Document Type : Review Paper

Authors

1 Department of Medical And Surgical Nursing,School of Nursing and Midwifery,Shahid Beheshti University of Medical Sciences, Tehran, Iran

2 M.D.,Internist,Assistant professor ,department of Internal Medicine ,Faculty of Medicine ,Mashhad University of Medical Sciences,Mashhad,lran

3 Resident, Department of internal medicine, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

4 Islamic Azad University of Medical Science - Qeshm Internationa branch,Qeshm, Iran

5 Regional Centre of Advanced Technologies and Materials, Czech Advanced Technology and Research Institute, Palacky University, Šlechtitelů 27, 78371 Olomouc, Czech Republic

6 Student Research committee, Kermanshah University of Medical sciences, Kermanshah, Iran

Abstract

Influenza virus have its place in the Orthomyxoviridae family, comprising four types of viruses namely influenza A, B, C, and D. Several methods are commonly used to diagnose influenza, including PCR, rapid test, viral culture, and immunofluorescence while antiviral drugs are available for the therapeutic intervention including vaccines for preventive purposes which can inhibit the infection and virus spread more efficiently. The emergence of drug resistance is frequently detected due to the high occurrence of mutations in the virus's genome.  Nowadays, nanotechnology has evolved to overcome these hurdles wherein it could be deployed for both, the diagnosis and treatment of viral infections  via development of nano drugs and nano vaccines. Numerous nanostructures have been developed, such as peptides, proteins, polymers, metals, silicones, liposomes, and virus-like particles (VLPs), which can be used to diagnose and treat the influenza virus. These nanoparticles can be incorporated into nano biosensors or be employed as biological tags as nano drugs or nanocarriers for drug delivery as well as nano vaccines to stimulate the immune system more effectively. Herein, an overview of the potential application of nanotechnology-based strategies in the treatment, analytical methods, and vaccine production is presented for combating influenza viruses.

Keywords

Main Subjects

INTRODUCTION
Respiratory viruses such as rhinovirus (RV),  respiratory syncytial virus (RSV), and influenza virus (IV) attack the respiratory tract and cause viral infections such as cold, pneumonia, bronchitis, and bronchiolitis. In addition to causing health burden, they impose exorbitant costs on the society, and billions of dollars are annually specified for the cure and care of patients afflicted with these viral infections [1-3]. The influenza virus is an enveloped, segmented single-stranded RNA virus belonging to the family of Orthomyxoviridae [4] and is  one of the ordinary respiratory tract infectious agents that spread worldwide annually and raises concerns in the health community [5] represented essentially by  four different types: A, B, C, and D.  Notably, each type has its unique antigens and is categorized into different subtypes. Among influenza virus types, only types A, B, and C can infect the human body. The A and B virus types are polymorphic, their major form is usually observed in spherical shapes, and their size is in a range between 80-120 nm. The influenza virus type C is morphologically filamentous, and its size could be up to 500 nm [6, 7].
The diagnosis, treatment, and prevention of viral infections such as the influenza virus are among the most significant clinical and public health concerns. Nowadays, several methods have been recruited for virus diagnosis[8]. Moreover, different antiviral therapies have been employed for virus infection treatment, including neuraminidase inhibitors, M2-inhibitors, and polymerase inhibitors are available as cures for influenza viruses[9].
Due to the strong impact of nanotechnology on human life aspects, medical science has taken tremendous strides where nanomaterials provide various advantages and thus becoming an appropriate choice to interact with pathogenic agents. Efficient drug delivery system development has been well accepted through nanotechnology, leading to improved remediation[10, 11]. Vaccine development is one of the most exciting fields to employ nanotechnology. Nanoparticles can be recruited as the carrier and immunostimulatory adjuvants simultaneously thus leading to a more robust immune response [12]. Furthermore, nanomaterial can be effectively used for virus detection via analytical procedures such as electrochemical or optical methods [13].
Herein, we aimed to deliberate the potential application of nanotechnology-based strategies in the treatment, detection, and vaccine production for influenza viruses.

