Human viruses and viral diseases

Course: Virology

Lecturer: Dr. Weam Saad
Lecture: Human Viral Diseases
Human Viral Diseases
There are many examples of common human diseases caused by viruses include the common cold, influenza, chickenpox, and cold sores. Many serious diseases such as Ebola virus disease, AIDS, avian influenza, and SARS are caused by viruses. These viruses have different ability to cause disease due to different virulence.
To produce disease, viruses must enter a host, come in contact with susceptible cells, replicate, and produce cell injury. The steps involved in viral pathogenesis are the following:
Viral entry into the host and Primary viral replication.
Viral spread.
Cellular injury.
Host immune response.
Viral clearance or establishment of persistent infection.
Viral shedding.

Entry and Primary replication:

The virus must first enter the body and attach to the cells of one of the body surfaces e.g. skin, respiratory tract, gastrointestinal tract, urogenital tract, or conjunctiva. Most viruses enter through the mucosa of the respiratory or gastrointestinal tract. Other blood borne viruses are introduced directly into the bloodstream by needles (hepatitis B, human immunodefciency virus [HIV]), by blood transfusions, or by insect vectors (arboviruses).
Some Viruses usually replicate at the primary site of entry e.g. influenza viruses (respiratory infections) and noroviruses (gastrointestinal infections), then produce disease at the portal of entry and do not needsystemic spread, they spread locally in the epithelial surfaces.

Viral Spread and Cell Tropism (cellular response and injury):

Many viruses produce disease at their sites of entry (eg, enteroviruses, which enter through the gastrointestinal tract). After primary replication at the site of entry, these viruses then spread within the host. Mechanisms of viral spread are different, but the most common route is via the bloodstream or lymphatic system. The presence of virus in the blood is called viremia.
Virions may be free in the plasma (eg, enteroviruses, togaviruses) or associated with particular cell types (eg, measles virus). The viremic phase is short in many viral infections. In some cases, neuronal spread is involved e.g. rabies virus reaches the brain to cause disease and herpes simplex virus moves to the ganglia to initiate latent infections.
The tropism (growing and movement) determined by viral specification for cells and organs to produce systemic illness during a viral infection. For example, hepatitis B virus has a tropism for liver hepatocytes, and hepatitis is the disease caused by the virus. This specification is due to specific cell surface receptors for that virus, virus capsid or envelope can specifically attach and initiate infection. Some cells have activating proteolytic enzymes that activate the cleavage of viral proteins in the capsid and envelope.
Cell injury and Clinical illness:
Viral diseases development occurs due to the destruction of virus-infected cells in the target tissues and physiologic alterations produced in the host due to injury. Some tissues, such as intestinal epithelium, can rapidly regenerate and control the damage better than other tissues such as the brain. Some physiologic effects may result like loss functions of cells, such as loss of hormone production. A few human viruses can infect the fetus inside uterus and may cause serious damage, leading to fetal death or congenital defects (e.g. measles).
The symptoms and clinical illness associated with many viral infections,such as malaise and anorexia, may result from host responsefunctions such as cytokine production. Clinical illness is an indicator of viral infection; but unapparent viral infections are very common and do not show symptoms.
Host immune response:
Nonspecific host defense mechanisms are usually elicited or start very soon after viral infection. The innate immune responses against viruses represented by the induction of Interferons (IFNs) and many other cytokines to inhibit viral growth during the time to start specific humoral and cell-mediated immunity. Both humoral and cellular immune responses are involved in control of viral infections. Viruses induce a tissue response different from the response to pathogenic bacteria.
IFN-α and IFN-β prevent the reproduction and replication of virus RNA and DNA, (IFN-α can be used to treat hepatitis B and C infections). While, IFN-γ (gamma) is called immune interferon because it activate T-cytotoxic cells and NK cells during cell mediated immune response CMI.
Polymorphonuclear leukocytes PMNs form the principal cellular response during the acute inflammation and infiltration of mononuclear cells and lymphocytes characterizes the inflammatory reaction of uncomplicated viral lesions.
Virus-infected cells may be lysed by cytotoxic T lymphocytes as a result of cell mediated immunity after recognition of viral polypeptides presented on the infected cell surface. Humoral immunity protects the host against reinfection by the same virus. Neutralizing antibody produced against capsid proteins blocks the initiation of viral infection, at the stage of attachment, entry, or uncoating. Secretory IgA antibody is important in protecting against infection by viruses of the respiratory or gastrointestinal tracts. Some viruses infect and damage cells of the immune system for example the HIV human retrovirus the pathogen of acquired immunodefiiency syndrome (AIDS) that infects T lymphocytes and destroys their function in both cellular and humoral mediated immunity.
5. Viral clearance and recovery from infection or establishment of persistent infection:
The host susceptibility is a critical factor in development and cure after viral infections. In acute infections, recovery is associated with viralclearance by the help of both cellular and humoral immunity. But, sometimes the host remains infected persistently with the virus.
Viruses have evolved a variety of ways that suppress or evade the host immune response and avoid clearance:
Interfere with immune cells activity. Infecting cells of the immune system and stop their function like (HIV).
Interfere with MHC expressing. Infecting neurons that express little or no class I major histocompatibility complex (MHC) (herpesvirus). Or they may encode immunomodulatory proteins that inhibit MHC function (adenovirus, herpesvirus) or inhibit cytokine activity (poxvirus, measles virus).
Affect antigenic stability, Viruses may mutate and change antigenic sites on virion proteins (e.g. influenza virus, HIV) or may down-regulate the level of expression of viral cell surface proteins (herpesvirus).
Interfere with immune response regulation by cytokines and interferon's production. Virus-encoded microRNAs may target specific cellular transcripts and suppress proteins important for the host innate immune response (polyomavirus, herpesvirus), they have anti-IFN mechanisms.
Development of auto-antibodies and cause cellular injury in normal tissues or loss of function this problem in human viral diseases is currently unknown.


