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Review Article ISSN: 0974-6943

Abhinaba Ghosh et al. / Journal of Pharmacy Research 2010, 3(10),2533-2536

Available online through www.jpronline.info Influenza and its challenge:A Review


Abhinaba Ghosh, V. Mohanasrinivasan* and C.Subathra Devi
School of Bio Sciences and Technology, VIT University, Vellore, Tamil Nadu.

Received on: 15-06-2010; Revised on: 18-08-2010; Accepted on:13-09-2010 ABSTRACT


Influenza has been a disease of great concern since the Spanish Influenza pandemic of 1918-1919.It continues to be a menace in many parts of the world including some parts of Asia. It is a zoonotic disease capable of transmitting among humans with a high fatality rate of about 63%.Because of their capacity to cross species barrier it is feared that the current circulating strain might mutate and cause a pandemic more devastating than the previous ones. Special concerns was raised for the H5N1 strain which was considered to be more pathogenic than the other strains and was considered to be the agent for the next pandemic. But unexpectedly the new H1N1 spread its catastrophe worldwide causing a wave of Pandemic. What makes Influenza keep on causing fatal outbreaks in from of epidemics and pandemics? The need of the current hour is to revive our knowledge on Influenza and fill the gaps in between our research to find a clue to prevent the virus to make any more history of pandemic!

Key words: Influenza, Flu, H1N1, H5N1, Pandemic


INTRODUCTION Influenza has caused a great havoc to the human society and continues to be a great threat against human health (1).Human society first confronted with the potential effects of Influenza during 1918-1919 which killed around 40 million people around the globe (2), the statistical value which depicts more number of deaths than in World War-I. The 1918 Influenza pandemic is also termed as Mother of all Pandemics (3).Currently; the world is facing the menace of another pandemic due to the unexpected H1N1 strain of influenza virus. Influenza viruses, the causative agent of Influenza are the members of Orthomyxoviridae family. The name myxo- refers to their attraction to mucus. They are spherical or ovoid with a lipid bilayer. The genome is RNA .The total genome length is 12000-15000 nucleotides. Table1 shows the classification of Influenza viruses and Figure1 shows the H1N1 Pandemic strain. The virus particle contains two membrane glycoprotein spikes: Haemagglutinin (HA) and Neuraminidase (NA) (4).The HA is a trimer and major glycoprotein of 135 A 0 and the NA is a tetramer protein of 60 A 0.The HA and NA spikes are antigenic in nature and forms the basis of classification for the Influenza A type virus into subtypes. There are 16 HA (H1-H16) and 9 NA (N1-N9) till date. Numerous combinations of HA and NA were found in avian and crept into humans have caused three major pandemics: HINI in 1918, H2N2 in 1957 and H3N2 in 1968.The avian virus which was a threat to fresh pandemic is H5N1 (5). However, unexpectedly the new pandemic was caused by H1N1 strain. Epidemiology: Influenza caused pandemic in 1918-1919 during which the death estimates were very high. The H5N1 strain has become endemic in many parts of Asia and outbreaks are seen in parts of Africa and Europe. Further, the sporadic nature of transmission from avian species to humans worsens the situation. Apart from the H5N1 virus, the H9N2 and the extremely virulent H7N7 viruses are also prevalent in the domestic poultry and causes human diseases periodically (6,7).Table 2 gives the Cumulative number of Confirmed Human Cases of Influenza A(H5N1) reported to the World Health Organization. According to World Health Organization, by November1, 2009, worldwide more than 199 countries and overseas territories/communities have reported laboratory confirmed cases of pandemic influenza H1N1 2009, including over 6000 deaths. Antigenicity and Virulence: Influenza contains two different types of spikes, Haemagglutinin (HA) and Neuraminidase (NA) as the major structural and antigenic components (8) Structure of Influenza Virus is given in figure 2. HA mediates the binding of the virus to the cell surface receptors (Sialic acid, Neuraminic Acid) to initiate the infection .NA removes the sialic acid or the neuraminic acid residues from the virus and cellular glycoprotein to aid the release of new virions and spread of infection to the new cells (4).HA is also the antigenic part against which neutralizing antibodies are synthesized (9). The success of the influenza virus is due to the two types of antigenic variations exhibited by the virus which in turn contributes their capacity to cause World Epidemics. These variations a person susceptible to new strains despite being previously experienced with other influenza viruses. The first variation is the Antigenic drift which allows antibody mediated selection (2). It is the gradual point mutation and the target is the surface HA glycoprotein (10).The other surface protein, NA encoding gene is also subject to mutation (2). The other variation is the Antigenic shift which is based on the phenomenon of reassortment. Influenza viruses have 16 different HA and 9 different NA that are currently circulating in the environment and infecting species of ducks, pigs, whales and seals also(11). This increases the risk of a new virus strain creeping into the human population anytime due to the phenomenon of antigenic shift. An example of the same can be the human influenza infection of H2N2 in 1957 which is thought o have occurred by the co-infection of the same host by human H1N1 and H2N2 (2). The new A/H1N1 strain is a mixture of the genetic material of North America Avian, Classical North American swine, Eurasian swine and Human influenza. Thus, this strain is diverse in genetic content and our immune system is very nave to it, which contributes towards its catastrophe nature. Apart from the HA and NA, an initially unnoticed amino acid sequence motifs functioning may partially contribute to the virulence of H5N1 viruses which is the virus-encoded protein called NS1. It is the only non structural protein which is synthesized in the host cells and are not incorporated into the new virions .This small multi-functional protein participates in both RNA-Protein and protein-protein interactions during the influenza infection. This protein has a RNA binding domain with NH2- terminal that binds to the dsRNA with low affinity (12) but the role it plays during viral infection is still controversial (9).Also the NS1 protein binds to two cellular proteins that are essential for the modification of the 3 ends of the host cellular mRNAs and prevents their functioning (9).As a result the synthesis of an essential component of the antiviral response in host, interferon- mRNA is greatly reduced (13) and the virus is protected and renders its pathogenic activity. Apart from the above mentioned proteins three other proteins, namely PB1, PB2 and PA that is the component of viral polymerase is associated with each of the eight viral genomic strands. The polymerase participates in transcription of RNA as well as catalyses the replication for new virions. Molecular studies have revealed the sequence of the amino acids in the above-mentioned three proteins, which functions at the specific steps of the virus-specific RNA synthesis or in the interaction amongst the proteins. Further the amino acid at the position 627 in the protein PB2 is assumed to be one of the factors of the

