Etiology of influenza & viruses
Viruses are smallest size than bacteria and the large size does not reach 1/10 tenth the size of bacteria and the scientists couldn't see the viruses only after discovery of electron microscopy. Viruses form of organic material that lives in the cells of other organism called host, using the properties of these cells to make copies in order to invade others cells. There are not living forms even if they are multiplies or having genetic material but it cannot reproduce or perfume any of viral function without presence of host cells. So the study of viruses has historically provided and fundamental understanding of molecular biology, genetics and medicine through medical virology (Greenwood et al., 2002).
So from the studying of medical viruses, many of them can cause clinical infection that can lead to life death. One of the most common infections that the world involves it over years is influenza.
Influenza is a serious disease caused by viruses that infect respiratory tract. It affects millions of people in the world every year. It is the most common contagious disease that occurs in the different seasons. It affects all age groups and the greatest severity is in young children, elderly people, immunosuppressed people, and those with chronic diseases leading sometimes to severe complication. The virus gets name from the Latin word influentia and virus was first isolated from pigs in 1931 by Shope after that in 1933 by three English scientists, Wilson Smith, Sir Christopher Andrewes, and Sir Patrick Laidlaw found that the cause of flu is virus not bacterium as thought by scientists(Wilschut et al.,2006).
Etiology of influenza
Influenza caused by influenza virus belonging to Myxovirus group which comprises of Orthmyxoviridae. Influenza viruses classify into three types thus, type A, B and type C viruses. For type A and type B the virus has ability to change or mutant to new strains so the immune system cannot recognize it. On the other hand type C virus is stable. According to the internal ribonucloprotein (RNP) which is a group specific antigen that distinguishes the three types (Mins et al., 2004);
1. Influenza A
• It is the most common and also the scariest of the three influenzas, causing the most serious epidemics in history. Influenza A viruses are capable of infecting people as well as animals, although it is more common for people to suffer the ailments associated with this type of flu. Influenza A viruses infects a wide range of avian and mammalian species. Influenza A often associated with increased rates of hospitalization and death.
2. Influenza B
• Also it is outbreaks also can cause epidemics, but the disease it produces generally is milder than that caused by type A. but sometimes it leads to hospitalization and death.
3. Influenza C
• It does not connected with a large epidemic, usually just causing mild respiratory infections similar to the common cold. It does not cause epidemics and does not have the severe public-health impact of influenza types A and B
Influenza A viruses are classified into subgroups and these further divided into strains and this according mainly on the basis of two surface antigens which are hemagglutinin (H) and neuramindase (N). And these subtypes are further distinguished by variations in genetic sequence and antibody response to these viruses. There are 16 subtypes of HA ad 9 subtypes of NA exist in the animal while in the human 1-3 of HA subtypes and 1-2 NA subtypes are exist. There are three subtypes of influenza A virus, H1N1, H2N2 and H3N2. Prototype virus is named according to type of virus, where the virus was isolated, specimen number and year. For example, A/PR/8/34 indicates that the virus was type A, isolated from specimen number 8 obtained from a patient in Puerto Rico in 1934(Mins, 2004).
It is Belongs to the genus orthomyxovirus in the family of Orthomyxoviridae. The virion of the virus is ssRNA enveloped viruses and the particule is 80-120 nm in diameter and usually roughly spherical, although filamentous forms can occur. Influenza A genome contains eight pieces of segmented negative-sense RNA (13.5 kilobases total), which encode 11 proteins (HA, NA, NP, M1, M2, NS1, NEP, PA, PB1, PB1-F2, PB2). The best-characterised of these viral proteins are hemagglutinin and neuraminidase, two large glycoproteins found on the outside of the viral particles. Neuraminidase is an enzyme involved in the release of progeny virus from infected cells, by cleaving sugars that bind the mature viral particles. By contrast, hemagglutinin is a lectin that mediates binding of the virus to target cells and entry of the viral genome into the target cell. Also the viral RNA polymerase which is essential for infectivity as the viron RNA is negative sense and that why it has to be transcribed to produce messenger RNA (Mins., 2004).
The matrix protein (M protein) surrounds the nucleocapsid and makes up 35-45% of the particle mass. As the figure shows below;
Transmission of the virus
It is transmitted by aerosol or direct contact. Inhalation of few as three particular can transmit the infection. Young children are most likely to transmit the infection and also spread the infection. Influenza is primarily spread from person to person through the air. Virus particles are released into the air through coughing and sneezing of persons who are ill with influenza. Crowded conditions in enclosed spaces provide ideal conditions for the spread of influenza (Mins, .2004).
The Epidemiology of Influenza affects us each day because it is a daily risk and is a threat to our health. It is the most important emerging and re-emerging infection disease. Discovering the best way to control the spread of influenza will be beneficial. Influenza has been known to cause epidemics and pandemics for centuries. Epidemics occurs every two or three years with excess mortality, and more recently influenza epidemics tend to occur every winter. The term pandemic applies to the occurrence of epidemics throughout the world.
