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Host Defense Against Viruses

Date: 10. January 2018

Defence Mechanism of Host

  • Physical barriers
  • Chemical barriers
  • Intrinsic cellular defences
  • 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

Specific vs Nonspecific defences: Host defenses against viruses fall into two major categories: (1) nonspecific, of which the most important are interferons and natural killer cells; and (2) specific, including both humoral and cell-mediated immunity. Interferons are an early, first line defense, whereas humoral immunity and cell-mediated immunity are effective only later because it takes several days to induce the humoral and cell-mediated arms of the immune response.

Evasion of Host Defenses: Viruses have several ways by which they evade our host defenses. These processes are often called immune evasion. Some viruses encode the receptors for various mediators of immunity such as interleukin-1 (IL-1) and tumor necrosis factor (TNF). For example, vaccinia virus encodes a protein that binds to IL-1, and fibroma virus encodes a protein that binds to TNF. When released from virus-infected cells, these proteins bind to the immune mediators and block their ability to interact with receptors on their intended targets, our immune cells that mediate host defenses against the viral infection. By reducing our host defenses, the virulence of the virus is enhanced. These virus-encoded proteins that block host immune mediators are often called cytokine decoys.

In addition, some viruses (e.g., human immunodeficiency virus [HIV] and herpesviruses, such as herpes simplex virus and cytomegalovirus [CMV]) can reduce the expression of class I MHC (major histocompatibility complex) proteins, thereby reducing the ability of cytotoxic T cells to kill the virus-infected cells, and others (e.g., herpes simplex virus) inhibit complement. Several viruses (HIV, Epstein–Barr virus, and adenovirus) synthesize RNAs that block the phosphorylation of an initiation factor (eIF-2), which reduces the ability of interferon to block viral replication. CMV encodes a microRNA that binds to the mRNA of a cell surface ligand for natural killer cells. Binding of the microRNA prevents synthesis of the ligand, which prevents killing of the CMV-infected cells by the natural killer cells. Measles virus blocks synthesis of IL-12, thereby reducing an effective Th-1 response. Ebola virus synthesizes two proteins, one of which blocks the induction of interferon, whereas the other blocks its action. Collectively, these viral virulence factors are called virokines.

A third important way by which viruses evade our host defenses is by having multiple antigenic types (also known as multiple serotypes). The clinical importance of a virus having multiple serotypes is that a patient can be infected with one serotype, recover, and have antibodies that protect from infection by that serotype in the future; however, that person can be infected by another serotype of that virus. The classic example of a virus with multiple serotypes is rhinovirus, which has more than 100 serotypes. This is the reason why the “common cold” caused by rhinoviruses is so common.


Interferons
Alpha and beta interferons are a group of proteins produced by human cells after viral infection (or after exposure to other inducers).

Function of interferons: They inhibit the growth of viruses by blocking the synthesis of viral proteins. They do so by two main mechanisms: One is a ribonuclease that degrades mRNA, and the other is a protein kinase that inhibits protein synthesis.

Types of interferons: Interferons are divided into three groups based on the cell of origin, namely, leukocyte, fibroblast, and lymphocyte. They are also known as alpha, beta, and gamma interferons, respectively. Alpha and beta interferons are induced by viruses, whereas gamma (T cell, immune) interferon is induced by antigens and is one of the effectors of cell-mediated immunity. The following discussion of alpha and beta interferons focuses on the induction and action of their antiviral effect.

Induction of α & β interferons: The strong inducers of these interferons are viruses and double-stranded RNAs. Induction is not specific for a particular virus; many DNA and RNA viruses are competent inducers, although they differ in effectiveness. The double-stranded RNA poly (rI-rC) is one of the strongest inducers and was under consideration as an antiviral agent, but toxic side effects prevented its clinical use. The weak inducers of microbiologic interest include a variety of intracellular bacteria and protozoa, as well as certain bacterial substances such as endotoxin.