*Corresponding author.
Dr. V. Mohanasrinivasan Assistant Professor School of Bio Sciences and Technology (SBST) VIT UniversityVellore, Tamil Nadu. E-mail.: v.mohan@vit.ac.in Tel: +91-9486802902

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Abhinaba Ghosh et al. / Journal of Pharmacy Research 2010, 3(10),2533-2536


Table 3. Symptoms of Influenza Infection
Adults Febrile illness Headache Sore throat Dry cough Myalgias Anorexia Malaise Pyrexia Substernal soreness Photophobia Nausea Infants and children Fever and chills Sore throat Dry cough Vomiting Abdominal pain Diarrhoea Febrile convulsions Myositis Otitis media Reyes syndrome

Table 4. Complications involved in Influenza


Upper Respiratory tract Bacterial Sinusitis Otitis media Lower Respiratory tract Chronic obstructive- pulmonary disease Chronic congestive heart failure Bronchitis Wheezing attack in asthmatics Other complications Rapid respiration- rate Tachycardia Cyanosis High fever Hypotension Acute respiratory- failure Myocarditis Rapid respiration- rate Tachycardia

Figure1: H1N1 Pandemic strain (Source: http://www.cdc.gov/h1n1flu/images.htm)

Haemagglutinin(HA)
PB2

Table 5.Efficacy of various Antiviral Drugs against Influenza


Drug class NA Inhibitors NA Inhibitors M2 Protein Inhibitors M2 Protein Inhibitors Drug name Zanamivir Oseltamivir Amantadine Rimantadine Efficacy % 84 82 60-70 72

PB1
PA HA NP NA M NS

Neuraminidase(NA) M2 channel protein

Table 6.Various TIVs, their contents and their reactogenicity (Source: WHO,2005)
TIV Content Inactivated Virus Reactogenicity

Figure 2 Structure of Influenza Virus Table 1. Classification of Influenza Virus Genome : (-)ss RNA (Eight Segments) Order :Mononegavirales Family :Orthomyxoviridae Genus :Influenza A Species :Influenza A virus Subtype :H5N1 or H1N1 Table 2. Confirmed Human Cases of Avian Influenza A/(H5N1) reported to WHO (Source: WHO; 10 September 2008)
Year-----Country ... Azerbaijan Bangladesh Cambodia China Egypt Indonesia Iraq Myanmar Pakistan Viet Nam 2004 C 0 0 0 0 0 0 0 0 0 46 D 0 0 0 0 0 0 0 0 0 32 2005 C 0 0 4 8 0 20 0 0 0 98 D 0 0 4 5 0 13 0 0 0 43 2006 C 8 0 2 13 18 55 3 0 0 115 D 5 0 2 8 10 45 2 0 0 79 2007 C 0 0 1 5 25 42 0 1 3 88 D 0 0 1 3 9 37 0 0 1 59 2008 C 0 1 0 3 7 20 0 0 0 36 D 0 0 0 3 3 17 0 0 0 28 Total C 8 1 7 29 50 137 3 1 3 383 D 5 0 7 19 22 112 2 0 1 241

