**7. Complementary and alternative medicine (CAM)**

The National Centre for Complementary and Integrative Health-National Institute of Health (NCCIH-NIH), the United States, describes complementary and alternative medicine (CAM) as a collection of varied medicinal practices, natural products, and health-care systems, different from conventional medicine [31]. CAMs treat the disease effectively with fewer side effects and low toxicity [32]. Several plant products are globally applied for the treatment of influenza, though the mechanism of their action is still unknown. The extracts of plants are prepared at very high dilution and are given in small doses. The interaction of active components of plant extracts and viral proteins of the influenza virus is further explored for discovering a potent organic antiviral against a pandemic virus such as H1N1. Some of the reported natural compounds for the treatment of human influenza are baicalin, tinosporon, allicin, curcumin, ursolic acid, carvacrol, ajoene, methanol, andrographolide, coumarin, theaflavin, and eugenol [33]. In *in silico* study, these natural compounds blocked H1N1 NA effectively with significant values of binding energies. Several traditional plants such as *Trachyspermum ammi*, *Ocimum sanctum*, *Zingiber officinalis, Allium sativum, Curcuma longa*, *Tinospora cordifolia,* and *Mentha piperita* are potential antiviral agents against H1N1 swine flu. Another plant-based antiviral agent, ginseng (*Panax quinquefolium*), has triterpenes and saponins that are the potent inhibitors of influenza A(H1N1) pdm09 [34]. The CAM therapies for the treatment of influenza virus also include influenzinum that induces cytokine release from macrophages and furthermore activates the innate immune response [3]. In a study, IAV H3N2-infected MDCK cells were treated with influenzinum and it was observed that there was no cytotoxic effect due to influenzinum, yet the morphology of cells were altered [35].

### **8. Prevention and control**

pro-inflammatory cytokines cause local inflammation and fever that activate the adaptive immune response against influenza virus. Chemokines instruct downstream immune cells by recruiting neutrophils, monocytes and natural killer (NK) cells to the respiratory tract. NK cells target and eliminate the virus-infected epithelial cells initiating viral clearance [26]. Monocytes and neutrophils participate in the removal of dead cells infected with virus. Alveolar macrophages cause the phagocytic clearance of infected cells, a crucial step for virus clearance [27]. The innate and adaptive immune system works hand in hand for the clearance

**Table 1.** Role of pertinent interferon-stimulated genes (ISG) in controlling influenza virus infection (adapted from Ref. [4]).

**Interferon-stimulated genes (ISGs) Intracellular location Mode of action**

Cholesterol 25-hydroxylase (CH25H) Cytosol Inhibits fusion of virus with host cell

Protein kinase R (PKR) Cytosol Inhibits translation and activates

ISG15 Cytosol Ubiquitin-like protein that targets newly

MX1 Nucleus Inhibits viral transcription in nucleus

face of the endoplasmic reticulum

membrane

Nucleus Binds with nucleocapsid for proteasomal degradation

Endosomes Inhibits viral attachment, fusion and

endocytosis

downstream NF-κB pathway

translated viral proteins for modification

Inhibits egression of virus by blocking

formation of the lipid raft

Cytosol Stimulates cleavage of viral RNA

Numerous antiviral drugs inhibiting influenza viruses are available. The most targeted sites for restricting influenza viruses are matrix protein 2 and NA, inhibited by antivirals such as adamantanes (amantadine and rimantadine), oseltamivir, and zanamivir [28]. The adamantanes interfere with viral uncoating and had shown toxic effects that lead to the generation of adamantanes-resistant strains of the influenza virus. Furthermore, the budding off progeny virions from host cells is impeded by the neuraminidase inhibitors that caused only one round of replication, hence preventing the spread of infection. Influenza viruses such as influenza A(H3N2) and A(H1N1)pdm09 were observed to be resistant for adamantanes; therefore, for the clinical treatment of influenza virus A, adamantanes are not recommended. However, IAV and influenza B virus are susceptible to oseltamivir and zanamivir [29]. The other potential targeted sites are viral entry, HA, pH-dependent endosomal fusion, nucleoproteins and polymerase proteins of influenza viruses. HA1 and HA2 play key roles in the invasion of the influenza virus in target host cells. HA1 binds with the sialic acid receptors while HA2

of the influenza virus from the host system.

