Influenza: Diagnosis, Treatment, Prevention - V.D. Moskalyuk 2010

General information about influenza and other ARVI
Modern concepts of cytokine status in ARVI

The Study of The Role of cytokines in viral infections is still at the stage of accumulating data, but there is already evidence that helps us understand A number of mechanisms by which many Viruses overcome the body's defenses and utilize intracellular processes and intercellular interactions to facilitate Replication (T. Ito, R. Amakawa, M. Inaba et al., 2001).

The functioning of Multicellular Organisms is driven primarily by various intercellular interactions. In the early 1990s, specific concepts regarding the existence of a specialized cytokine system began to take shape (E.I. Isaeva, Z.I. Rovnova, 1994; Yu.V. Lobzin, V.P. Mikhaylenko, N.I. Lvov). Modern literature describes about 50 immunologically active cytokines, which are divided into four main groups: 1) ILs; 2) IFNs; 3) hematopoietic colony-stimulating growth factors; and 4) tumor growth-inhibiting factors.

A prominent group among cytokines is the IL family, which derived its name from their ability to mediate internal communication between Cells. World literature describes about 18 classes of ILs, whose Functions are numerous and not yet fully understood.

The most extensively studied are IL-1 and IL-2. IL-1 is the primary mediator of local inflammatory responses and the acute-phase reaction associated with microbial invasion, immune-mediated inflammation, and tissue damage. IL-1 exhibits a wide spectrum of immunological and non-immunological activities. First and foremost, it is a pro-inflammatory cytokine whose secretion is triggered by inflammatory stimuli from activated immune system cells. IL-1 stimulates the function of various leukocyte types (T AND B lymphocytes, macrophages, neutrophil granulocytes) (E.P. Selkova, G.Yu. Nikitina, 2000).

It has been established that The production of IL-1 by peripheral Blood monocytes is reduced in malnourished individuals, who also exhibit a diminished Immune Response to infection and trauma. Furthermore, protein-deficient diets have been shown to blunt the response to endotoxin.

Thus, IL-1 plays a vital role in the Pathogenesis of various diseases, acting as a universal mediator of The Immune System and of local and systemic protective inflammatory responses with a broad spectrum of biological activity, thereby engaging numerous Organs and body systems in the process.

According to researchers, further investigation into the MECHANISM OF ACTION of IL-1 is required. Is its regulatory effect specific in all cases? Answering these questions is a pressing challenge in modern immunology.

There is a concept known as early cytokine reactions (ECRs). These represent the body's rapid response to viral infection. A classic example of an ECR is the production of IFN, which is observed almost immediately after Cell infection. This is a natural (innate) and most common variant of ECR to viruses as intracellular parasites, where the viruses themselves trigger the IFN system, acting as natural Inducers (A.L. Belyaev, E.I. Burtseva, A.N. Slepushkin et al., 1996; V.V. Berezhnoy, I.B. Ershova, E.N. Kunegina, 2003).

The cascade of intracellular reactions triggered by viral entry is driven by the induction of IFN synthesis and the subsequent degradation of viral messenger RNAs via the action of 2'-5' oligoadenylate synthetase and the activation of endonuclease. Simultaneously, activated protein kinase phosphorylates the a-subunit of the Translation initiation factor eIF-2, which blocks viral Protein Synthesis. All of this leads to the suppression of replication across a wide range of DNA and RNA viruses through a direct intracellular antiviral effect. These described changes occur within the first few hours following viral entry into the body (L.V. Kolobukhina, R.Z. Gatich, N.L. Merkulova et al., 2003).

IFNs (primarily IFN-a/ß, or so-called type I IFNs) possess The ability to activate NK cells and CTLs. As a result, during the initial stage of viral infection, three interrelated events take place locally (at the portal of entry):

1) intracellular inhibition of viral replication by IFN;

2) elimination of infected material with the help of NK cells and CTLs;

3) protection of surrounding uninfected cells from potential infection by the synthesized IFN.