Influenza outbreaks are known to occur in three patterns: pandemics every 30 to 40 years, with high excess mortality; epidemics much more frequently, with lower excess mortality; and usually mild sporadic outbreaks. Influenza viruses can change in two different ways (www.who.int).
Influenza viruses can change in two different ways
One is called "antigenic drift." These are small changes in the virus that happen continually over time. It produces new virus strains that may not be recognized by the body's immune system. As a person infected with a particular flu virus strain develops antibody against that virus. As newer virus strains come out, the antibodies against the older strains no longer realize the "newer" virus, and reinfection can occur. This is one of the main reasons why people can get the flu more than one time.
The other type of change is called "antigenic shift." Which is a major change in the influenza A viruses, resulting in new hemagglutinin and/or new hemagglutinin and neuraminidase proteins in influenza viruses that infect humans and or combination that has emerged from an animal population that is so different from the same subtype in humans that most people do not have immunity to the new (e.g. novel) virus. Such a "shift" occurred in the spring of 2009, when a new H1N1 virus with a new combination of genes emerged to infect people and quickly spread, causing a pandemic. When shift happens, most people have little or no protection against the new virus. While influenza viruses are changing by antigenic drift the entire time, antigenic shift happens only occasionally (Zuckerman, 2004).
In late April, WHO state the emergence of a novel influenza A virus. This particular H1N1 strain has not circulated previously in humans. The virus is entirely new. The virus is contagious, spreading easily from one person to another and from one country to another.
The Flu incubation period is usually from 2 to 5 days. After you have been displayed to the flu virus you will not have symptoms for at least the first two days. During this flu incubation period your body will attempt to fight the virus by increasing your WBC. For the record, the flu incubation period varies. Each person's immune system is different and is able to fight off infection at different ranges.So generally it takes longer to fight the effects increasing of the duration. So incubation period for influenza is usually two days but can be as much as five days. Because influenza is a viral infection the flu duration is longer than a common cold.The flu duration is usually 5 to 7 days for fever and major symptoms.And general population the flu duration is about a week. Influenza is often confused with the common cold due to the symptom similarity. Both common cold and the "flu" can introduce with the following:
- body aches
- runny nose
- sore throat
There are many complications that follow influenza which are pneumonia (lung infection), bronchitis, Secondary bacterial infections (Streptococcus aureus bacterial infection and Haemophilus influenza bacterial infection ), Myocardial complications, Several complications can occur in children with the flu which are Reye's syndrome , Febrile convulsions(seizure), Croup(respiratory infection with characteristic cough) ,Otitis media (middle ear infection ). In addition there are a lot of actions that makes disease such as aggravation of pre-existing asthma, pre-existing chronic obstructive pulmonary disease, pre-existing heart failure and sometimes death (Mins, .2004).
The pathogenicity and virulence of the influenza virus is influenced by several interacting factors:
- Host factors:
- Bearing of target receptors on host cells
- Accessibility of enzymes in host cells which are important for viral entry and replication
- Express of immunocompetence of the individual host
- Ability of the immune system to check the viral replication without causing serious damage for the host by its inflammatory reaction
- Ability to bind to host cells
- Ability of virus shedding
- Limitation of cytopathogenic results to allow an appropriate balance between viral replication and control by the host
- Evasion from immunosurveillance by evolution of antigenic variation driven by selective pressure of the immune response
- Intonation of the immune response to weakened effective host defence mechanisms
The replication of the influenza A viruses involves such steps in order to release to other cells and infect it. The main targets of the influenza virus are the columnar epithelial cells of the respiratory tract. These cells may be susceptible to infection if the viral receptor is present and functional. An influenza virus infection begins in the upper respiratory tract by inhalation of droplets produced when an infected individual sneezes or coughs. It multiplies in the respiratory mucosa, causing cellular destruction and inflammation. Viral replication is in ciliated columnar epithelial cells of the respiratory tract, this prefers the swift spread of the virus within the lungs due to the rapid infection of neighbouring cells (www.influenzareport.com).
As the above diagram illustrate the replication of the virus and how it binds to the host;
- The hemaglotinin HA binding to the specific sialic acid structure on the host cell surface
- The virus is adopted in a membrane introduced endosome by the process of receptor mediated endocytosis.
- Uncoating occurs in the endosome and the viral RNA (genome) is released into the cytoplasm.
- The (-)RNA is transported into the nucleus where it is replicated and copied by a viral enzyme into (+)RNA which is both messenger RNA and role as a template for more (-)RNA. The (+) RNA is transported into the cytoplasm.
- The viral core proteins are transported into the nucleus to set up the capsid around the viral (-) RNA forms the "ribonucleoprotein core" of the virus.
- The nucleocapsid recognizes specific points on cell membrane where viral proteins have become inserted and buds off of the membrane to be released during enclosure in the viral envelope.
Once influenza has efficiently infected respiratory epithelial cells, replication occurs within hours and legion virions are produced. Infectious particles are released from the apical plasma membrane of epithelial cells into the airways by a process called budding (step6).