Viperin Lipid droplets and the cytosolic

**6. Antiviral therapeutics**

2ʹ-5ʹ-Oligoadenylate synthase (OAS)

8 Influenza - Therapeutics and Challenges

Tripartite motif-containing protein 22

IFITM3 and other IFN-inducible transmembrane (IFITM) proteins

and RNase L

(TRIM22)

The transmission of influenza virus between humans and other hosts like avian and swine was reported to be possible and significantly caused pandemics in various countries [36]. The viruses responsible for infecting humans are HPAI or low-pathogenicity avian influenza (LPAI) viruses. Owing to the enormous ability of re-assortment (due to shift and drift) in influenza viruses, absolute prediction of the responsible subtype(s) for the next pandemic infection is impractical. Thus, a vaccine which can effectively target a broad range of influenza viruses is required for the protection of the human host. The development of the vaccine should be dependent on several strategies such as epidemiological data of the previous pandemic influenza viruses, the presence of viruses in nature, and viruses responsible for infecting human population. The current influenza vaccines are live-attenuated influenza vaccines (LAIV), influenza-inactivated vaccine (IIV), recombinant subunit, DNA and vectored virus vaccine [37]. According to Centers for Disease Control and Prevention (CDCs), the United States, available vaccines are of two types—trivalent and quadrivalent flu vaccines. Trivalent influenza vaccine protects against influenza A(H1N1) and A(H3N2) as well as influenza B virus. The standard-dose trivalent flu shots are IIV 3, given to individuals between 18 and 64 years. The CDC has not recommended using LAIV as the vaccines for the year 2017–2018 due to its low effectiveness found during 2013–2017. There are some limitations associated with influenza virus vaccines suggesting that the circulating virus and the vaccine virus should be of same strains to give a high efficacy or else the vaccine might provide a false sense of security. The early influenza vaccination of individuals at a high risk might prevent influenza from becoming a pandemic. The Advisory Committee on Immunization Practices (ACIP) has recommended to primarily providing vaccination to children, pregnant women, individuals of age more than 65 years, and to people suffering from chronic ailments [38]. The other effective methods to control influenza are properly washing hands, use of masks, and covering mouth during coughing and sneezing, avoiding physical contacts with influenza-infected individuals, wearing gloves while working with infected poultry or swine, and the intake of effective antiviral medications.

**Author details**

**References**

Shailendra K. Saxena1,2\*, Amrita Haikerwal<sup>1</sup>

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\*Address all correspondence to: myedrsaxena@gmail.com

1 Centre for Advance Research, King George's Medical University, Lucknow, India

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11

Introductory Chapter: Human Influenza A Virus Infection - Global...

#### **9. Conclusions and future perspectives**

Several factors play a pivotal role in preventing influenza virus infection such as increasing antigenic and genetic variants of influenza virus subtypes, the ability to cross the species barrier, antiviral drug resistance, incapability in predicting the upcoming pandemic virus, the low probability of correctly matching the circulating and vaccine viruses, and the high cost of vaccination. Thus, a robust surveillance system that monitors the human influenza viruses will provide the candidate virus vaccine (CVV) as an adequate strategy required for preparing the pandemics. Apart from this, a comprehensive understanding at the molecular and genetic level of the avian and swine influenza virus will strengthen us in understanding their mechanism of re-assortment and transmission in humans. The veterinary vaccines designed for avian and swine population should be examined to evaluate their efficacy on the avian and swine influenza viruses. Furthermore, there is a crucial requirement of the universal vaccine that can target both seasonal and pandemic influenza viruses. Awareness regarding the prevention and control methods of influenza should be widely spread.

#### **Acknowledgements**

The authors are grateful to the Vice Chancellor, King George's Medical University (KGMU), Lucknow, and Director, Centre for Cellular and Molecular Biology, Council of Scientific and Industrial Research (CSIR-CCMB), India, for the encouragement and support for this work. SK Saxena is also supported by CCRH, the Government of India, and US NIH grants: R37DA025576 and R01MH085259. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