The Significance of these effects cannot be overstated, given that virtually every Organism is repeatedly infected by various viral agents throughout its lifetime.

In the simplest cases, where the disease does not develop at all, ECRs are limited to The First stage. Accumulated data indicate a universally broad antiviral spectrum of IFN activity, with little dependence on virus-specific features. Overall, the first stage of the ECR is executed locally at the level of infected cells, thereby preventing the further generalization of the infection.

However, the outcome is far from always rapid and favorable, and the described IFN effects may prove insufficient to halt the infectious process. This typically occurs in cases of high infectious dose, lowered bodily resistance, defects in the IFN and immune systems, adverse environmental conditions, The impact of stress, etc. As a result, an acute or chronic infectious disease develops, accompanied by a cascade of early cytokine production (the Second Stage of the ECR), activation of CD4⁺ and CD8⁺ T cells, and the subsequent development of specific T- and B-cell-mediated Immunity. In such instances, alongside type I IFNs, early cytokines such as TNF and y-IFN are synthesized. Furthermore, IL-1, IL-6, IL-10, IL-15, and IL-18 are produced, as well as transforming growth factor (TGF). The Variability of ECRs across different viral infections is noteworthy. A characteristic feature of all studied viral infections is the production of IFN-a/ß, which can be considered a key dominant hallmark of viral infection (V.A. Isakov, M.G. Shamanova, R.N. Nasorina, E.B. Chepik, 1995).

a/ß-IFNs exhibit a range of other effects unrelated to antiviral activity: they induce leukopenia, reduced drainage in the Thoracic duct, lymphadenopathy, and the migration of cells from the red pulp of the Spleen to the white pulp. Thus, a redistribution of cells occurs for subsequent immunoregulatory effects. Finally, a/ß-IFNs can enhance the specific immune response during primary infection by recruiting B- and T-cell populations to sites of inflammation for antigen presentation (V.A. Isakov, M.G. Shamanova, R.N. Nasorina, E.B. Chepik, 1995).

ECRs may depend on the type of virus that has entered the organism. All the aforementioned cytokines are produced by non-specific defense cells such as monocytes/macrophages, NK cells, polymorphonuclear leukocytes, and cells of various organs and Tissues. Clearly, there are numerous variants of ECRs that function as non-specific reactions to the progression of the infectious process and collectively serve as a crucial mechanism of the non-specific immune response.

Cytokines with direct antiviral activity include a/ß-IFNs and TNF produced by NK cells. TNF enhances IL-12-dependent production of y-IFN.

Overall, the effector mechanisms of the second stage of the ECR can be outlined as follows: 1) production of a/ß-IFNs; 2) activation of NK and CTL cells; 3) production of y-IFN; 4) redistribution of lymphocytes; 5) expression of IL-1 and TNF genes; 6) activation of other cytokine production.

All of this combined constitutes an essential mechanism for activating innate immunity against viral infection and fundamentally differs from the body's reaction to non-viral pathogens. TNF and y-IFN produced by lymphocytes activate the recruitment of macrophages to the focus of viral infection to participate in antiviral defense.

Another key feature of the ECR to viral infection is The regulation of genes responsible for the production of IL-12, which is directly linked to the synthesis of y-IFN. All the mechanisms described above comprise the second, more complex stage of the ECR, which is observed as a viral infection progresses and is necessary to arrest the infectious process or transition to a subsequent T-cell-mediated immune response. Obviously, in a number of cases, the combination of these described reactions may prove sufficient to halt the infectious process.

With the further Development of the second stage of the ECR, the activation of non-specific Components of the immune system continues, primarily including the expression of cytokine receptor genes, the redistribution of immunocompetent cells, an increase in the cytolytic activity of CTLs and the production of y-IFN, and the induction of proliferation in NK and CD8+ memory T cells (H. Scharfenorth, H. Glathe, H. Giese, S. Diffmann, 1991).

