion, the interferon molecules diffuse to nearby cells, where they can trigger various anti-viral activities by binding to interferon receptors Not all viruses are equally susceptible to interferons (IFNs), adenoviruses are rather resistant, as are poxviruses, whereas orthomyxoviruses and rhabdoviruses are among the most susceptible. any of a group of DNA viruses first discovered in adenoid tissue, most of which cause respiratory diseases. Orthomyxoviruses:  Influenza virus A, Influenza virus B, Influenza virus C

Interferons released from virus-infected cells bind to interferon receptors on other cells. This interaction induces processes that, if the cells become infected, either block virus replication or kill the infected cells

Types of Interferons IFN-α IFN-β IFN-γ Produced by leukocytes (B cells, macrophages) & virus infected cells. Attract and stimulate Natural killer (NK) cells and give viral resistance IFN-β Produced by fibroblasts, epithelial cells and macrophages. Slow inflammation in damaged area IFN-γ Produced by T-lymphocytes and NK cells. Stimulate macrophage activity NK cells are a type of cytotoxic lymphocyte critical to the innate immune system

Mechanism of Action of IFN on Viral Replication: IFNs act at the cellular level, they induce antiviral state within the cell:

Mechanism of Action of IFN on Viral Replication 2'-5'-oligoadenylates

Viral Countermeasures Against Interferons Many viruses produce proteins that inhibit either the production of interferons or their activities. The NS1 protein of influenza A virus and the NS3-4A protein of hepatitis C virus block pathways involved in interferon production. Some viruses, such as poliovirus, prevent the synthesis of interferons as a result of a general inhibition of cell gene expression The presence of HIV particles in the blood alters the expression of a number of molecules on the surface of NK cells. This reduces the efficiency of NK cell activities, including the ability to kill virus-infected cells and to secrete γ-interferon.

VIRAL PATHOGENESIS

Important Events in Pathogenesis Viral pathogenesis is the process by which a viral infection leads to disease The virus must: Invade the host (enough no., virulence factors). Establish a bridgehead by replicating in susceptible cells at the site of inoculation. Overcome the local defenses, e.g., lymphocytes, macrophages, and interferon. Spread from the site of inoculation. Undergo further replication in its target area. Exit from the host in numbers large enough to infect other hosts.

Invasion Routes Entry through skin (via abrasions, inoculation, insect or animal bite) e.g., Papillomaviruses (warts), Poxviruses (smallpox), Herpes simplex viruses (herpetic lesions), Hepadnavirus (hepatitis B), HIV (AIDS), Arboviruses (tropical fever), Lyssavirus (rabies). Entry via respiratory tract e.g., Orthomyxoviruses (influenza), Paramyxoviruses (measles, mumps), Rhinoviruses (common cold), Varicella-Zoster virus (chickenpox). Entry via gastrointestinal tract e.g., Poliovirus (poliomyelitis), Rotavirus (gastroenteritis). Entry via conjunctiva e.g., Adenovirus type 8 (keratoconjunctivitis). Poliomyelitis: شلل الاطفال

Invasion Routes Entry via genital tract e.g., Lentivirus (HIV); (AIDS), Hepadnavirus (hepatitis B), Herpes simplex (herpetic lesions of cervix), Papillomavirus (warts on cervix). Transplants (bone marrow & kidney). e.g., Herpesvirus Blood transfusion and blood products (Hepatitis B, C and AIDS). Surgical treatment. Spread from mother to fetus e.g., rubella

Transmission Routes of Viruses

Incubation Period Short Less than a week e.g., common cold, influenza Medium 7-21 days e.g., measles, rubella Long Weeks to months e.g., hepatitis A (2-6 weeks), hepatitis B (6-20 weeks) Very long Years e.g., Prions, HIV

Types of Infections Acute non-persistent infections, e.g., rubella, enteroviruses. Persistent infections with acute onset: due to latency resulting from persistence in the host of viral DNA. Viral DNA may be integrated into the host cell genome. Chronic infection: infective virus is continually being produced, with or without integration of viral DNA into the host cells. e.g., Hepatitis B virus. Insidious (gradual) infections with fatal outcomes, e.g., slow virus infections, lymphocytic choriomeningitis (an arenavirus infection of mice). Carrier state.

Resistance to Infection General factors (non-specific) in resistance Mechanical and chemical barriers Skin, sweat fatty acids Stomach acidity. Epithelial cilia prevent infection of the respiratory tract. Hair in nostrils. Lysozyme in tears. Mucus membranes trap microorganisms. Complement. Interferons. Cough reflex. Proteolytic enzymes in small intestine. Low pH of vagina.

Resistance to Infection Fever Temperature above 37oC may inhibit the replication of many viruses. Age Very young and elderly people are more susceptible to infection. Nutritional status Poor nutrition may increase the severity of virus infection. Hormones Treatment with steroids increases the severity of herpes simplex infection. Pregnancy increases the severity of viral hepatitis, probably due to hormonal influence.

Resistance to Infection Genetic factors Species resistance Host range of many viruses are restricted due to lack of receptors, e.g., Poliovirus receptors are present only on cells of human and other primates.

The Immune Response to Viral Infection Immune system has the ability to distinguish between self and nonself molecules. During second exposure to the virus, the body is able to defend itself much better than the first exposure due to developed memory. Viruses could be inactivated by specific antibodies, which are produced by B-lymphocytes. Cytotoxic T-cells kill virus-infected cells. During early virus infection, interferon suppresses virus replication.

The Immune Response to Viral Infection

The Immune Response to Viral Infection Immunocompetent Lymphocytes are exposed to foreign antigen, specific receptors receive the antigen, then lymphocytes undergo proliferation and differentiation producing clones of cells with the same surface receptors T lymphocytes are activated producing cytokines which activate other cells including B lymphocytes which produce specific antibodies, foreign antigen is eliminated by active cytotoxic T cells or by the secreted antibodies