Whole Virus Vaccine Split Virus Vaccine Subunit Vaccine

15-20% vaccines experience local reactions lasting for 1-2 days; Systemic reaction occurs within 6-12 hours of vaccination Virus disrupted by some detergent Reduced systemic reactogenicity compared Purified HA and NA to the above vaccines

that facilitates these HA moieties to be cleaved by several intracellular proteases. The above remark is supported as the recombinant H5N1 viruses lacking these bases were found to be non-virulent in mice (14).Thus it can be assumed that cleavage by intracellular proteases are important factor which contributes for the virulence of these viruses. Pathogenicity: Transmission of influenza is primarily by bioaerosols expelled into the air by coughing and sneezing of an infected person (15) .This droplet if inhaled by healthy persons can cause spread of the infection. The incubation period ranges from 1-5 days. Human flu viruses upon infection bind to sialosaccharides which are a (2, 3-galactose) receptors that populate the human respiratory tract. Avian HA protein prefer the (2, 3-galactose) form which are common in birds and were initially thought to be absent in humans. Adaptation from avian to human recognition pattern can occur very rapidly as the virus disseminates and evolves. However a team of scientists recently showed that using marker molecules which bind to one receptor or the other humans also possess a(2,3galactose) receptors but in and around alveoli of lungs. In addition, a research team in Netherlands showed that H5N1 readily binds to the alveoli of lungs but does not bind to tissues higher up in the respiratory tract. In the human lower respiratory tract,H5N1 viruses primarily binds to type II pneumocytes, alveolar macrophages and the non-ciliated cuboidal epithelial cells present in terminal bronchioles. This binding of viruses is progressively low towards the trachea. Thus, the attachment of the viral particles to the superficial epithelial cells of the respiratory tract unfolds the wider distribution of protease enzymes needed for the cleavage of HA of the virus. The occurrence of systemic illness accompanied with fever depicts dissemination of the virus via blood stream (16). Symptoms: The range of symptoms, which occur during Influenza virus infection, is variable which ranges from the mild respiratory disease accompanied with

Note: C-Cases; D-Deaths virulence of H5N1 viruses in humans and do not perform any of the above functions.H5N1 strains which are found to be virulent in mice has lysine at this position while those that are non-virulent H5N1 viruses encodes glutamic acid this position (14).This change in the amino acid residue at this position 627 of PB2 protein may attribute to the adaptation of H5N1 virus for efficient replication in mammals and thus cause infection . HA, in the outer membrane is cleaved into two disulphide linked subunits for initiation of infection in the host tissue.H5N1 viruses which are highly pathogenic in mice has a series of basic residues just closer to the HA cleavage site

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Abhinaba Ghosh et al. / Journal of Pharmacy Research 2010, 3(10),2533-2536