Influenza causes an acute infection of the host and starts an arrange of immune reactions activating almost all parts of the immune defence system. The initial innate response, including cytokine release (IFNa/Β), influx of neutrophil granulocytes or natural killer cells, and cell activation, is responsible for the acute attack of the clinical symptoms. Innate immunity is an essential for the adaptive immune response and that to limit the initial viral replication and secondly, because the antigen-specific lymphocytes of the adaptive immune response are activated by molecules that are made on cells of the innate immune system during their interaction with viruses. The adaptive immune response needs some days to be effective but then helps to hold the viral spread, and finally to demonstrate a memory response leading in a long-lived resistance to re-infection with homologous virus. Influenza infection has both systemic and local antibody (humoral immunity), as well as cytotoxic T cell responses (cellular immunity), each of this is important in recovery from acute infection and resistance to re infection (www.influenzareport.com).
There are three immune responses that help in protection;
- Serum antibody; infection with influenza virus stimulate antibodies to the viral envelope glycoprotein HA, NA, matrix and nucleoprotein NP. Serum IgM, IgA and IgG appear after two weeks of infection. Anti HA antibody protect against disease. Anti NA antibody reduced efficient release of virus from infected cells.
- Local immunity; because the replication of the virus occur in the epithelial cells of respiratory tract so the mucosal immunity has high effective protection against influenza with development of both HA specific IgG and IgA. But studies in human shows the HA specific IgA has more protective in the local immunity.
- Cellular immunity; influenza viruse infected cells can be lysed with antibody in presence of complement either by antibody dependent cellular cytotoxity or the action of T lymphocyte (Tc). These are restricted by class I that recognize HA and internal proteins and those which recognized may be cross reactive. As well as class II which exhibit cytotoxic activity. Virus specific class I can reduce the duration and viral replication. Memory Tc lymphocyte response play role in improving the severity of disease so the interest to improve ability of influenza vaccine to induce Tc lymphocyte (Defrance, .2007).
Diagnosis of influenza A
The accurate and timely diagnosis in case of influenza helps to give the appropriate treatment for a patient. And early diagnosis reduces the inappropriate in using antibiotic and gives chance for using antiviral drug. Also the clinical diagnosis of influenza can often make in a community of epidemic. That by using tissue culture of virus from throat swab, nasopharym and sputum gives positive results within 48-72 hrs. Rapid tests for viral nucleoprotein or neuraminidase are highly sensitive with specificity of 60-90%. A definitive diagnosis can be done with high titre of antibody in a serum during convalescence. In addition rapid detection technique such as fluorescent antibody and enzyme immune assay for influenza antigens in nasopharyngeal epithelial cells are increasing available.
Treatment of influenza A
The aim of the treatment is to limit the infection to the upper respiratory tract. So for uncomplicated influenza infection focus on rest which helps to decrease the oxygen requirement of the body and reduces the respiratory rate and chance of spreading the virus from the upper to the lower respiratory tract., keeping warm at 37C helps in inhibiting viral replication which occurs at 35C and drinking a large amount of liquids to avoid dehydration. There are four antiviral drugs available to treat influenza which is amantadine, rimantadine, zanamivir and oseltamvir. The first generation are amantadine and rimantadine which inhibit the uncoating viral RNA in the host cells and prevents its replication. Due to the new strains that resistant to the first generation the second generation of antiviral drugs has been developed. Those are zanamivir and oseltamvir which acts as inhibitors of NA which is necessary for viral replication and release. Zanamivir can cause bronchospasm so it is not recommended for patient with asthma or chronic obstructive lung disease. The antiviral drugs should be given within 30 hours after onset of symptoms. Anti bacterial antibiotic should be reserved for bacterial complication.
Prevention and Control of influenza A
Immunization against influenza supply fair defences, or may lessen symptoms if the disease is compressed. Every year, scientists develop a vaccine against the most recently circulating strain of the virus. The vaccine is composed of inactivated organisms from several virus strains which scientists try to consider the most recent mutation. These vaccines are commonly prepared using eggs grown viruses. Lately, a new mist vaccine, Flu Mist, was developed for patients between the age of 5 and 65. The vaccine is sprayed into the nose and it works same as injection. One major difference is that this vaccine includes live virus, so it cannot be given to persons with immunocompromised patient or pregnant women. Also there are many vaccines that progress and has effective in recovering from influenza infection such as genetically engineered live influenza virus vaccines , Live influenza virus vaccine candidates expressing altered NS1 genes and use of replication-defective influenza viruses as vaccine candidates DNA vaccination
There are prevention and control guideline that you can protect yourself from getting influenza infection. Hand hygiene by washing hands because it is the best way to prevent many common infections. Also avoid crowds during flu season because it spreads easily. Balanced diet, enough amount of sleep and regular exercise needed for a healthy immune system.
Conclusion and future outlook
There have been many achievements in the development of influenza vaccines and antiviral medications to prevent and treat influenza, and there are systems in place to give early warning for the happening of pandemic viruses. Influenza remains a serious disease despite the availability of antiviral and inactivated trivalent vaccines, which are effective for most recipients. In addition live-virus vaccines are being designed and tested in animals and are intended to be studied in humans. Major advances, based on novel adjuvant and recombinant DNA techniques, promise to change the landscape of vaccinology against influenza and many other infectious diseases.