Influenza A virus
It is well known that the influenza A virus can be initially transmitted from waterfowl as the primary virus source. The virus is transmitted to humans and other species, including pigs, horses, and birds [14-18];it is more prevalent in humans than other species being the main cause of flu in the humans. It is classified into several subtypes based on the presence of surface glycoproteins, namely hemagglutinin (HA) and neuraminidase (N)[19-21]. The World Health Organization has so far identified 18 types of HA and 11 types of NA. HA is further sub-divided into two groups, Group I and Group II that includes H[1-3, 5, 6, 9, 12, 14, 16, 22], and H [3, 4, 7, 13, 17, 18], respectively. Obtained evidence suggests that the influenza A virus, especially the strain H3N2, has the highest rate of morbidity and mortality compared to other genera and strains of assorted influenza virus species [23-29].

Influenza B virus
The influenza B virus has fewer subtypes diversity than type A and essentially comprise two major lineages named B / Yamagata and B / Victoria, providing the basis of the lineage distinction. This genus has gained the ability to escape the immune system and persist in humans circulation [30-33].

Influenza C virus
Unlike types A and B of influenza, which causes a wide range of lower respiratory infections, the influenza C virus causes a mild infection in the upper respirational area . This type of virus encodes a unique protein called hemagglutinin-esterase-fusion (HEF), and the hosts of this virus being humans and swine [34].  The influenza C virus has a lower prevalence, milder symptoms, and lower infection risks than types A and B due to lack of neuraminidases on its surface and having different hemagglutinin isoforms [35, 36]. 
The most common cause of pandemic and seasonal influenza outbreaks and the highest deaths number due to influenza virus infection is attributed to the influenza type A virus. Investigations have revealed that the influenza type B virus can also cause seasonal influenza. In most cases, the host of the influenza C virus is children, with mild respiratory symptoms. So far, the influenza D virus effect on human health has been less studied, and precise information does not exist [37, 38]. 
Temperature and humidity are critical environmental factors in virus transmission, so influenza is more prevalent in winter, especially in areas with cold and dry winters; virus being resistant to relatively low temperatures. Studies have indicated that the virus has the highest activity at a temperature of 5 ℃ and the most insufficient activity at temperatures higher than 30 ℃ [39].

THE INCUBATION PERIODS
The mean incubation period of influenza is about 1–2 days and could be in a range of 1–4 days. The disease duration is approximately 3–5 days in adults and may continue for several weeks in young children. Respiratory droplets higher than 10 μm in diameter are thought to be responsible for the direct transmission of the disease and, most likely, infection of the lower respiratory tract. The virus directly damages the airway epithelial cells[40-43].
The immunopathogenesis and peaks following the acute infection are the two factors contributing to the disease severity. Approximately 2-3 days following the virus infection, the highest viral load would be present in the upper respiratory tract. This time coincides with the emergence of featured clinical symptoms. After day 3 of the infection, the virus starts to multiply, and then the viral load would  gradually decrease [44-46]

RISK FACTORS
In pathological conditions, individuals with immunodeficiency and autoimmune disorders, cardiovascular diseases, chronic respiratory diseases (e.g., asthma), hematological disorders, HIV infection, cancer, diabetes, and neurological disorders are among the most vulnerable targets for viral infection.  Under physiological conditions, aging, with weakened immune system, pregnancy, and childhood, are the most risk factors for healthy subjects [47, 48]

CLINICAL SYMPTOMS
The outstanding symptoms of influenza infection include high fever, coryza, coughing, headache, prostration, malaise, fatigue, acute respiratory distress syndrome (ARDS),primary viral pneumonia, syndrome pulmonary edema, and, in certain instances , secondary bacterial pneumonia. In some children, myoglobinuria, rhabdomyolysis, febrile seizures, and encephalopathy may also occur [49-52].

DIAGNOSIS
Polymerase chain reaction (PCR)
Rapid and accurate diagnosis of influenza for therapeutic purposes and controlling its prevalence are critical in clinical settings. Molecular assays based on polymerase chain reaction (PCR) have been accepted as the gold standard for the influenza virus diagnosis. US Food and Drug Administration (FDA) has approved the RT-PCR assay for the RNA viruses detection in respiratory samples (sputum, throat swab, nasal swab, and nasopharyngeal aspirates) for influenza and several other respiratory viruses. Despite the advantages of nucleic acid amplification, including high sensitivity, detection of another species of respiratory viruses in the sample, determine the type or subtypes of viruses, and time-saving, this method requires expensive equipment and expertise to correctly interpret the results [53-58].