The Stages of the body's reaction to viral infection that follow the ECR are associated with The Development of an adaptive (specific) immune response. They proceed according to well-known pathways of CD4+ helper-mediated CELLULAR REACTIONS IN one of two main directions: the Th1 type, characterized by the production of IFN and other pro-inflammatory cytokines, or the Th2 type, characterized by the production of IL-4 and IL-6. These mechanisms are well-studied with respect to extracellular parasites. They may also occur during viral infections, although, as recently demonstrated, the latter do not neatly fit into the binary Nature of the T-cell response. Indeed, to date, unambiguous data regarding the preferential development of a pro-inflammatory Th1-type cascade in response to viral infection have not been obtained (positive results exist only regarding cytomegalovirus infection) (C. Scholtissek, 1996; M.C. Steinhoff, N.A. Halsey, N.H. Wilson et al., 1990).

In many viral infections, the production of y-IFN by T cells is characterized by a certain elevation in IL-2 levels. The involvement of CD4+ and CD8+ cells in y-IFN production during viral infections can vary markedly. CD8+ T cells often constitute the primary population of cells expressing y-IFN. This is rarely observed in non-viral infections, which is why the body's response to viruses differs substantially from its reaction to other pathogens (C. Scholtissek, 1996).

A fundamentally important issue concerns the significance of cytokines other than a/ß-IFN in mounting a non-specific antiviral response. For instance, in HIV infection, the T-cell response is typically of the Th0 type, characterized by the concurrent expression of Th1 and Th2 cytokines. In some cases, a pronounced imbalance is observed in the relative involvement of CD4⁺ and CD8⁺ cells. The authors note the fundamental possibility of non-specific cytokine production driven by the preferential Selection and Activation of a specific T-cell response to the virus. Regardless, non-specific cytokines (IL-12 and y-IFN), while playing a vital role in activating the CD4⁺ T-cell response, are not strictly obligatory for the CD8⁺ T-cell response in certain viral infections.

Which cytokines can be considered unequivocally "meaningful" during viral infections? First and foremost are the classical a/ß-IFNs, which not only exhibit direct antiviral activity but also increase the number of CD4⁺ cells expressing the y-IFN Gene and act as the primary immunoreregulators of the CD8⁺ response to viral infection. Mention should also be made of the activation of a/ß-IFN cytokine receptors, the induction of various cytokine gene expressions, and NK cell activation.

Naturally, it would be ideal to mimic such a multifactorial response to viral infection using pharmacological agents capable of simulating and preventing the progression of the infectious process, much like Vaccines do. This is partially achieved through The Use of various established antiviral agents (chemotherapeutic drugs, interferons and their inducers, and various immunomodulators). When screening for novel antiviral drugs, it is crucial to identify one or more of the mechanisms described above. Most simply, this principle can be demonstrated using interferons or their inducers, as the engagement of RCR and the activation of NK and CTL cells readily explain the universally broad spectrum of antiviral activity exhibited by these agents, which additionally possess the ability to stimulate the immune response.

However, this raises at least two questions:

1. If the administration of a drug restores THE SPECTRUM OF cytokines suppressed by viruses, can this be considered an objective indicator of the drug's efficacy?

2. To what extent does the cytokine response to a viral infection reflect the body's defensive potential in a specific disease? The antiviral action of drugs is mediated through the activation of cytokines that are otherwise suppressed during viral infection. The validity of this assumption is supported by data obtained from the effects of the domestic interferon inducer cycloferon on hepatitis C virus (HCV) replication and cytokine mRNA expression in infected MT-4 human lymphoblastoid cell line cultures. Uninfected cells contain mRNA for all investigated cytokines except IL-8. In HCV-infected cells, The activity of a-IFN, y-IFN, IL-2, IL-4, and IL-6 is inhibited. Concurrently, viral titers increase markedly in infected cells (up to 11.5 lg). Treatment of infected cells with cycloferon restores the mRNA activity of the studied cytokines; in parallel, a pronounced inhibition of viral replication is registered. Consequently, the antiviral effect of cycloferon is likely mediated through the drug's activation of cytokines that are suppressed during viral infection. This example demonstrates that a comparative Study of the effects of viruses and antiviral drugs on cytokine activity can be valuable for understanding the antiviral efficacy of these agents. In other words, identifying a drug's ability to "prevent the shutdown" of cytokines during viral infections could serve as a convenient screening method for novel antiviral drugs.