Action of Alpha & Beta Interferons: Interferons inhibit the intracellular replication of a wide variety of DNA and RNA viruses but have little effect on the metabolism of normal cells. The selectivity arises from the presence of double-stranded RNA in virus-infected cells, which is not present in uninfected cells. Interferons have no effect on extracellular virus particles. Interferons act by binding to a receptor on the cell surface that signals the cell to synthesize three proteins, thereby inducing the “antiviral state”.

Alpha interferon has been approved for use in patients with condyloma acuminatum and chronic active hepatitis caused by hepatitis B and C viruses. Beta interferon is used in the treatment of multiple sclerosis. Gamma interferon reduces recurrent infections in patients with chronic granulomatous disease. Interferons are also used clinically in patients with cancers such as Kaposi’s sarcoma and hairy cell leukemia.

 

Specialized Host Defences
Natural killer cells: Natural killer (NK) cells are an important part of the innate defenses against virus infected cells. They are called “natural” killer cells because they are active without the necessity of being exposed to the virus previously and because they are not specific for any virus. NK cells are a type of T lymphocyte but do not have an antigen receptor. They recognize virus-infected cells by the absence of class I MHC (major histocompatibility complex) proteins on the surface of the virus-infected cell. They kill virus-infected cells by secreting perforins and granzymes, which cause apoptosis of the infected cells.

Phagocytosis: Macrophages, particularly fixed macrophages of the reticuloendothelial system and alveolar macrophages, are the important cell types in limiting virus infection. In contrast, polymorphonuclear leukocytes are the predominant cellular defense in bacterial infection.

Alpha defencins & APOBEC3G: α-Defensins α-Defensins are a family of positively charged peptides with antiviral activity. They interfere with human immunodeficiency virus (HIV) binding to the CXCR4 receptor and block entry of the virus into the cell. The production of α-defensins may explain why some HIV infected individuals are long-term “non progressors.”

APOBEC3G is an important member of the innate host defenses against retroviral infection, especially against HIV. APOBEC3G is an enzyme that causes hypermutation in retroviral DNA by deaminating cytosines in both mRNA and retroviral DNA, thereby inactivating these molecules and reducing infectivity. HIV defends itself against this innate host defense by producing Vif (viral infectivity protein), which counteracts APOBEC3G, thereby preventing hypermutation from occurring.

 

Factors that Modify Host Defences
Fever & mucociliary clearance: Elevated body temperature may play a role in host defenses, but its importance is uncertain. Fever may act in two ways: (1) The higher body temperature may directly inactivate the virus particles, particularly enveloped viruses, which are more heat sensitive than nonenveloped viruses; and (2) replication of some viruses is reduced at higher temperatures; therefore, fever may inhibit replication.

The mucociliary clearance mechanism of the respiratory tract may protect the host. Its damage (e.g., from smoking) results in an increased frequency of viral respiratory tract infections, especially influenza.

Circumcision & age: There is evidence that circumcision prevents infection by three sexually transmitted viruses: HIV, human papillomavirus (HPV), and herpes simplex virus type 2 (HSV2).

Age is a significant variable in the outcome of viral infections. In general, infections are more severe in neonates and in the elderly than in older children and young adults. For example, influenza is typically more severe in older people than in younger adults, and herpes simplex virus infections are more severe in neonates than in adults.

Corticosteroid levels & Malnutrition: Increased corticosteroid levels predispose to more severe infections with some viruses, such as varicella-zoster virus; the use of topical cortisone in herpetic keratitis can exacerbate eye damage. It is not clear how these effects are mediated, because corticosteroids can cause a variety of pertinent effects, namely, lysis of lymphocytes, decreased recruitment of monocytes, inhibition of interferon production, and stabilization of lysosomes.   Malnutrition leads to more severe viral infections (e.g., there is a much higher death rate from measles in developing countries than in developed ones). Poor nutrition causes decreased immunoglobulin production and phagocyte activity as well as reduced skin and mucous membrane integrity.

