**Abstract**

Much to the current worldwide pandemic caused by the SARs-Cov-2 virus, common flu caused by Influenza virus remain a long-standing mayhem to global health. Influenza viruses are important human pathogens responsible for substantial seasonal and pandemic morbidity and mortality. Despite the efficiency of widely available antiviral neuraminidase (NA) inhibitor drugs, and multiple formulations of the influenza vaccines, including inactivated influenza vaccines (IIV); a recombinant inactivated vaccine (RIV); and a live, attenuated influenza vaccine (LAIV), Influenza virus infection still remains an ongoing health and economic burden causing epidemics with pandemic potential keeping scientist on their toes in researching to combat the complexity often associated with the pathogenesis of these viral infection and perhaps its associated genetics. Most recent strides and advances within the global research landscape has seen efforts channeled towards the discovery and production of universal vaccines in a bid to address the unique challenge associated with the multiple viral strain explosion often encountered with influenza viruses. An important strategy for accomplishing this is to provoke an immune response to the virus's "Achille's heel", i.e., conserved viral proteins, through targeting the hemagglutinin (HA) glycoprotein or protein domains shared by seasonal and pre-pandemic strains.

**Keywords:** influenza virus, ARDS, hemagglutinin, neuraminidase, universal vaccines

### **1. Introduction**

Influenza viruses are RNA viruses that cause infectious respiratory diseases that are majorly characterized by fever, congestion, and myalgia, which ranges in severity from mild to life-threating, and they are estimated to cause about 250,000 to 500,000 deaths globally per year [1]. They are single-stranded, helically shaped, and belongs to the orthomyxovirus family consisting of 5 influenza virus genera, ranging averagely from 80 to 120 nm in size [2]. They often contain 8 gene segments that encodes 11 proteins (**Figure 1**). These segments encode viral proteins including hemagglutinin (HA), neuraminidase (NA), nonstructural 1 (NS1), NS2, matrix 1 (M1), M2,

#### **Figure 1.**

*Showing all the eight gene segments and encoded proteins of influenza A virus. Influenza virus's genome is eightsegmented and encodes for two surface glycoproteins which includes neuraminidase (NA) and hemagglutinin (HA); matrix protein 2 (M2) ion channel that are securely buried into the viral lipid envelope; matrix protein 1 (M1) which lies beneath the membrane; protein-basic protein (PB1, PB2) protein-acidic protein (PA) which makes up the RNA polymerase complex that is associated with the encapsilated genome; nucleoprotein (NP) which coats the viral genome and nonstructural proteins (NS1 and NS2) which suppresses host cell's mRNA production and serves as interferon antagonism.*

nucleoprotein (NP), nuclear export protein (NEP), polymerase acid (PA), polymerase basic 1 (PB1) and PB2 [3]. Influenza viruses are uniquely known to express spike glycoproteins such as hemagglutinin (HA) which facilitates viral recognition of host receptor binding site and neuraminidase (NA) which also aids viral release after replication within the host cells [2, 4]. HA binds Sialic acid bonded with galactose, in avian influenza (H5N1) affinity binding occurs with the α-2,3 sialic acid galactose receptor complex of birds in contrast with the α-2,6 binding in human Influenza virus A infections [1, 4, 5].

Till date, three types of influenza virus have been known to cause infection in humans: A, B, and C. Type A influenza has subtypes determined by the surface antigens hemagglutinin (HA) and neuraminidase (NA). There are 18 different H subtypes and 11 different N subtypes. Eight H subtypes (H1, H2, H3, H5, H6, H7, H9, H10) and six N subtypes (N1, N2, N6, N7, N8, and N9) have been detected in humans. Type B influenza is classified into two lineages: B/Yamagata and B/Victoria [2]. Influenza B commonly affects children while Influenza C is rarely reported as a cause of human illness, which is probably because most cases are subclinical. Influenza C has still not been associated with any epidemic disease outbreak so far. WHO currently classifies influenza A(H1N1) and A(H3N2) as circulating seasonal influenza A virus subtypes, while also classifying avian influenza virus subtypes A(H5N1) and A(H9N2) and swine influenza virus subtypes A(H1N1) and (H3N2) as zoonotic or variant influenza [2, 6].

Enormous efforts are currently aimed at preventing and treating influenza infections, including seasonal and pandemic influenza, however, outbreaks still remain a major public health challenge globally [1, 4]. This is majorly due to influenza viruses rapidly undergoing genetic mutations that restrict the long-lasting efficacy of vaccine-induced immune responses and therapeutic regimens [1]. These

#### *Influenza Viruses: Targetting Conserved Viral Ha-Stem, Matrix and Nucleo-Proteins to Disarm… DOI: http://dx.doi.org/10.5772/intechopen.104770*

major viral genetic changes involve Antigenic Drift, which is caused by point mutations in genes encoding HA and N glycoproteins spikes thereby allowing for viral immune invasion against host responses and generated antibodies like vaccines. Similarly, antigenic shift which occurs in influenza virus A, caused by viral genome reassortment/swapping mechanisms among two different subtypes of influenza A which are replicating within the same host causing a jump to new species of host, and a highly diverse structure of virus able to cause the occasional pandemics seen in the world [2]. A combination of antiviral agents and vaccines remains the general prevention and treatment measures for influenza-related morbidity and mortality, however complications arising from viral genetic changes has bolstered scientific efforts on a journey to the discovery of universal vaccines.