Rapid tests
Rapid approaches are swift and straightforward tests that facilitate the infection diagnosis used outside the laboratory setting. Rapid influenza diagnostic tests (RIDTs) are attributed to the immunoassay approaches to detect viral antigens in the patient’s respiratory secretions with high specificity. Despite being widely used as they deliver results in less than 30 minutes, rapid tests represented different sensitivity levels from modest to very high sensitivity. Despite the considerable advantages RIDTs provide, they possess increased sensitivity for detecting influenza A compared with influenza B [59-63]. 

Viral culture
Viral culture is another diagnostic method for the influenza detection that has been reported to be more sensitive compare to rapid tests. The viral culture has been used as a time-honored and gold-standard method to diagnose the virus in the past. However, the time-consuming process feature of this method turned it into a less popular technique regarding diagnostic purposes  [64-71]. 

Immunofluorescence
The immunofluorescence diagnostic method is used as a screening test and has less sensitivity than the cell culture technique. Unlike the cell culture method, this technique is not time-consuming, and the results can be obtained within a few hours. The immunofluorescence test has various advantages such as the level of expertise, the precision of laboratory tools, and the quality of collected samples. The sample source (e.g., epithelium cells) could be a determinative factor in the results obtained [72].

ANTIGENIC VARIATION IN INFLUENZA VIRUS
The antigenic variation, including antigenic shift and antigenic drift, is referred to as the influenza virus’s specific characteristic. The antigenic shift is a consequence of an alteration in hemagglutinin or neuraminidase genes observed in the influenza A virus. The new gene source has been tracked and found in waterfowl. In this regard, 15 antigenically distinct subtypes of hemagglutinin and nine subtypes of neuraminidase have been identified. In contrast to antigenic shift, antigenic drift appears in both A and B influenza viruses. It has been described as mutations within the antibody-binding sites in the hemagglutinin, the neuraminidase, or both. As such, available antibodies cannot overcome novel subtypes. Influenza A viruses tend to antigenic drift more rapidly that could cause a severe epidemic in the population [73-76].
Antigenic variation is related to emerging novel subtypes and high mortality rates despite previous protection [77, 78].

TREATMENT
Typically approaches deployed to treat influenza virus infections include antiviral drugs and vaccination [79-81]. The main medications used as antiviral therapy against influenza viruses are summarized in Table 1. 

RESISTANCE TO ANTIVIRAL THERAPY
Drug resistance is one of the main concerns in the medical society, affecting human life quality[82]. Rimantadine  and Amantadine have been deployed to avert and remedy influenza virus infection through antagonist activity on the M2 proton channel in influenza virus A.  Recently, the center for disease control and prevention (CDC) forewarn clinicians to avoid using M2 ion-channel inhibitors because of the high rate of amantadine-resistant in isolates of the influenza A virus [83-86].
The Oseltamivir and zanamivir are new antiviral drugs with Na inhibitor activity against influenza viruses type A and B. It has been reported that mutations in the NA gene are associated with reduced susceptibility toward oseltamivir, zanamivir, and peramivir. Increased frequency in oseltamivir-resistant influenza viruses has been documented in recent years [87-93]. During 2009–2010, the prevalence of oseltamivir-resistant strains among seasonal H1N1 viruses enhanced dramatically, even in countries where oseltamivir had not been used [94, 95]. Although resistant mutants have less ability to replicate, spread, and transmit, they could cause ineffective therapy or death during infection [96-98]. Nevertheless, NA inhibitors remain an appropriate choice for the influenza treatment [99, 100].