Additional proof supporting this Conclusion comes from experiments investigating the regulation of cytokine activity by well-known antiviral agents such as interferons and their inducers.

Thus, a positive answer can be given to the first question. There appears to be a direct correlation between the cytokine response and viral replication. The administration of antiviral drugs can prevent and/or reverse the disruptions caused by viruses within the cytokine network.

Addressing the second question requires further observation. Interferons and their inducers kagocel and cycloferon, which are widely used in medical practice for various viral infections, possess the ability to regulate cytokine activity.

Depending on The Cell type and the specific agent studied, either induction or suppression of cytokine mRNAs is observed, which may reflect differences in their antiviral action. Furthermore, these identified differences open up Prospects for regulating the activity of various cytokines through the induction/suppression of cytokine signals aimed at preventing infection or overcoming immunodeficiency states.

It follows from the foregoing that interferons and their inducers act as regulators of cytokine activity and can be utilized in research investigating the mechanisms of antiviral activity and tumor growth inhibition.

Overall, it can be concluded that RCR during viral infections differs markedly from the cytokine response to other (non-viral) pathogens. RCRs appear to be directly linked to the antiviral effects of cytokines. They may act locally at the infected cell level (the first stage of RCR) and/or activate non-specific cellular immunity (the second stage of RCR). The final stage of RCR is the induction of a specific immune response.

According to V.A. Isakov (2002), the course of Influenza infection is also accompanied by shifts across various Links of the immune system (G.I. Karpukhin, 2001; S.A. Ketlinsky, A.S. Simbirtsev, A.A. Vorobyov, 1992; E.P. Selkova, V.N. Yakovlev, T.A. Semenenko et al., 2000). In severe forms of influenza at the peak of the illness, suppression of the T-cell branch of systemic immunity is observed: the number of CD3⁺ and CD4⁺ cells decreases, natural killer cell activity declines, and the level of circulating immune complexes rises (G.I. Karpukhin, 1996).

Frequently, especially in severe influenza, leukopenia, lymphopenia, and neutropenia develop. These changes are most pronounced by the end of the first week of illness. Even in uncomplicated influenza, transient T-cell suppression lasting 3–4 weeks is possible, which may be one of the factors contributing to the development of complications (S.A. Ketlinsky, A.S. Simbirtsev, A.A. Vorobyov, 1992; B.S. Nagoev, N.G. Orazaev, 2000; M. Basinga, 1992).

SUMMARY

Upper Respiratory Tract infections hold a leading share in The Structure of not only human infectious pathologies but also the caseload of general practitioners. ARVI accounts for nearly 60% of primary physician consultations.

WHO experts emphasize that in recent years there has been a persistent upward trend in the incidence rates of these infection groups. This phenomenon is primarily driven by social factors associated with global processes of continuous urbanization, intensifying migration, and closer human contact across all Regions of the globe. Immunodeficiency, which almost invariably develops against the Background of an infectious disease, plays a crucial role in The Emergence of ARVI.

Today, a large arsenal of medicinal products is available featuring a low incidence of adverse or long-term reactions, high antiviral and immunomodulatory activity; yet, morbidity rates remain high. This is due to several circumstances: the emergence of new variants of certain viruses resistant to antiviral drugs; The formation of mutant influenza strains resistant to amantadine and rimantadine; the heterogeneity of the resistant strain population (comprising both sensitive and insensitive clones); and cross-resistance to Chemotherapy within a single Class of substances, which necessitates the use of drugs with alternative Mechanisms of action or combinations of drugs from different groups. This is a reality that, on the one hand, is discouraging, but on the other hand, stimulates the search for fresh ideas and practical solutions to the problem.