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Possible Immunological Solutions to End the Flu Pandemic
Introduction
The Influenza virus is responsible for severe respiratory infections in humans as well as animals from poultry, pigs, and other domesticated animals. The Influenza virus belongs to the Orthomyxoridae family characterized by segmented, negative senses that are single-stranded RNA (ssRNA) (Chen et al.). In general, they are categorized into four genera, including type A, B, C, and D. upon infections, there are key features and differences in host immune responses activated against the influenza pathogens. These include the innate immune system, adaptive immune system- humoral immune system response, and cell-mediated immunity system, including the CD4+ helper T cells- (Bohadoran et al.). The following report aims to provide a concise discussion on the key features and differences of host immunity against influenza infection. Due to the broader healthcare system burden, the paper shall also provide proposed immunological interventions that could be implemented to end this pandemic.
Key Features and Differences of Host Immunity against Influenza Infection
- Innate Immune Response
The innate immune response has an essential role in the rapid response system against viral infections and consequential, adaptive immunity response. Primarily, the most common Influenza infections are type A in humans (Allen and Thomas 248). These types of viruses often attack the respiratory system with a specific affinity for the airway and alveolar epithelial cells. When the virus attacks the cells, it causes alveolar injury, which affects gas exchanges. In humans, the Influenza infection can lead to acute respiratory distress syndrome (ARDS), which can lead to death, according to Grant et al. (132). For example, Influenza types H1N1 attacks the ciliated epithelial and goblet cells on the upper respiratory tract, while the H5N1 has a low affinity to these cells in humans. Another example, the H3N1, attaches abundantly to the human trachea and bronchioles compared to H5N1 (Chen et al.).
The process of detection of the Influenza virus is the first step that involves human PR receptors (pathogen recognition). The unique characteristic of the PRR is the ability to differentiate between the self from non-self-molecules of the infected cells. They include the retinoic acid-inducible gene I (RIG-I), the Toll receptors (TLR3, TLR7, and TLR8)- which detect the virus outside the cell membrane, in the endosomes and lysosome-, in addition to the nucleotide-binding oligomerization domain receptors (Chen et al.). In the retinoic acid-inducible genes, I are mandated to detect the 5′-triphosphates on the ssRNA, for instance. In general, each receptor has a specific task to conduct regarding how to identify the presence of the Influenza virus in the host (Allen and Thomas 249). RIG-I is the primary receptor that recognizes the virus, including the PAMP recognition. The subsequent step is the recruitment of the domains caspase activation and recruitment domains (CARD), which triggers a down-stream activation of the outer mitochondria membrane, which triggers B cells activation through the interferon regulatory factor 3 (Chen et al.).
The initial phase of Influenza infection is the activation of the macrophages and the monocytes. They result in a pro-inflammation cytokine response, which includes the TNF-α and IL-6. The activation of the macrophages is necessary as it reduces the rate of infection in the host. The inhibition process involves the activation of the phagocyte-mediated opsonophagocytosis of the Influenza virus and the phagocytosis of the infected apoptotic cells. The first response, therefore, includes the natural killer cells which use the cytotoxic lymphocytes to eliminate the infection. The process involves binding to the HA proteins, which allow the natural killer cells to attach to the Fc portion of the antibodies to the influenza virus (Grant et al. 140). Another form of response is the use of dendritic cells- which are described as the mediators between the innate and adaptive immune response (Waithmanand. Mintern 605). When the dendritic cells are involved, the adaptive immune system is initiated (Allen and Thomas 250). The dendritic cells are tasked with a constant patrol of the lung for foreign materials or pathogens (Waithmanand. Mintern 605). During an Influenza infection, antigens are detected through two forms: (1) direct infection of the dendritic cells and (2) phagocytosis of the epithelial cells.
The antiviral immune response entails the activation of the specific transcription factors such as NF-kB, IRF3, and IRF7. The factors initiate the transcription of genes encoding IFN and the pro-inflammatory cytokines. These play an essential role in antiviral response to both the infected and noninfected cells. Infected cells trigger an over-production of Type I and type III IFN genes, which are crucial to the antiviral immune response against the Influenza virus. The IFN activates the Janus Kinase-signal transducer, which enables the transcription signaling pathways (Grant et al. 140). The Type I and Type III IFN provide antiviral defenses against the Influenza virus infections.
