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      Anti-inflammatory Properties of Stingless Bee Honey May Reduce the Severity of Pulmonary Manifestations in COVID-19 Infections

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          Abstract

          Dear Editor, We are closely observing the progress of the new coronavirus global pandemic. The virus spreads rapidly, and in worst-case scenarios, it can deplete local medical resources. According to the World Health Organization (WHO), this highly contagious respiratory disease followed an exponential trajectory to arrive at 1,210,956 confirmed cases of infection (3,662 in Malaysia) with 67,594 deaths globally, as of 6 April 2020. To date, the lack of early treatment options has caused a major problem in disease management. The uncertainty of the outbreak will continue to affect the general public until the first antidote or vaccine arrives. Within this difficult context, this letter describes the evidence-based therapeutic properties of a local resource, stingless bee honey. As a healthy and functional food, it may be used to reduce the severity of pulmonary manifestations for newly-infected patients. Coronavirus disease 2019 or officially named as COVID-19 has caused devastating social, economic and medical impacts worldwide. Originally detected in Wuhan, China (1), it was first reported to the WHO on 31 December 2019. The disease emerged as a new pandemic, leading to the most aggressive disease containment effort in human history. Mainly targeting the lungs, the virus appears to be mediated via virus-laden droplets and aerosol micro-particles (2). The virus seems transmittable via asymptomatic infection and includes prolonged virus shedding in survivors of up to 37 days (1), inducing a panic situation. In a retrospective cohort study in Wuhan, China, published in March 2020, most patients presented with fever and cough, followed by sputum production and fatigue. Further complications include sepsis and acute respiratory distress syndrome (ARDS) with ventilator-associated pneumonia occurring in 31% of patients requiring invasive mechanical ventilation. Half of the non-survivors experienced a secondary infection, dying as a result of respiratory failure, heart failure, and/or septic shock whereby 48% of those who died had comorbidity. These patients had clearly elevated interleukin-6 (IL-6) cytokine, which increased with illness deterioration in non-survivors throughout the clinical course as compared with survivors. Viral detection appears to be sustained in the throat samples of both survivors and non-survivors (1). Similar to Severe Acute Respiratory Syndrome (SARS) in late 2002, histopathological examination of patients who died from COVID-19 revealed diffused alveolar damage, morphological changes with varying degrees of severity, prominent hyperplasia of pulmonary epithelial cells, and activated alveolar and interstitial macrophages. These findings indicate an association between the profound pulmonary pathology observed and the intense local inflammation due to excessive host immune response (2). It is well-known that the innate immune cells, mainly the pulmonary macrophages and dendritic cells (DC), are involved in acute inflammatory response, mediating early host defense in response to viral infection until an adaptive response can be generated (2). During a viral infection, the viral proteins are recognised by the pathogen-associated molecule patterns (PAMPs) that trigger the toll/interleukin-1 receptor-like (TIR) domain-dependent association and further recruit the IL-1 receptor-associated kinase (IRAK), subsequently inducing other factors involved in activating the transcription factor, nuclear factor kappa B (NF-κB). The activation generates the expression of several inflammatory cytokines, such as the IL-1b, IL-6, and tumour necrosis factors (TNF)-α (3). Studies indicate that the IL-6 regulates the differentiation of monocytes into macrophages and aggregates the production of B-cell IgG while affecting the negative regulation of dendritic cell maturation and promoting the Th2 response; these roles highlight IL-6’s essential contribution in the activation and regulation of the immune response against viruses (4). One prominent Severe Acute Respiratory Syndrome-Coronavirus (SARS-CoV) study found that highly-polarised human bronchial epithelial Calu-3 cells responded to the viral infection by secreting IL-6, IL-8 and gamma interferon (IFN-γ)-inducible protein 10 (IP-10). These pro-inflammatory cytokines played a pivotal role in the production of other cytokines and phagocytosis while activating the naive T cells by modulating various functions of macrophages and DC (2). Further in-vitro verification using human peripheral blood also showed profound production of various inflammatory cytokines and confirmed that the SARS-CoV-induced Calu-3 cell cytokines were potent in stimulating macrophages and DC (2). In another coronavirus study using mouse hepatitis virus 3 (MHV3), the fixation of the spike (S) protein of MHV3 on toll-like receptor 2 (TLR2) activated the pro-inflammatory cytokines IL-6 and TNF-α production, but not viral replication (3). Although this early epithelial response is beneficial to combatting pathogens, extreme reactions could potentially exacerbate inflammatory responses, leading to severe tissue damage (4, 2). Empirical studies support the important role of IL-6 during viral infections but numerous reports also propose that the up-regulation of IL-6 expression may have negative consequences for the cellular immune response against viruses. Here, several potential