rhinitis or pharyngitis to primary viral pneumonia with fatal outcome. The presence of cough and fever accompanied with the sudden onset helps in distinguishing influenza from other respiratory infections. Table 3 gives a detailed pattern of symptoms for adult as well as infants and children separately. Complications in Influenza: Complications in influenza arise due to secondary infections. Out of these, the major is pneumonia. It can be either bacterial or viral pneumonia or both. Symptoms include cough. Pleuritic chest pain and chills. Organisms commonly involved are Streptococcus pneumoniae, Staphylococcus aureus and Haemophilus influenzae .Bacterial pneumonia have a low fatality rate than the viral pneumonia. Table 4 gives the major complications involved during advanced period of Influenza infection. Serious complications are observed in case of people of age 65 years and above infants. Also the mortality rate is higher for the elderly persons with pulmonary cardiovascular and other pulmonary diseases (17). Treatment: Treatment currently involves two methodologies currently to reduce its impact: Immunoprophylaxis with vaccines and chemoprophylaxis with antiviral drugs. Two classes of antiviral drugs, which are currently used for chemoprophylaxis, and treatment of influenza are the NA inhibitors and the M2 protein inhibitors. Examples of NA inhibitors are Oseltamivir (brand name is Tamiflu) and Zanamivir (brand name is Relenza). These drugs act on the neuraminidase of the virus and prevent its functioning in the release of virions. The second class, M2 protein inhibitors, namely Amantadine (brand name is Symmetrel) and Rimantadine (brand name is Flumadine) acts on the M2 protein in the membrane of the virus and prevents its uncoating during infection in the host cells. Further, it has been found that the M2 inhibitors are effective against Influenza A virus only whereas NA inhibitors act against both Influenza A and B viruses .The efficacy of these antiviral drugs are shown in the Table 5 given. Thus the anti-influenza drugs can play a vital role as a first-line defense against influenza pandemics. But the scenario is being worsened on getting reports of the drug-resistant strains of Influenza. The dissemination of such strains can reduce the effectiveness of the drugs as a first-line defense. However, the current H1N1 strain has been found to respond to the drugs well. The doctors are not recommending the drugs to be used at low concentrations as prophylactic measure as they fear of emerging drug resistance. In addition, if the co-infection of an individual occurs by the circulating drug resistant strain and the pandemic H1N1 strain, the pandemic would be hard to control. Vaccines are formulated by World Health Organization surveillance network (2).During February each year the members of WHO meet well before the approaching winter so as to decide which strains should be n the following season in the trivalent vaccines. However, the predictions of the strains that spread infection during the season are turned wrong due to mutation sometimes. Currently, according to WHO recommendations existing internationally licensed vaccines contain two Influenza A subtypes, namely H3N2 ad H1N1 and one Influenza B virus (18). Broadly, influenza vaccines are classified under two major categories: Trivalent inactivated Influenza Vaccines (TIV):Inactivated influenza vaccines have been used since 1940s. However, the reports depict a large variation in vaccine efficacy and effectiveness. The reasons are being mentioned below: 1. Antigenic similarity between the strain used in the vaccine and the circulating strain 2. Potency of the vaccine 3. Health status of the vaccines 4. Accuracy of diagnosis.However their protective efficacies are believed to be equal and if antigenicity of the vaccine content and the circulating strain matches. They can prevent illness in around 70-90% of healthy adults in laboratory confirmed illness (18). The various types TIV and their differences in reactogenicity is depicted in table 6.However during some influenza seasons it has been found that TIV increases the risk of Guillain Barrie syndrome (about 20 cases per million vaccine recipient) (18). For seasonal flu the most common vaccine is Subunit vaccine which involves the use of Purified HA and NA subunits. The culture of Influenza virus follows an old traditional method of inoculating hens egg with the viral sample followed by incubating them and purifying the HA and NA from the virus for the vaccine preparation. It is a long and tedious process-involving minimum of five months. By this time the viral strain would have already spread its menace in form of pandemic since the infectivity of this virus is by aerosols and is relatively easy. However, a major drawback of the subunit vaccine is hypersensitivity reaction it causes because while purifying the viral subunits some amount of egg albumin also creeps into the preparation whatsoever care is taken. Live attenuated Influenza Vaccine: Russian federation has a long-standing history of using live attenuated Influenza vaccine. This vaccine is cold adapted and replicate well in cold environment of nasopharynx but poorly in the lower respiratory tract. This vaccine is administered by nasal route and its efficacy is comparable to that of inactivated Influenza Vaccines (2,18) .This vaccine is able to elicit immune response by stimulating the CD8+ cell memory (2).Also since this vaccine replicates in the host, lower doses are effective. The Holy Grail vaccine targets the antigen of Influenza that is constant universally. This can be the M2 protein, which is the ion channel present on the surface of the viral particle required for the efficient uncoating of the viral particle inside the host cell. However, it must be kept in mind that the number of M2 ion channels on the particle is low the ratio being 400HA/100 NA/ 10M2. Concluding Remarks: There is an increase reports on drug resistance of influenza. Hence, the need of the current hour is to make an ideal influenza vaccine. Though the phenomenon of antigenic variations remains as an obstacle to this development, the phenomenon of reverse genetics can hold a promise in this area .The insertion of small genetic elements (probably encoding less than 45 amino acids) into influenza virus will enhance the antigenicity but minimize the antigenic drift and pathogenicity.The Holy Grail vaccine is a good attempt but due to less number of M2 protein, as discussed earlier its potentially capable of combating the infection only upto certain extent. The use of live attenuated vaccine must be thought upon before administering to the immunocompromised as well as elderly persons. Further encouragement to alternate drugs research as Cyanoviridin-N, Nostoc ellipsosporum which neutralizes the virus by binding to high-mannose oligosaccharide at the sites of glycosylation on the viral HA,HA1 subunit may help to overcome the drug resistance for time being.An ideal vaccine is yet to develop to act on wider range of Influenza strains to prevent the outbreak of suspected new pandemic due to H5N1 strains. Immunogen-design strategies are underway which targets the functionally conserved regions of Influenza virus. Undoubtedly, the alternative system of medicines as Cyanoviridin-N and similar compounds hold a promise as better therapeutic agent. ACKNOWLEDGEMENT: The authors are thankful to Mr. Sekar Viswanathan, Vice President, VIT University for his enormous encouragement and support and Prof. C. Rajasekaran for his support and guidance. REFERENCES:
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Source of support: Nil, Conflict of interest: None Declared

Journal of Pharmacy Research Vol.3.Issue 10.October 2010

2533-2536

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