- Adaptive Immune System
The adaptive immune system includes a humoral immune response. The humoral immune system is tasked with the production of antibodies against the different antigens produced by Influenza viruses. The importance of understanding the humoral immune system is the development of vaccines against influenza viruses. As such, the (hemagglutinin) HA-specific antibody is the most crucial in vaccine development as it is essential in the neutralization of the virus to prevent the binding of the virus globular head with the host cells (Grant et al. 140). Additionally, the (hemagglutinin) HA-specific antibodies can inhibit further infection through phagocytosis by binding to the infected Fc receptors expressing cells.
The first type of response in adaptive immunity is the use of antibodies IgA and IgM- to some extent. Most of the pathogens in the Influenza virus enter the host through mucosal tissues. The IgA and IgM neutralize the mucosal pathogens by limiting replication and preventing pathogen entry (Iwasaki and Pillai 315). With respect to IgA, the isotype acts against the HA and NA of the influenza virus. The first actions occur through the lymphoid tissues, while the subsequent attack is through the periphery (Grant et al. 140). The IgM dominates in the initial response while the IgG antibody takes over the following step. Studies have shown that high levels of IgM indicate high clearance levels of the virus, similar to IgG (Van De Sandt et al.). The hypothesis is that whenever IgM and IgG are involved, there is an innate link between the antibodies and the Influenza virus. For the humoral immunity to be active, B lymphocytes stimulators are prudent as well as proliferation-inducing ligands, which are critical in the production of optimal humoral immunity as well as protection against any secondary infections.
The second type of response in adaptive response is cellular immunity. In this, the T and B lymphocyte cells are involved. The T cells include the CD4+ T and the CD8+ T where, the latter differentiates into cytotoxic T lymphocytes crucial to the production of cytokines and effector molecules to restrict viral replication thus, destroy the infected cells. During infection, the naïve CD8 + T cells are activated by the dendritic cells which migrate from the lungs to the T-cell zone, which result in T-cell proliferation and differentiation into cytotoxic lymphocytes (CTL) (Waithmanand. Mintern 605). In association, the type I IFn, IFN-y, IL-2, and IL-I2 aid the CD8 + T cells in differentiation to CTL. The CTLs produce cytotoxic granules that contain molecules (granzymes and perforin) (Maarouf et al.). Perforin is responsible for binding with target cells, whereas granzyme is tasked with apoptosis (Chen et al.). Memory CTL is essential in the quick response to any secondary infection, including the activation as well as the differentiation process received during the initial infection.
As for the CD4 + T cells, they target the epithelial cells through the MHC class II, where induction of MHC Class II is expressed in the cells. The CD4 + T cells are crucial to the activation of the B cells antibody production. The CD4+ T cells differentiate into T helper cells in response to the infection based on the type of stimulator and antigen as well as co-stimulatory molecules and cytokines secreted by the dendritic cells (Maarouf et al.). The T Helper effector CD4 + cells express antiviral cytokine, which activates the alveolar macrophages (Grant et al. 140). The antiviral cytokines include the IFN-y and TNF and IL-2, which clear the viral infection. In humans, studies have shown T helper 17, and regulatory T cells are essential in the regulation of cellular immune response (Allen and Thomas 251). The T helper 17 is tasked with improving T helper activity in the production of IL-6 preventing regulatory T cells functions. The regulatory T cells are essential in the control of CD8 + T cells and T helper cells responses after infections.
As for the B cells, they are prudent in the priming for the defense against an Influenza infection. The B cells work hand in hand with the memory T cells, where the naïve B cells reduce the illness and stimulate recovery during infection. Similarly, the non-neutralizing antibodies generated by the B cells facilitate the viral elimination and the acceleration memory of the CD8+ T cells expansion after infection (Iwasaki and Pillai 320).