mechanisms involving IL-6 might affect viral clearance, leading to the establishment of a persistent viral state in infected hosts (4). For example, during chronic hepatitis C virus (HCV) infections, the serum IL-6 levels are associated with the viral load and the period of infection (3). Clinical studies also show exacerbation of outcomes involving viral infection in humans and animals, linking the increased systemic levels of IL-6 with the chronic occurrence of influenza and several other viruses. (4). Therefore, it is hypothesised that over-expression of IL-6 during certain viral infections potentially enhances virus endurance and/or exacerbation of disease pathogenesis (4). Potentially useful in these cases, honey is a natural substance with several known benefits. Honey is rich in phenolic compounds, mainly flavonoids and phenolic acids, which act as potent antioxidants (5). Honey’s anti-inflammatory action is also well-documented (6). Stingless bee honey is a type of honey produced by a stingless bee (Meliponine sp.) (7) that is richer in polyphenols compared to other types of honey (8). Stingless bee honey is only produced in tropical and subtropical regions and features a sweet-sour taste, high moisture content and minimal crystallisation. Recent evidence indicates that stingless bee honey has many potential therapeutic benefits, including antibacterial qualities (9), anti-obesity impacts, (10) and others (11–13). Stingless bee honey possesses several valuable properties under pathological conditions, rendering it a promising functional food that could be a reasonable dietary intervention to prevent or treat chronic subclinical systemic (CSSI) related diseases (8). Recent research in late 2019 showed that in-vitro treatment of the lipopolysaccharide (LPS)-stimulate macrophages with stingless bee honey inhibited the TNF-α parameter by 23.0% and IL-6 secretion was reduced by 43.9%. Stingless bee honey also significantly reduced interferon secretion with inhibition of up to 88.8% (14). The findings of this study aligned with previous in-vivo research where stingless bee honey decreased the circulating levels of C-reactive protein (CRP), TNF-α, IL-1β, IL-6, IL-8 and monocyte chemoattractant protein-1 (MCP-1). It also diminished NF-κB and p38 mitogen-activated protein kinase (MAPK) signaling in different tissues of LPS-induced rats. Simultaneously, stingless bee honey boosted antioxidant defenses and showed a capability to reduce inflammation (8). Analytical chemistry of stingless bee honey indicates several potential phenolic compounds, including gallic acid, caffeic acid, chrysin, cinnamic acid, 2-hydroxycinnamic acid, kaempferol, p-coumaric acid, catechin, quercetin-3-O-rutinosid, caffeic acid phenethyl ester and 4-hydroxybenzoic acid (8). Vitamin C was also detected at 83.34 mg/100 g stingless bee honey, much higher than Tualang honey at 29.5 mg/100 g (16). In a clinical observation of healthy adults after honey (Apis sp.) consumption, results showed a potential use of honey during pathological conditions (15). A clinical trial indicated supplementing a diet with 1.5 g/kg of honey increased antioxidant levels (8). Even though the high heterogeneity of honey composition associated with geographical origin could give variable outputs in clinical settings (14), the anti-inflammatory properties seem to be related to the phenolic compound that is consistently present in stingless bee honey. Additionally, secondary bacterial infection following viral infection occurs in 50% of COVID-19 patients (1). The consumption of stingless bee honey could again be beneficial here as stingless bee honey has shown potential antibacterial activity against Gram-positive and Gram-negative bacteria. The properties against the pathogenic bacterial result from the synergistic action of the different antimicrobial factors in honey, such as osmosis, the presence of phenolic compounds, and the production of hydrogen peroxide, all of which act against the pathogenic bacteria (9). In summary, primary cytokines initiation is crucial in the establishment of innate immunity; however, an over-reactive inflammatory response can also exacerbate the disease without an increase in viral replication (3). Virus manipulations that lead to the overexpression of IL-6 cytokines perhaps aggravate the pathogenesis. Here, acute epithelial cytokine-mediated up-regulation of cytokine responses, in association with macrophages and DC, possibly represent a vital pathway in SARS pathogenesis (2). The inhibitory properties of honey on inflammatory signaling and its crucial role in harmonising the IL-6 cascades may be an alternative approach to limiting the disease progression of coronavirus. The pharmacological features of stingless bee honey are often related to the presence of bioactive compounds, mainly phenolic compounds (14). Therefore, it is crucial that we standardise quality control on stingless bee honey production and begin strategic design for clinical trials in pneumonia management. Meanwhile, acknowledging the inevitability of conventional infectious disease management, the key role of alternative medicine like honey should not be dismissed in this critical moment. As mentioned in Quran surah Al-Nahl (the Bee) verse 69: “then eats from all the fruits and follows the ways of your God laid down [for you], there emerges from their bellies a drink, varying in colours, in which there is healing for people, indeed that is a sign for a people who give thought”. Thus, the stingless bee honey may be considered as a functional food to complement treatment of early infected patient during this lethal outbreak.

