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.

　

https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/viral-neuraminidase

　

　

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。

干扰素激活和先天免疫
P Genin, M G Baines, J Hiscott

特里·福克斯分子肿瘤学小组，戴维斯夫人医学研究所，蒙特利尔，加拿大。

干扰素是一组细胞因子介质，在宿主细胞的病毒感染时，对细胞免疫系统发出警报。干扰素不仅表现出重要的抗病毒作用，而且对细胞免疫反应的质量发挥关键影响，并放大抗原递呈到特异性T细胞。I型干扰素(IFN-alpha和IFN-beta)是由病毒感染的细胞分泌的，而II型、免疫或伽马干扰素(IFN-gamma)主要由T细胞、NK细胞和巨噬细胞分泌。干扰素与特定的细胞受体相互作用，促进第二信使的产生，最终导致抗病毒和免疫调节基因的表达。IFN基因本身受转录和转录后机制的调控，包括由宿主细胞合成的干扰素调节因子(IRFs)家族的调控。ifn可激活巨噬细胞，诱导B细胞改变免疫球蛋白类型，改变T辅助反应，抑制细胞生长，促进细胞凋亡，诱导未感染细胞进入抗病毒状态。ifn的治疗潜力目前是许多病毒相关疾病、肿瘤和自身免疫性疾病密切关注的焦点。

　

https://pubmed.ncbi.nlm.nih.gov/11256746/

　

INTERFERON

Dr Margaret Hunt

Dr Richard Hunt

University of South Carolina School of Medicine
Columbia SC
USA

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.



interferon.jpg (72628 bytes)
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

fever

malaise

fatigue

muscle pains

High levels of interferons can cause kidney, liver, bone marrow and heart toxicity.

　

　

干扰素



玛格丽特·亨特博士



理查德·亨特博士



南卡罗来纳大学医学院

哥伦比亚SC

美国



干扰素对急性病毒感染的反应

干扰素在抵御病毒感染的第一道防线上起着重要作用。它们是非特异性免疫系统的一部分，在病毒感染的早期阶段被诱导——在特异性免疫系统有时间做出反应之前。



干扰素由细胞根据适当的刺激产生，并被释放到周围的介质中;然后它们与靶细胞上的受体结合，在靶细胞中诱导大约20-30个基因的转录，从而在靶细胞中产生抗病毒状态。



类型的干扰素



I型干扰素



干扰素(白细胞干扰素)是由病毒感染的白细胞等产生的



干扰素(成纤维细胞干扰素)是由病毒感染的成纤维细胞或病毒感染的上皮细胞等产生的



干扰素-a(大约20种相关蛋白的家族)和干扰素-b是特别有效的抗病毒药物。它们在正常细胞中不表达，但是病毒感染细胞会产生干扰素并从细胞中释放出来(通常细胞最终会因为感染而死亡)。干扰素与靶细胞结合，诱导抗病毒状态。DNA和RNA病毒都能诱导干扰素，但RNA病毒倾向于诱导更高水平的干扰素。病毒感染过程中产生的双链RNA可能是一种重要的诱导因子。其他刺激也会产生这些干扰素:例如外源性双链RNA、脂多糖、某些细菌的其他成分。



II型inteferon



干扰素(免疫干扰素)是由某些激活的t细胞和NK细胞产生的。



干扰素是在抗原(包括病毒抗原)或淋巴细胞有丝分裂原刺激的反应中产生的。



interferon.jpg(72628字节)

干扰素的作用

干扰素和干扰素(I型干扰素)



这些干扰素诱导大约20-30种蛋白质，其中许多蛋白质的功能尚不完全清楚。然而，其中三种似乎在诱导抗病毒状态中发挥重要作用的蛋白质已被深入研究。其中一种蛋白(2’5’oligo A合成酶)的表达导致第二种蛋白(一种核糖核酸酶)的激活，该蛋白可以分解mRNA，第三种蛋白(一种蛋白激酶)的表达抑制蛋白质合成的起始步骤。这些活性作用于病毒蛋白合成，但也会抑制宿主蛋白的合成。因此，这些蛋白质只在需要的时候被制造和激活是很重要的。



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。



干扰素的其他影响



上述途径绝不是干扰素保护细胞免受病毒和其他病原体侵袭的唯一途径。



这三种干扰素都能增加I类MHC分子的表达，从而促进细胞毒性T细胞的识别。这三种干扰素都可以激活NK细胞，然后杀伤病毒感染的细胞。



干扰素增加了抗原呈递细胞上II类MHC分子的表达，从而促进抗原呈递到辅助T细胞。干扰素还可以激活巨噬细胞抵抗病毒感染的能力(内在抗病毒活性)和杀死其他被感染细胞的能力(外在抗病毒活性)。



干扰素对基因表达还有许多其他的影响，并不是所有的都能被理解。



干扰素的治疗用途



干扰素和已被用于治疗各种病毒感染。目前批准的用于治疗急性和慢性丙型肝炎和慢性乙型肝炎的各种类型的干扰素a的应用。



干扰素已被用于治疗多种疾病，其中巨噬细胞的激活可能在恢复中发挥重要作用。麻风病，利什曼病，弓形虫病。



由于干扰素具有抗增殖作用，它们也被用于治疗某些肿瘤，如黑素瘤和卡波西肉瘤。



干扰素的副作用



干扰素的常见副作用



发热



不适



乏力



肌肉疼痛



高水平的干扰素会导致肾脏、肝脏和骨质疏松

　

https://www.microbiologybook.org/mhunt/interferon.htm