VACCINATION
The fundamental solution to reduce the detrimental effects of influenza infections on communities appears to be vaccination. Considering aforementioned challenges, primarily the antiviral resistance phenomenon, the prevention appears to be more efficient and cost-beneficial than the treatment. Vaccination could decrease the complications and the morbidity and mortality rates of the viral infection [101-104]. 
 Vaccination is the utmost effective mean to avert influenza virus infection separation [105]. As described previously, different people may be more vulnerable to influenza viral infection than others due to their biological conditions, such as genetic or epigenetic components. Thus, special attention for vaccination appears to be an urgent requirement. Pregnant women, six months to five years children, aged population above 65, and individuals with particular chronic disorders are the most high-risk groups [106].  
During pregnancy, due to physiological changes in the body and the balance of sex hormones, the potency of the immune system is altered, making pregnant mothers more prone to be affected by infectious diseases. On the other hand, pregnant women are strongly restricted from medication use during pregnancy. The influenza vaccine administration during pregnancy has a relatively long history without severe side effects. During the inactivated influenza vaccination for pregnant mothers in the 1950s, their safety has been ascertained in mothers, fetuses, and infants [107-118]. Considering the challenging process of infants vaccination, as well as their vulnerability to viral infection, it appears that the administration of the vaccines to pregnant mothers would be beneficial since the ensuing antibodies can be easily transferred from mothers to their infants [119-122]. 
Influenza vaccine may stimulate the immune system to improve immune responses against the virus and reduce the deleterious consequences of the viral infection. Nowadays, the influenza vaccine is used in the form of trivalent or quadrivalent. The trivalent form contains strains of 2 influenzas A subtypes 1 B lineage  (Victoria or Yamagata)  and (H1N1 and H3N2) , while the quadrivalent form vaccine renders protection against four influenza virus strains (two A subtypes and two B types). Influenza vaccines classify into recombinant influenza vaccine (RIV), inactivated influenza vaccine (IIV), and live-attenuated influenza vaccine (LAIV) according to the other criteria [123-127]. The LAIV form of the vaccine is suitable for non-pregnant women and individuals who are 2-49 years old [128]. 
The boosting process of immune system response is an ideal feature for a well-designed vaccine. Some trivalent vaccine forms have inadequate vaccine responses, despite their effectiveness in providing immune protection in different affected populations, so they need to be re-administered to boost the immune system within a certain period. The immune system’s optimal stimulation is possibly achieved by using higher doses of influenza viruses or employing adjuvants to incite the proper immune response. The adjuvants’ use is considered a valid factor in this context [129-133].
Adjutants dosage and administration methods must be carefully optimized not to inflict tissue damages due to the local and systemic adverse reactions in the human body [134]. Here, we have reviewed frequently used compounds as adjuvants in influenza vaccines which are presented in Table 2.

THE APPLICATION OF NANOTECHNOLOGY TO COMBAT INFLUENZA VIRUS
Viral infections are among the most common human diseases, annually causing many health problems worldwide. Despite numerous efforts and vaccination programs, and antiviral drugs, the influenza virus is still a significant human health concern. The main problem of relevant infection arises from the high occurrence of mutations in the virus’s genome and the emergence of new strains due to the antigenically variable pathogens nature of the influenza viruses. Nanotechnology has become a powerful tool for diagnosing and treating infectious diseases [135-137]. Furthermore, nanomaterials with unique characteristics can be adequate substitute for conventional drugs and vaccines[138, 139]. Here, we have discussed nano-drugs and nano-vaccines as well as nanotechnology-based diagnostic methods.

Nanotechnology in the diagnosis of influenza virus
Nanostructures can be employed to diagnose viral infections due to their unique physicochemical potential as they have optical, acoustic, and electrical properties[140, 141]. Unlike traditional methods, nanostructures, as highly sensitive, rapid, and user-friendly tools, can be effective in the quick analysis of viral infections. Signature proteins and viral DNA perform a significant function in the diagnosis of viral infection. Nanostructures can benefit from electrochemical, surface plasmon resonance (SPR), fiber optics, and acoustic wave technologies to efficiently diagnose infectious agents [142-152]. Numerous nanoparticles have been designed to diagnose the influenza virus, some of which are listed in Table 3.
The use of nanotechnology for therapeutic approaches
Nano drugs
As mentioned earlier, the high mutation incidence in the influenza virus genome and the emergence of new strains cause many health problems and limitations. One of the most critical problems is drug resistance discussed previously [9]. For this purpose, the use of nanoparticles is becoming increasingly popular, as they have high drug solubility and high bioavailability[153]. They are readily transferred into target tissues/cells, and multiple doses are not needed [154]. Nanostructures are highly selective and can carry more elevated amounts of compounds to their targets without affecting normal tissues/cells, leading to a marked reduction in side effects. Therefore, nanotechnology, with its unique attributes, can be used as a potential therapeutic option to improve the treatment of viral infections (Table 4) (Fig. 1) [135-137, 155, 156].

