Mechanics of Viral Infection
Viruses are obligate intracellular parasites that usurp the metabolic processes of the hosts they invade for their own replication purposes.
In brief, viruses must attach to and penetrate susceptible host cells—that is, cells that have appropriate receptors for viral binding and the necessary intracellular machinery for viral replication.
Next, the virus uncoats, a process by which the viral DNA/RNA separates from the viral capsid. The virus then exploits the host's RNA/DNA/protein synthesis machinery.
Viral subunits are then assembled, allowing the progeny viruses to be released, as the host cell disintegrates.
Rev Immunogenet, 2000;2(3):374-86.
Interferon activation and innate immunity
C Le Page 1, P Génin, M G Baines, J Hiscott
1Terry Fox Molecular Oncology Group, Lady Davis Institute for Medical Research, Montreal, Canada.
The interferons are a family of cytokine mediators critically involved in alerting the cellular immune system to viral infection of host cells. Interferons not only exhibit important antiviral effects but also exert a key influence on the quality of the cellular immune responses and amplify antigen presentation to specific T cells. Type I interferon (IFN-alpha and IFN-beta) is secreted by virus-infected cells while type II, immune or gamma interferon (IFN-gamma) is mainly secreted by T cells, natural killer (NK) cells and macrophages. Interferons interact with specific cellular receptors, which promote production of second messengers ultimately leading to expression of antiviral and immune modulatory genes. The IFN genes themselves are regulated by transcriptional and posttranscriptional mechanisms including modulation by a family of interferon regulatory factors (IRFs) synthesised by host cells. IFNs activate macrophages, induce B cells to switch immunoglobulin type, alter T helper response, inhibit cell growth, promote apoptosis and induce an antiviral state in uninfected cells. The therapeutic potential of the IFNs is currently the focus of intense attention in a number of virus-associated diseases, tumours and autoimmune disorders.
Immunogenet牧师,2000;2 (3):374 - 86。
P Genin, M G Baines, J Hiscott
Dr Margaret Hunt
Dr Richard Hunt
University of South Carolina School of Medicine
Interferon response to an acute virus infection
Interferons play an important role in the first line of defense against viral infections. They are part of the non-specific immune system and are induced at an early stage in viral infection – before the specific immune system has had time to respond.
Interferons are made by cells in response to an appropriate stimulus, and are released into the surrounding medium; they then bind to receptors on target cells and induce transcription of approximately 20-30 genes in the target cells, and this results in an anti-viral state in the target cells.
TYPES OF INTERFERON
Type I interferon
Interferon-alpha (leukocyte interferon) is produced by virus-infected leukocytes, etc
Interferon-beta (fibroblast interferon) is produced by virus-infected fibroblasts, or virus-infected epithelial cells, etc
Interferon-a (a family of about 20 related proteins) and interferon-b are particularly potent as antiviral agents. They are not expressed in normal cells, but viral infection of a cell causes interferons to be made and released from the cell (that cell will often eventually die as a result of the infection). The interferon binds to target cells and induces an antiviral state. Both DNA and RNA viruses induce interferon but RNA viruses tend to induce higher levels. Double-stranded RNA produced during viral infection may be an important inducing agent. Other stimuli will also cause these interferons to be made: e.g. exogenous double-stranded RNA, lipopolysaccharide, other components of certain bacteria.
Type II inteferon
Interferon-gamma (immune interferon) is produced by certain activated T-cells and NK cells.
Interferon-gamma is made in response to antigen (including viral antigens) or mitogen stimulation of lymphocytes.
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Effects of interferon
INTERFERON-alpha AND INTERFERON-beta (TYPE I INTERFERONS)
These interferons induce about 20-30 proteins, and the function of many of these is not fully understood. However, three of the proteins that appear to play an important role in the induction of the anti-viral state have been intensively studied. Expression of one of these proteins (2’5’ oligo A synthase) results in activation of the second of these proteins (a ribonuclease) which can break down mRNA, and expression of the third protein (a protein kinase) results in inhibition of the initiation step of protein synthesis. These activities target viral protein synthesis, but also result in inhibition of host protein synthesis. Thus it is important that these proteins are only made and activated when needed.
Interferon treatment induces the synthesis of the inactive form of these proteins in the target cell. Double-stranded RNA is needed for activation of these proteins. It directly activates 2’5’ oligo A synthase and protein kinase R, and indirectly activates ribonuclease L (since this needs 2'5'oligo A, the product of 2’5’ oligo A synthase, for activation). Thus, these potentially toxic pathways are only activated in the interferon-treated cell if double-stranded RNA is made, this will usually only happen if virus infection actually occurs. The activation of these proteins may sometimes result in the death of the cell, but at least the progress of the infection is prevented.
OTHER EFFECTS OF INTERFERONS
The pathway described above is by no means the only way that interferons protect cells against viruses and other pathogens.
All three interferons increase expression of class I MHC molecules and thus promote recognition by cytotoxic T cells. All three interferons can activate NK cells which can then kill virus-infected cells.
Interferon-gamma increases expression of class II MHC molecules on antigen-presenting cells and thus promotes presentation of antigens to helper T cells. Interferon-gamma can also activate the ability of macrophages to resist viral infection (intrinsic antiviral activity) and to kill other cells if they are infected (extrinsic antiviral activity).
Interferons have many other effects on gene expression, not all of which are understood.
THERAPEUTIC USES OF INTERFERONS
Interferons-alpha and -beta have been used to treat various viral infections. One currently approved use for various types of interferon-a is in the treatment of certain cases of acute and chronic hepatitis C and chronic hepatitis B.
Interferon-gamma has been used to treat a variety of disease in which macrophage activation might play an important role in recovery, eg. lepromatous leprosy, leishmaniasis, toxoplasmosis.
Since interferons have anti-proliferative effects, they have also been used to treat certain tumors such as melanoma and Kaposi’s sarcoma.
SIDE EFFECTS OF INTERFERONS
Common side effects of interferons
High levels of interferons can cause kidney, liver, bone marrow and heart toxicity.
干扰素治疗诱导靶细胞中这些蛋白质的无活性形式的合成。这些蛋白质的激活需要双链RNA。它直接激活2’5’oligo A合成酶和蛋白激酶R，间接激活核糖核酸酶L(因为这需要2’5’oligo A合成酶的产物2’5’oligo A才能激活)。因此，只有在干扰素处理的细胞中产生双链RNA时，这些潜在的毒性通路才会被激活，这通常只会在病毒感染实际发生时发生。这些蛋白质的活化有时会导致细胞死亡，但至少可以阻止感染的进程。