 

Specific Defences
There is evidence for natural resistance to some viruses in certain species, which is probably based on the absence of receptors on the cells of the resistant species. For example, some people are resistant to HIV infection because they lack one of the chemokine receptors that mediate entry of the virus into the cell. However, by far the most important type of defense is acquired immunity, either actively acquired by exposure to the virus or passively acquired by the transfer of immune serum. Active immunity can be elicited by contracting the actual disease, by having an inapparent infection, or by being vaccinated.

Active immunity: Active immunity, in the form of both antibodies and cytotoxic T cells, is very important in the prevention of viral diseases. The first exposure to a virus, whether it causes an inapparent infection or symptomatic disease, stimulates the production of antibodies and the activation of cytotoxic T cells. The role that antibodies and cytotoxic T cells play in the recovery from this first infection is uncertain and may vary from virus to virus, but it is clear that they play an essential role in protecting against disease when exposed to the same virus at some time in the future. The duration of protection varies; disseminated viral infections such as measles and mumps confer lifelong immunity against recurrences, but localized infections such as the common cold usually impart only a brief immunity of several months. IgA confers protection against viruses that enter through the respiratory and gastrointestinal mucosa, and IgM and IgG protect against viruses that enter or are spread through the blood. The lifelong protection against systemic viral infections such as the childhood diseases measles, mumps, rubella, and chickenpox (varicella) is a function of the anamnestic (secondary) response of IgG. For certain respiratory viruses such as parainfluenza and respiratory syncytial viruses, the IgA titer in respiratory secretions correlates with protection, whereas the IgG titer does not.

Passive immunity: Transfer of human serum containing the appropriate antibodies provides prompt short-term immunity for individuals exposed to certain viruses. The term passive refers to the administration of preformed antibodies. Two types of immune globulin preparations are used for this purpose. One has a high titer of antibody against a specific virus, and the other is a pooled sample from plasma donors that contains a heterogeneous mixture of antibodies with lower titers. The immune globulins are prepared by alcohol fractionation, which removes any viruses in the serum. The three most frequently used high-titer preparations are used after exposure to hepatitis B, rabies, and varicella-zoster viruses. Low-titer immune globulin is used mainly to prevent hepatitis A in people traveling to areas where this infection is hyperendemic. Two specialized examples of passive immunity include the transfer of IgG from mother to fetus across the placenta and the transfer of IgA from mother to newborn in colostrum.

Herd immunity: “Herd immunity” (also known as “community immunity”) is the protection of an individual from infection by virtue of the other members of the population (the herd) being incapable of transmitting the virus to that individual. Herd immunity can be achieved by immunizing a population with a vaccine that interrupts transmission, such as the live, attenuated polio vaccine, but not with a vaccine that does not interrupt transmission, such as the killed polio vaccine (even though it protects the immunized individual against disease). Note that herd immunity occurs with the live polio vaccine primarily because it induces secretory IgA in the gut, which inhibits infection by virulent virus, thereby preventing its transmission to others. In addition, the live virus in the vaccine can replicate in the immunized person and spread to other members of the population, thereby increasing the number of people protected. However, the important feature as far as herd immunity is concerned is the induction of IgA, which prevents transmission.

Afridi, Maham
  • Academics: MS 
  • Specialization: Medical Genetics
  • Current: Research Scholar 
  • University: Quaid-e-Azam University
  • Location: Islamabad, Pakistan
  •   
  • Course: Biochemistry 
  • Clinical Years: 2
  • Teaching Years: 1

Ms. Maham Afridi joined Quaid-e-Azam University as a research scholar in 2017, Before that she served in Core lab of National University Science and Technology Islamabad. She also served in Armed Forces Institute of Pathology in their department of Immunology, where her major roles were detection of antibodies and other immunology tests, genetic counselling etc.

Ms. Maham has full command on Genotyping of human genes, Risk assessment of genetic disorders, Diagnostic tests (TyphiDot, ELISA, Allergy tests), HPLC, PCR, Immunohistochemistry, Cell and tissue staining, Bacterial culturing, Cell culturing, DNA extraction, SDS PAGE, Gel Electrophoresis, Spectrophotometry.

Ms. Maham was awarded by Pak China Business forum in Recognition for poster presentation.

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