The Flu Natalie Dziadosz PATHOGEN AND PATHOLOGY “Since 1700

The Flu
Natalie Dziadosz
PATHOGEN AND PATHOLOGY
“Since 1700, there have been approximately a dozen influenza A virus pandemics; in the past 120 years there were pandemics in 1889, 1918, 1957 and 1968” (6). The pandemic in 1918 was the worst in in recorded history which caused approximately 546,000 deaths (6). These are all reasons why the flu is worth studying and finding a vaccine for. There are multiple types of the flu virus, specifically influenza A, B, C, and D. These names are given based on the antigen they have, or antigenic type (2). “Human influenza A and B viruses cause seasonal epidemics of disease almost every winter in the United States” (2). “The emergence of a new and very different influenza A virus to infect people can cause an influenza pandemic” (2). ‘Influenza type C infections generally cause a mild respiratory illness and are not thought to cause epidemics” (2). “Influenza D viruses primarily affect cattle and are not known to infect or cause illness in people” (2). Influenza A and B viruses have a similar structure, whereas influenza C is more divergent meaning the structure is different (4). “A and B type viruses contain eight discrete gene segments, each of them coding for at least one protein” (4).

Fig 1. A diagram of the influenza virus. (1)
The influenza virus is an enveloped virus that contains single stranded RNA. The virus that humans are most concerned with is influenza A, as we are the primary host. This virus is typically grouped into subtypes based on antigenic properties of the viral-encoded hemagglutinin and neuraminidase envelope proteins (2) Enveloped viruses must un-coat to transfer their genomes into their target, which primarily happens at a low pH (7). The suggested method of transfer, as supported in Yoshimura et al., is that after the virion is endocytosed the vesicle fuses with the lysosome. After this has occurred, the virus envelope quickly fuses with the vesicle membrane due to the low pH inside the lysosome (7). After this occurs, the viral DNA is released into the cytoplasm allowing for viral replication (7). The experiment run in this paper suggests that envelope fusion and cell fusion is activated in the presence of acid, and that the speed of endocytosis is temperature dependent (7).
“After infection, a patient will experience high fever, coryza, cough, headache, prostration, malaise, and inflammation of the upper respiratory tree and trachea” (6). “The influenza virus replicates in the epithelial cells in the respiratory system where the virus can be recovered from both the upper and lower respiratory tract of infected patients” (6).
“It was recorded that in the acute stage, multifocal destruction and desquamation of the pseudostratified columnar epithelium of the trachea and bronchi are characteristic. Often only a basal layer of the epithelium remains” (6). “More observations were recorded in the 1918 pandemic where the trachea and bronchi had markedly reddened and swollen mucosal surfaces, sometimes overlaid with mucopurulent material” (6). “Hemorrhagic tracheitis and bronchitis were observed in 50% of cases” (6). Seasonal influenza cases differ from the earlier pandemic cases that include the features of fatal primary influenza virus pneumonia (6). “A biopsy showed variable features of influenza virus pneumonia that included patchy fibrinous alveolar exudates, alveoli with hyaline membranes, interstitial edema, late-stage severe diffuse alveolar damage, and bronchiolar necrosis” (6). “Reparative changes were also seen, defined as the proliferation of type II alveolar pneumocytes and mild interstitial chronic inflammatory infiltrates, as well as organization in air spaces and the interstitium” (6).
IMMUNE RESPONSE
As stated above there are two strains of the influenza virus that cause seasonal outbreaks of the flu. The first response is by the innate immunity, per the usual foreign particle route. Innate immunity happens to the process that aims to prevent infection of respiratory cells and control virus replication (4). The influenza A virus infection is first sensed by the infected cells via pattern recognition receptors (PRRs) that recognize viral RNA (4). “The PRRs are toll-like receptors (TLRs), retinoic acid inducible gene-1 (RIG-1) and the NOD-like receptor family pyrin domain containing 3 (NLRP3) protein. Specifically, TLR7 binds to single stranded viral RNA and TLR3 and RIG-1 bind double stranded viral RNA” (4). “Once these receptors become activated, they prompt the release of inflammatory cytokines and type 1 interferons” (4). IFN-? and IFN-? are produced, which can lead to a myriad of effects intracellularly (4). These interferons have strong antiviral activity that they exert by inhibiting protein synthesis in host cells and limiting viral replication (4). Type 1 interferons can also stimulate the dendritic cells to enhance the presentation of antigens on the cell surface to CD4+ and CD8+ T cells to accelerate the adaptive immune response (4).
Adaptive immunity is the second line of defense against the flu virus, humoral and cellular immunity. Humoral immunity in the inducement of virus-specific antibody responses (4). Especially antibodies specific for the two surface glycoproteins HA and NA are of importance since the presence of antibodies recognizing these proteins correlates with protective immunity (4). The HA specific antibodies bind to the trimeric globular head of the HA predominately and inhibit virus attachment and entry in the host cell (4). An added benefit of antibody production from the HA stem region is that the antibody can recognize HA molecules of different subtypes and have a broad neutralizing capacity (4). The HA stem region of the molecule is highly conserved unlike the variable region, as it is masked for the immune system (4). Antibodies that are produced in response to the NA region can also have protective potential, as it inhibits enzymatic activity that would release newly formed virus particles (4).
Cellular immunity involves the activation of CD4+ T cells, CD8+ T cells and regulatory T cells. CD4+ T cells are activated after recognizing virus derived MHC class II- associated peptides on APCs that also express costimulatory molecules (4). The most important phenotype of these cells in the T helper cells (4). The main function of virus-specific CD8+ T cells is that of cytotoxic T lymphocytes (4). These cells recognize and eliminate virus-infected cells to prevent production of progeny virus (4).
VIRAL EVASION
The flu viral proteins have multiple ways of evading both the innate immune system and the adaptive immune system. For example, influenza virus NS1 protein can bind viral RNA and its RNA binding domain so it masks recognition by TLRs and RIG-1 that would otherwise induce type 1 interferon production (4). Escape from the host adaptive immune response requires a little more finesse.
The main target of the humoral immune response is the influenza virus HA (4). Viral particles lack proofreading, so random point mutations can occur in the genome creating a new quasi-species (4). Some viral particles are positively selected to have mutations in the coding for the antibody binding sites in the HA, a phenomenon known as antigenic drift (4). Changes in these sites alter antigenicity or increase receptor binding affinity (4). A more dramatic change in virus antigenicity is called antigenic shift, where a completely new virus subtype enters the human population, or an influenza A virus reasserts with an animal influenza A virus subtype (4). This phenomenon can occur when two viruses infect a “mixing vessel” and a new influenza virus emerges with gene segments from both parent viruses (4). Epitopes recognized by virus-specific CD8+ T cells are also under selective pressure (4). Substitutions in the HLA anchor residue of the epitope as well as in the T cell receptor contact residues can affect influenza virus-specific T cell responses significantly (4). For example, a number of amino acid substitutions observed in CD8+ T cell epitopes during the evolution of influenza A/H3N2 viruses were associated with escape from recognition by virus specific CD8+ T cells (4). With this capability, the virus has the capacity to overcome functional restraints to evade T cell immunity (4).
FLU TREATMENTS
Usually treating the flu is easy, to which all a patient will need is bed rest and plenty of fluids (3). In some cases, antiviral medication may need to be prescribed, the most common being Tamiflu and Relenza (3). These drugs are chemically related to neuraminidase inhibitors which react with both the influenza A and B strains (2). Taking these medications soon after you notice symptoms may shorten your illness about a day or so and help prevent any serious complications (3). Researchers are skeptical of any other clinical effects other than a slight reduction in illness time (3). Adding onto that, some influenza strains have become resistant to some antiviral drugs (3). The best ways to ease flu symptoms are drinking plenty of fluids, get lots of rest and taking an over-the-counter pain reliever to help with the achiness (3).
ERADICATION
There have only been two diseases that have successfully been completely eradicated or mostly eradicated, smallpox in 1979 and poliomyelitis in 2006 (5). There are some issues that can occur with eradication, of which an example is the OPV live vaccine that can revert back to a pathogenic form (5). Viral disease eradication in general is a very complex process, as it is dependent on the virus itself if eradication is even possible (5). Eradication of the influenza virus would be difficult because of constantly changing antigens due to antigenic drift (5). “Antigenic drift involves point mutations in the hemagglutinin and neuraminidase genes, encoding envelope glycoproteins, thus reducing the binding affinity of antibodies raised against previous strains” (5). A vaccine that uses more conserved antigens could provide a solution to that problem, but the error prone nature of the RNA dependent RNA polymerase used by influenza could result in even conserved genes mutating rapidly under selective pressures (5). An example of this is the 2009 pandemic of the H1N1 virus, which resulted from recombination between several influenza viruses circulating among swine (5). With all of those difficulties, it could be possible to eradicate the influenza virus, but it would require a lot more research and would not be for a long time yet.