Virus Shedding
The last stage in pathogenesis is the shedding of infectious virus into the environment. This is a necessary step to maintain a viral infection in populations of hosts. Shedding usually occurs from the same body surfaces involved in viral entry. Shedding occurs at different stages of disease depending on the type of virus involved.
It represents the time at which an infected individual isinfectious to transmit the infectious virus in contacts (usually called convalecent carrier). In some viral infections, such as rabies, humans represent dead-end infections, and shedding does not occur.

Diagnosis of viral Infections in Laboratories:

Serological properties are usually used in diagnosis of viral infections. Many viruses are good antigens (produce strong antibody) and this property has been widely used to produce specific antibodies that can be used for virus detection and for examining relationships between viruses. Many studies used agar diffusion plates for diagnosis; but in the last 20 years, the technique ELISA (enzyme-linked immunosorbent assay) was most common used. On the genetic level; polymerase chain reaction technique (PCR) in viral identification and taxonomy is now widely used for nucleotide sequence data determination.

Prevention and Control of viral diseases:

Vaccination:
Worldwide, the WHO initiated the Expanded Program for Immunization in 1977 to protect children against several diseases (e.g. polio, measles, mumps and rubella.). Vaccines are not available for all viruses to decline morbidity (illness) and mortality (death) associated with viral infections . Some are used for at-risk populations and others are for universal vaccination. The universal vaccination is usually against polio, measles, mumps, rubella, and hepatitis B. With universal vaccination, the original goal was to induce herd immunity, and stop transmission of the virus in the population and second vaccinations are generally required to achieve universal coverage.
Problems with viral vaccines are:
Antigenic drift and shift (in RNA viruses with segmented genome).
Many animal reservoirs cause reinfection after cure.
Integration of viral DNA (latent period), vaccines will not work and donot activate the immune system because virions did not express proteins (Antigens) for example HIV attenuated vaccine.
Viral vaccines are found in many forms, attenuated, killed (inactivated) and recombinant. The immunological response to inactivated vaccines is generally poor and can induce hypersensitivity to subsequent infection due to the immune response to viral surface antigens of the new infection that is not mimic with natural virus.
Attenuated viral vaccines have limited life problems, but this can be overcome by the use of viral stabilizers (eg, MgCl2 for polio vaccine). Also, interference by coinfection (second infection) with a naturally occurring virus (wild-type virus) can inhibit replication of the virus and decrease vaccine effectiveness. E.g. Sabin vaccine of attenuated poliovirus (enteroviruses). Attenuated viral vaccines can cause infections in immune-compromised patients but in people with good immune system can give humoral (specific IgG and IgA) and cellular immunity.
Killed virus vaccines have good immunity with no mutation and can be used in immune-compromised patients but these vaccines need booster dose with weak immunity mainly (mucosal IgA), e.g. Salik killed polio virus vaccine and smallpox vaccine.
Biotechnology and genetic engineering techniques are used recently to produce subunit vaccines. These vaccines use only the capsid proteins of the virus. Hepatitis B vaccine is an example of this type of vaccine. Subunit vaccines are safe for HYPERLINK "https://en.wikipedia.org/wiki/Immunocompromised" \o "Immunocompromised" immunocompromised patients because they cannot cause the disease. The yellow fever virus vaccine, a live-attenuated strain called 17D, is probably the safest and most effective vaccine produced.
Quarantine:
Quarantine is used to separate and restrict the movement of people, animals, goods and any other activity or communication with an infected area with any outbreak like viral infections (e.g. Hemorrhagic fever virus Ebola) to stop the spreading of infectious disease to healthy area. Cordon sanitaire, is the most extreme type of Quarantine used against bubonic plague and in 2014 used in West Africa Ebola virus outbreak.