Nano-vaccine
Despite numerous efforts made to improve the quality and performance of vaccines, there are still some lingering limitations, including immunogenic responses, instability, multiple doses requirement, and, in some cases, the lack of expected efficacy[8, 82, 138, 139, 157, 158]. Nanovaccines can load high antigens amounts and are controllable simultaneously. They can extend the presence of the antigens in lymph nodes, stimulate the immune system, and create an appropriate immune response by injecting fewer doses of antigens. To reach there, nanovaccines have been designed in such a way to combine pathogen-specific antigens with synthetic or natural nanomaterials to attain maximal efficiency. Another advantage of nanotechnology is the feasibility of applying biocompatible nanoparticles as adjuvants, reducing the need to use highly immunogenic adjuvants. This ability reduces the adverse reactions in response to inoculated antigens [159-163]. Nanovaccines can be used as prophylactic or therapeutic agents. Nanoparticles used in nanovaccines can mimic the function of antigen-presenting cells (APCs) to facilitate the immune response against particular antigens. Nanovaccines can improve both, the primary and secondary immune responses [164, 165]. Fig. 2 depicts the nanostructure’s various types impact on the immune system’s performance to help immunological responses against the influenza virus.
Nanoparticles can simultaneously transfer the antigens and adjuvants to improve the antigen presentation process occurring on the surface of dendritic cells. This capability improves the primary and secondary safety responses and thus could be effective in both, the prevention and treatment [166-173]. Nanovaccines could be used to treat different diseases (e.g., cancer), thereby meditating strong cell-mediated cytotoxic responses such as stimulating CTL responses [174, 175].
In general, it appears that nano-vaccines can activate the cell-mediated immunity, adaptive immunity, innate immunity, antibody-mediated immunity, and immunological memory [176]. Table 5 depicts different nanoparticles that can be applied as adjuvants, immunogens, and antigen delivery vehicles to activate or robust the immune system in influenza vaccines.

The use of natural killer (NK) cells 
NK cells comprise ~5–15% of peripheral blood lymphocytes as a component of the innate immune system. After production in lymphoid progenitors in the bone marrow, their survival and development are highly dependent on and IL-15-mediated signaling. CD56 and CD16 are the specific markers of NK cells in humans and are distinguishable from natural killer T cells (NKT through the absence of CD3. It has been shown that NK cells have a great function against viral infection. The virus-induced interferons α/β (IFN-α and -β) can effectively mediate the cytotoxicity of NK cell [177]. Animal studies have revealed that a high dose of influenza virus could cause cytotoxicity and IFN-γ production destruction through NK cells. NK cells secrete various cytokines by interactions with the virus and viral-infected cells to restrict the infection. The activation of NK cells during influenza infection is performed through influenza nucleoprotein (NP) and matrix 1 (M1) antibodies mechanisms. On the other hand, CD16 resemblance plays a vital role in NK cell activation following the vaccination [178, 179]. 
Nanotechnology might play an essential role in influenza infection therapy through NK-cells. It has been reported that selenium nanoparticles (Se) could promote antiviral immunity through maintain NK-cell activity that leads to enhance T cell proliferation [180]. In another study, the effect of PS-GAMP biomimetic nanoparticles has been investigated as an adjuvanted influenza vaccine. The results indicated that the adjuvant has quickly stimulated the NK cells’ recruitment and differentiation [181]. 
However, our efforts did not find many publications pertaining to nanomaterials and nanotechnology used to treat influenza using NK cells. But given the importance that these cells play in the body’s immunity, it appears that more research investigations are needed.

CONCLUSION 
Nowadays, in conjunction with an increase in the mutation rates of viruses, seeking new therapeutic approaches, such as nanotechnology-based ones would be needed to overcome the deficiencies of conventional methods for treating the viral infections. It has been shown that nanotechnology holds great promise in both the diagnosis and treatment of viral infections. The use of nanostructures in nanovaccines and nanodrugs can be helpful in the prevention and treatment of viral diseases. The application of nanoparticles for therapeutic purposes can increase the efficiency of drugs, ensure drug safety, and lower the cost of therapy than conventional treatments.

ACKNOWLEDGMENT
The authors use the Biorender website to design the figures and thank it.

AUTHOR CONTRIBUTIONS

CONFLICT OF INTEREST
The authors declare that they have no competing interests.

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