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          Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

          Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p<0·0001), and d-dimer greater than 1 μg/mL (18·42, 2·64–128·55; p=0·0033) on admission. Median duration of viral shedding was 20·0 days (IQR 17·0–24·0) in survivors, but SARS-CoV-2 was detectable until death in non-survivors. The longest observed duration of viral shedding in survivors was 37 days. Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.
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            The Role of Interleukin 6 During Viral Infections

            Our recently published research on the characterization of vesicular stomatitis virus (VSV) pathogenesis in swine, identified a systemic upregulation of interleukin 6 (IL-6) during the acute phase of infection (Velazquez-Salinas et al., 2018). This upregulation was observed during infection with a highly virulent VSV strain, suggesting a potential association between IL-6 levels and virus virulence in pigs. In this opinion note we would like to explore in more detail the biological functions of IL-6 in different virus models, and present our perspective regarding the debatable role of IL-6 during viral infections. While several studies show the essential role of IL-6 to mount a proper immune response during some viral infections, others link this cytokine with exacerbation of viral disease. These latter findings lend support to the hypothesis that upregulation of IL-6 during certain viral infections may promote virus survival and/or exacerbation of clinical disease. IL-6 is a pleotropic cytokine produced in response to tissue damage and infections (Tanaka et al., 2014). Multiple cell types including fibroblasts, keratinocytes, mesangial cells, vascular endothelial cells, mast cells, macrophages, dendritic cells, and T and B cells are associated with the production of this cytokine (Mauer et al., 2015). After targeting its specific receptor, IL-6 starts a cascade of signaling events mainly associated with the JAK/STAT3 activation pathway (Wang et al., 2013) promoting the transcription of multiple downstream genes associated with cellular signaling processes, including cytokines, receptors, adaptor proteins, and protein kinases (Pim-1, LDL-receptor, GADD45 beta, SOCS1, MAP3K8, SOCS3, GLUT3, HB-EGF, ICAM1, Mx1, PTP4A3, SGK, Pim-2, RHOBTB3, cAMP-GEFII, PDGF-receptor alpha, MLCK). It also controls the production of proteins implicated in regulation of gene expression (Blimp1, id-2H, MAFF, TTP, C/EBP-beta, SRY, TCF8, c-jun, junB, Bcl-3, Bcl-5, DEC1, Nmi, Stat1, eIF5, OBF-1, Oct-2, Stat3; Brocke-Heidrich et al., 2004). The number of genes regulated by IL-6 activity may explain the pleotropic nature of this interleukin. Accordingly, the biological consequences of IL-6 production have been associated with both pro- and anti-inflammatory effects (Scheller et al., 2011), highlighting IL-6's pivotal role in the activation and regulation of the immune response. Biological activities affected by production of IL-6 include: control of the differentiation of monocytes into macrophages by regulating the expression of macrophage colony-stimulating factor (Chomarat et al., 2000), increasing B-cell IgG production by regulating the expression of IL-21 (Yang et al., 2016), negative regulation of dendritic cell maturation by activation of the STAT3 signaling pathway (Park et al., 2004), as well as the promotion of the Th2 response by inhibiting Th1 polarization (Diehl and Rincon, 2002). Two different mechanisms have been described to promote the inhibition of Th1 polarization by IL-6: (1) IL-6 stimulates CD4 T cells to secrete IL-4 and direct the response to Th2, and (2) IL-6 affects the secretion of IFNγ by CD4 T cells, an essential interferon to promote Th1 polarization. A similar effect is produced in Th1 cells, where inhibition of IFNγ secretion in these cells affects CD8 T cell activation (Dienz and Rincon, 2009; Green et al., 2013). Moreover, in