**3. Discussion**

#### **3.1 Inflammatory cytokine (IL-6) and RNA virus infection**

After RNA virus entered the host. The innate immune system is the first line defensive mechanism for this virus. The response will be responsible for detecting pathogen-associated molecular patterns (PAMPs). Viral RNA is a potent inducer of antiviral innate immune signaling. It will provokes an antiviral state by directing expression of interferons (IFNs) and pro-inflammatory cytokines. The +RNA viruses developed various methods to avoid detection and downstream signaling. This mechanism includes isolation of viral RNA replication in membranous viral replication organelles (ROs) [5].

The defense mechanism of the host includes rapid production interferons and other pro-inflammatory cytokines. This is an important consequence of virus detection. This condition contributes to an antiviral state in both the infected host cell and other surrounding cells. The next phases showed that interferons will play an essential role in coordinating the antiviral adaptive response system [5].

#### *The Role of IL-6 in RNA Virus Infection DOI: http://dx.doi.org/10.5772/intechopen.104523*

One of the most studied cytokines is IL-6. In RNA virus infection IL-6 is considered one of the most important cytokines during an infection, along with interleukin 1 (IL-1) and tumor necrosis factor alpha (TNF-a). IL-6 is a pleotropic cytokine produced in response many types of tissue damage including fibroblasts, keratinocytes, mesangial cells, vascular endothelial cells, mast cells, macrophages, dendritic cells, and T and B cells. After targeting its specific receptor, IL-6 starts a cascade of signaling events mainly associated with the JAK/STAT3 (Janus kinase (JAK)/signal transducer and activator of transcription 3) activation pathway. This cascade will promote the transcription of multiple downstream genes associated with cellular signaling processes, including cytokines, receptors, adaptor proteins, and protein kinases. It will also regulate the production of proteins implicated in regulation of many gene expression. The biological consequences of IL-6 production have been associated with pro inflammatory effects [5, 6].

As an immediate answer after RNA virus infections, different immune cellular pathogen recognition receptors, including toll-like receptors (TLR:2, 3, 4, 7, 8, and 9), nucleotide-binding oligomerization domain-like receptors, and retinoic acid-inducible gene-1-like receptors, are able to sense a variety of pathogen-associated molecular patterns displayed by viruses (envelope glycoproteins, single and double-stranded RNA), which stimulate transcription of IL-6 among other proinflammatory cytokines [5].

IL-6 play significant role either in positive or negative ways. The animal studies showed its ability to repress the replication of CSFV (classical swine fever virus) in swine peripheral blood mononuclear cells. However, experimental scientific evidence also suggests the negative impact of increasing IL-6 level. The potential role of IL-6 increase is the establishment of a viral persistent state in infected hosts. The animal studies showed that overexpression of IL-6 during the viral immune response might induce viral persistence by impairing the polarization and functionality of Th1 cells and the lytic capacity of CD8 T-cells through different mechanisms, leading to chronic infections. As a consequence of the constant antigen stimulation, CD8 T-cells become unresponsive and fail to develop into memory CD8 T-cells, a situation that limits viral clearance. The other negative impact of upregulated IL-6 is increasing inflammation followed by cytokine secretion and cellular recruitment as described during autoimmune diseases. This inflammation state may be an advantage for some RNA viruses by providing new targets for subsequent infections [6, 7].

Previous report and reviews showed that high levels of interleukin 6 (IL-6) and Interleukin 8 (IL 8) were found in the very acute stage associated with lung lesions in SARS-CoV-1 patients. The IL-6 can induce the hyper-innate inflammatory response. In the cases of SARS-CoV-1, very high levels of IL-6 were associated with significant and severe inflammation state, and its correlated with high mortality. Some observational retrospective and systematic review/meta-analysis showed that high IL-6 and C-reactive protein (CRP) were significantly correlate with mortality and severity of the disease. Some recent evidences also proved that critically ill patients with severe respiratory failure and SARS-CoV-2 have either immune dysregulation or macrophage-activation syndrome, both of which are characterized by proinflammatory cytokines (IL-6). The immune dysregulation, in particular, is driven by the Interleukin-6 (IL-6). The most significant impact of this condition features of this immune dysregulation are: (1) over-production of pro-inflammatory cytokines by monocytes, and (2) lymphocyte dysregulation with CD4 lymphopenia [7, 8].

After the pandemic of COVID-19, some recent evidences showed that there are of many similarities between Macrophage Activation Syndrome (MAS) disease and COVID-19 pneumonia. This phenomenon is a pathological condition that called over production of cytokine secretion. The loss of first line anti-viral defense mechanism may be responsible for this activation. It will cause prolonging and sustained IL-6 secretion. The Sustained IL-6 secretion was also correlated with the serum viral RNA load [7–9].