Proposed Immunological Interventions
My proposed immunological intervention includes the inhibition of nucleus activity with a special interest in nuclear export. In particular, the therapeutic intervention could consist of the target of the ribonucleoprotein (RNP) from the infected cells in which studies have shown to be mediated by Exportin 1 interaction (Yip et al.). It is a viral nuclear export protein that is tethered to the vRNP. Exportin 1 is well documented for its role in the nuclear export of protein and RNA, including viral RNA to the host cells (Dou et al. 1580). In the Influenza virus, the viral RNA does not bind to the Exportin 1 directly. Instead, it holds together several proteins. Studies on understanding the functionalities of Exportin 1 have shown its silencing to reduce virus replication in a host with pro-influenza infection (Varanasi and Rouse 39). To achieve the silencing process, cellular Exportin 1 is proven to be crucial to nuclear transportation outside the vRNP complex. Exportin 1 is a member of the karyopherin-β superfamily and contains at least 15 different importin and exportin proteins. Among the designated proteins is Exportin 1, which includes specific transporting proteins from the nucleus to the cytoplasm. To understand the mechanism of exportin 1, studies have utilized natural inhibitor, Leptomycin, which has uncovered the transport molecules of Exportin 1 in vRNP (Varanasi and Rouse 39). Leptomycin binds with exportin 1 forming an irreversible covalent bond that prevents the nuclear transport of exportin cargo molecules into the host cells. However, the toxicity levels of Leptomycin are high and can cause the death of the host (Van De Sandt et al.). Therefore, different types of inhibitors other than Leptomycin can be developed given that Leptomycin has paved the way for nuclear export inhibition. However, the process should be Type-specific given the difference in efficacy activity against nuclear export inhibition, including tolerance and evidence of anti-cancer activity. Proposed medications could include verdinexor against the circulation of influenza A and B, and drug DP 2392-E10 against the binding for Exportin 1.
Another proposed intervention could be the target of the apical transport of viral components. After nuclear transport out of the viral capsid, the host cellular transport mechanism is used to deliver vRNP to the plasma membrane of the host for the assembly of the viral RNAs and proteins (Dou et al. 1580). This is a well-thought-out as the final stage of the viral replication. Studies have shown that vesicular components of the host, including Rab11A+ endosomes, recycle endocytic membrane protein as well as lipids to the plasma membrane for homeostasis (Yip et al.). The property function is ideal for the RNA virus in Influenza. Reports on the direct interaction between the vRNP complex and the RaB11A+ vesicles have been indicated, stating that there is a dependence of the vRNA on the Rab11A+ for viral replication (Laske et al.). Therefore, a specific understanding of the Rab11A+ is crucial to limiting viral replication in the host. It includes the identification of the molecular motor for plasma membrane transportation of vRNP Rab11A+, including the KIF13A (Laske et al.). The knockdown of KIF13A resulted in a decrease in virus production. On the other hand, it has been reported that the overexpression of KIF13A shows a lack of capacity hence, results in disruption of plasma membrane distribution of vRNP during viral replication (Laske et al.). Therefore, for immunological intervention, it would be best to understand the involvement of v in viral replication and how its silencing or splicing could help reduce viral replication in host cells.
The final proposed immunological intervention includes the interference of viral budding in the host. Studies on Influenza have shown that virus budding is conducted via the transmission between cells, including the apical membranes and the intercellular connections. Studies demonstrate that host cholesterol can play a significant role in viral budding (Yip et al.). The experiments indicate that the overexpression of annexin A 6- which is a phospholipid-binding protein- could decrease cholesterol levels within the Golgi apparatus and its membrane (Karawita et al. 194). The result is reduced viral infection within the host cells. Controlling cholesterol content could be the key to lowering viral budding and consequential reduction in infection rates (Van De Sandt et al.). The immunological intervention, therefore, should target the budding viral process through cholesterol reduction in hosts, including the proposed Gi-type G-protein receptor shown to be a principal host involved in Influenza virus replication.
Conclusion
The report has provided an in-depth discussion regarding the immune responses key features and differences in host immune responses. Specifically, the report has delved into adaptive and innate immune responses, including the processes involved in the identification and subsequent antiviral immune response in each immune response case. The report has shown that innate immune response is the first type of response in a host, which activates the secondary immune response, adaptive immune response. Due to the [prevalence of the Influenza virus among humans, it is paramount to find innovative measures and interventions to fight against the virus. The proposed immunological responses include inhibition of nucleus activity, interference of viral budding, and target on apical transport of viral components. The interventions may be the key to unlocking the antiviral response against influenza viruses.
Work Cited
Allen, E. Kaitlynn, and Paul G. Thomas. “Immunity to Influenza. Preventing infection and regulating disease.” (2015): 248-251.
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Chen, Xiaoyong, et al. “Host immune response to influenza A virus infection.” Frontiers in immunology 9 (2018): 320.
Dou, Dan, et al. “Influenza A virus cell entry, replication, virion assembly, and movement.” Frontiers in immunology 9 (2018): 1581.
Grant, Emma J., et al. “Human influenza viruses and CD8+ T cell responses.” Current opinion in virology 16 (2016): 132-142.
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Yip, Tsz-Fung, et al. “Advancements in host-based interventions for influenza treatment.” Frontiers in immunology 9 (2018): 1547.