3) Hygiene and Sanitation:
Proper waste water treatment is important in keeping viruses out of the water supply since virus contamination in sewage is between 103 and 104 particles per liter. Typically, activated sludge followed by anaerobic digestion removes most viruses (some countries require pasteurization), additional steps of coagulation, adsorption, and chlorination or ozone treatment are required.
In underdeveloped countries, the level of virus in wastewater or sewerage is higher; contamination of drinking water with waste water is a big problem, so waterborne epidemics of enteric disease usually occur.
Personal hygiene is of importance in lowering transmission of both enteric and respiratory viruses, particularly in family and workplaces. Proper hygiene is also important among food handlers.
Vector control:
Mosquito control is more effective than vaccination. Examples for mosquito borne viral diseases are malaria, dengue, and West Nile virus.
Lifestyle changes:
The viral diseases transmitted sexually (Cytomegalo virus CMV) and by intravenous drug use (AIDS), lifestyle change should change transmission patterns.
Eradication:
Not all viral diseases are eradicable. The necessary factors for eradication are:
An effective vaccine and easily administered
No animal reservoir
Lack of recurrent infection
One or a few stable serotypes
No infectivity before symptoms and no unapparent infections.
Low cost

Smallpox fit all of these criteria and was eradicated in 1977. The next two diseases were polio and measles, which do not fit all of these criteria. But, in 1988 the WHO started a worldwide eradication of polio program to be completed by 2000. Currently, polio remains endemic only in Central Africa and Southeast Asia.
Antiviral drugs:
Antiviral drugs are medications used for treating viral infections only. Most antivirals are used for specific viral infections, while a broad-spectrum antiviral is effective against a wide range of viruses. Unlike most antibiotics, antiviral drugs do not destroy their target pathogen; instead they inhibit their development. Mode of action of antiviral drugs is by inhibit viral development by inhibiting basic steps of life cycle replication.. Some antiviral drugs based on monoclonal antibodies. Natural antivirals are produced by some plants such as eucalyptus and Australian tea trees
Antiviral drug may be about 70%-90% effective in preventing illness. Examples: drugs used against flu virus and herpes blisters. Antiviral foods include the top antiviral herbs include Elderberry, Echinacea, Calendula, Garlic, Astragalus Root, Cat's Claw, Ginger and Liquorice Root.


Oncoviruses:

Any virus with a DNA or RNA genome causing cancer usually called oncoviruses, "tumor virus" or "cancer virus". e.g. retroviruses are called oncornaviruses. Some of human and animal viruses are able to transform infected host cells into cancerous cells. Examples of viruses associated with cancer are: papillomavirus-cervical cancer, hepatitis virus-liver cancer, Epstein-Barr virus-Burkitt's lymphoma
The WHO estimated cancer cases in 2002 and there were 11.9% of cancers caused by viral infections. These cancers can be easily prevented through vaccination (e.g., papillomavirus vaccines), diagnosed with simple blood tests, and treated with less-toxic antiviral compounds.
For example: DNA viruses. Human papilloma virus (HPV), a DNA virus, causes transformation in the host cells through interfering with tumor suppressor proteins such as p53. Interfering with the action of p53 allows a cell infected with the virus to move into a different stage of the cell cycle, enabling the virus genome to be replicated.

Virus latency

It is the ability of a pathogenic virus to stay dormant or latent within the host cell as the lysogenic part of the viral life cycle. A latent viral infection is a type of persistent viral infection which differs from a chronic viral infection. Latency is the phase in certain viruses' life cycles in which, after initial infection, proliferation of virus particles, the viral genome is not fully eradicated. The result of this is that the virus can reactivate and begin producing large amounts of viral progeny (the lytic part of the viral life cycle) without the host becoming re-infected by new outside virus, and stays inside the host continuously. Virus latency is not to be confused with clinical latency during the incubation period when a virus is not dormant.
The example is herpes virus family, Herpesviridae, these viruses establish latent infection. Herpes virus include chicken-pox virus and herpes simplex viruses (HSV-1, HSV-2), they cause latency in neurons and leave linear genetic material in the cytoplasm of host cell. This is also seen with human papilloma virus infections in which persistent infection may lead to cervical cancer as a result of cellular transformation.

Influenza Virus Mutations and new Strains:

New influenza viruses are constantly evolving by mutation. The influenza viruses are changing by antigenic drift all the time, antigenic shift happens only occasionally. Mutations can cause small changes in the HYPERLINK "https://en.wikipedia.org/wiki/Hemagglutinin" \o "Hemagglutinin" hemagglutinin and neuraminidase antigens on the surface of the virus. This is called antigenic drift, that happen continually over time as the virus replicates, a new strains can infect people who are immuned and vaccinated against the old strain (the pre-existing strains) because they are antigenically different and the immune system cannot recognize these viruses and causing an epidemic. So, due to the high mutation rate of the virus, a particular influenza vaccine usually gives protection for no more than a few years.
The second type of change is called Antigenic shift, the major change in the influenza A viruses, resulting in new hemagglutinin and new neuraminidase proteins in influenza viruses that infect humans. Shift results in a new influenza A virus with a hemagglutinin or a hemagglutinin and neuraminidase combination that has emerged from an animal population that is so different from the same strain in humans, most people do not have immunity to the new (e.g. novel) virus. For example: a “shift” occurred in the spring of 2009, when an H1N1 virus with a new combination of genes able to infect people and quickly spread, causing a pandemic. When shift happens, most people have no protection against the new virus strain.