### **2. Pathophysiology**

Following respiratory transmission, human influenza virus attaches to and penetrates the respiratory epithelial cells in the trachea and bronchi. Other cell types often affected in the respiratory tract includes several immune cells, which can be infected by the virus and initiate viral protein production. However, the efficiency of replication varies among various affected cell types, and, in humans, the respiratory epithelium is the only site where the hemagglutinin (HA) molecule is effectively cleaved [5, 7]. The primary mechanism of influenza pathophysiology is a result of lung inflammation and compromise that is caused by direct viral infection of the respiratory epithelium, combined with the effects of lung inflammation also caused by immune responses recruited to handle the spread of the virus [7]. Influenzamediated respiratory tract damage is caused by a combination of events, including: a) intrinsic viral pathogenicity due to its affinity for host airway and alveolar epithelial cells; and b) a robust host innate immune response, which, while aiding in viral clearance, can aggravate the severity of lung injury [7].

The host cell is then destroyed as a result of viral replication. Viremia, or the presence of a virus in the blood, has, on the other hand, is seldomly observed and never widely documented. Virus is released in respiratory secretions for 5 to 10 days, peaking 1 to 3 days after disease start [5, 7]. Inflammation caused by influenza pathogenic events can extend systemically and appear as multiorgan failure, the most common of which are lung compromise and severe respiratory distress [8]. Some links have also been found between influenza virus infection and cardiac complications, such as an increased risk of myocardial illness in the weeks following infection. Beyond the basic inflammatory profile, several of these processes remain uncertain [9, 10]. Researchers find it theoretically helpful to divide the progression of IAV infection into three stages, with the idea that many of these processes occur concurrently throughout the injury. The first is viral infection and replication in the airway and alveolar epithelium, during which methods that restrict viral entrance or replication might prevent or reduce the severity of the infection. The innate immune response to the virus is followed by the adaptive immunological response, which is crucial for viral clearance but may also cause severe damage to the alveolar epithelium and endothelium. The third step is the establishment of long-term immunity to the infecting virus strain, which is followed by the resolution of infiltrates and regeneration of damaged lung tissue, during which time the patient is more vulnerable to secondary bacterial infection [4, 5, 7].

#### **2.1 Acute respiratory distress syndrome**

The influenza viruses are significantly important human pathogens. In humans, infection of the lower respiratory tract of can result in flooding of the alveolar compartment, development of acute respiratory distress syndrome and death from respiratory failure. The extent to which the virus infiltrates the lower respiratory tract is an important factor in determining the degree of associated disease complications [8]. Infection of alveolar epithelial cells appears to cause the development of severe illness by damaging important mediators of gas exchange and permitting viral exposure to endothelial cells. Early interactions between the influenza virus, alveolar macrophages in the lung airways, and the epithelial lining are significant determinants of alveolar disease development [9]. Once this delicate barrier is penetrated, cytokine and viral antigen exposure to the endothelium layer can exacerbate inflammation, with endothelial cells being a primary source of pro-inflammatory cytokines that influence the amount and nature of future innate and adaptive immune responses [10].

In the final pathological stages, just like in the SARS-CoV-2 infection, where reports from Lancet on COVID-19 pathogenesis reveals that acute respiratory distress syndrome (ARDS) is the main cause of death in most patients [11–14], influenza virus infection also initiates hypoxia and progression to ARDS [15]. ARDS is majorly experienced as shortness of breath and it's also a common immunopathological event in SARS-CoV and MERS-CoV infections [11]. Clinically, severe Influenza A Virus infection can cause bilateral lung infiltrates and hypoxaemia, which are symptoms of acute respiratory distress syndrome (ARDS), and death from hypoxaemic respiratory failure is a major contributor to mortality [16–21]. The cumulative incidence of ARDS related to seasonal IAV infection has been estimated to be 2.7 cases per 100,000 person-years, accounting for 4% of all respiratory failure hospitalizations throughout the influenza season [22].

#### **2.2 Clinical manifestations and complications**

In most cases, influenza produces a simple respiratory illness with a cough, fever, myalgias, chills or sweats, and malaise that lasts two to eight days. The onset is usually quick. Children might have unusual gastrointestinal symptoms such as vomiting and diarrhea. A small percentage of patients, particularly elderly individuals, young children, and those with medical comorbidities, will develop severe illness from viral or secondary bacterial pneumonia, resulting in respiratory and multiorgan failure. Extrapulmonary events are extremely uncommon [23, 24].

Common symptoms such as running nose, sore throat, muscle pains, fever, headaches and fatigue can trigger the release of pro-inflammatory cytokines and chemokines such as tumor necrosis factor or interferon from infected cells might be capable of producing a life-threatening cytokine storm [25]. Influenza does cause tissue damage compared to common cold that is caused by rhinovirus and as such symptoms might not entirely depend on inflammatory response. Also, the large amounts of cytokines have been observed to be dependent on the levels of viral replication produced by the strains [26]. Flu epidemics are difficult to control due to their rapid spread. However, influenza virus has a short generation time of two days (the time from being infected and then to infect the next person). Individuals can become infectious before being symptomatic thus quarantines following noticeable sign and symptom of the

infection is not an effective public health intervention [27]. The virus shedding in an average person peak on day two while symptoms becoming apparent on day three [28].