References:
1. “Anti-Influenza Virus Monoclonal Antibodies.” Anti-Influenza Virus Monoclonal Antibodies | TCI America, www.tcichemicals.com/eshop/en/us/category_index/10195/.
2. “Influenza (Flu).” Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, 27 Sept. 2017, www.cdc.gov/flu/about/viruses/types.htm.
3. “Influenza (Flu).” Mayo Clinic, Mayo Foundation for Medical Education and Research, 5 Oct. 2017, www.mayoclinic.org/diseases-conditions/flu/diagnosis-treatment/drc-20351725.
4. Kreijtz, J.h.c.m., et al. “Immune Responses to Influenza Virus Infection.” Virus Research, vol. 162, no. 1-2, 2011, pp. 19–30., doi:10.1016/j.virusres.2011.09.022.
5. Russell, Clark Donald. “Eradicating Infectious Disease: Can We and Should We?” Frontiers in Immunology, vol. 2, 2011, doi:10.3389/fimmu.2011.00053.
6. Taubenberger, Jeffery K., and David M. Morens. “The Pathology of Influenza Virus Infections.” Annual review of pathology 3 (2008): 499–522. PMC. Web. 4 Apr. 2018.
7. Yoshimura, Akihiko, et al. “Infectious Cell Entry Mechanism of Influenza Virus.” Journal of Virology, vol. 43, no. 1, 31 Mar. 1982, pp. 283–293., www.ncbi.nlm.nih.gov/pmc/articles/PMC256119/pdf/jvirol00154-0296.pdf.