combination with the transforming growing factor beta, IL-6 induces the differentiation of naïve CD4 into Th17 cells, which are important for the defense against pathogens at mucosal sites (Guglani and Khader, 2010). Also, IL-6 synergic interactions with IL-7 and IL-15 induce the differentiation and cytolytic capacity of CD8 T cells (Cox et al., 2013). Importantly, IL-6 is a potent pyrogenic cytokine, and has an essential role organizing lymphocyte trafficking to lymphoid organs during febrile events (Evans et al., 2015). In addition to its roles modulating the host immune response, IL-6 has been implicated in the progression of several virus infectious. 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; Dienz and Rincon, 2009). Direct evidence supporting the importance of IL-6 during viral infections has been gathered in experimental infections using IL-6-deficient mice. Using this model, IL-6 has been shown to be essential for survival of mice infected with influenza virus by promoting optimal regulation of the T-cell response, inflammatory resolution, tissue remodeling promoting lung repair, migration and phagocytic activities of macrophages, preventing viral-induced apoptosis in lung epithelial cells, and regulation of IgG isotype switching (Lauder et al., 2013; Yang et al., 2017). Other reports have also emphasized the importance of IL-6 during virus infections. Disruption of the IL-6 gene in mice infected with vaccinia virus impaired the immune response by reducing the activity of specific cytotoxic T-cells, while murine infection with VSV impaired the production of specific IgG antibodies (Kopf et al., 1994). Additional evidence of IL-6's function during a virus infection was observed during lymphocyte choriomeningitis virus infection of mice where IL-6 and/or IL-6R activity was blocked using specific monoclonal antibodies. In this model, T helper and B-cell responses were reduced during the late stages of infection, negatively affecting viral clearance (Harker et al., 2011). Genetically engineered rabies virus carrying the IL-6 gene in its genomic backbone has been used as an alternative model of experimentation to assess the relevance of IL-6 during viral infections (Luo et al., 2018). Normal mice infected with this virus showed a higher resistance to the viral infection compared with mice infected with the parental virus. Animals infected with the engineered virus had an increased blood-brain barrier permeability with a higher number of specific CD8-T and B-cells, increased levels of circulating neutralizing antibodies, and an intensified innate immune response in the brain as defined by up-regulation of multiple interferon-stimulated genes (ISG15, ISG20, OAS1, OAS2, and MX2). As a warning signal during viral 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, DNA 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, and unmethylated CpG DNA), which stimulate transcription of IL-6 among other proinflammatory cytokines (Kawai and Akira, 2010; Tanaka et al., 2014). In this context, it has been shown that specific amino acid substitutions in a TLR-like structure in the NS4B protein of a highly virulent classical swine fever virus (CSFV) strain resulted in a completely attenuated phenotype in pigs. Infection of pigs with this mutant CSFV was characterized by the sustained accumulation of IL-6 in tonsils. Further in vitro experiments using exogenous IL-6 confirmed the ability of this cytokine to repress the replication of CSFV in swine peripheral blood mononuclear cells, the natural target cell during CSFV infection in pigs (Fernandez-Sainz et al., 2010). Similarly, evidence of the antiviral effect of IL-6 was described during in vitro studies conducted with hepatitis B virus (HBV) where the direct ability of exogenous IL-6 to suppress the replication of this virus was described. Disruption of HBV replication was characterized by a marked decrease in the number of viral genome-containing nucleocapsids, an effect mediated in an interferon-independent manner (Kuo et al., 2009). Furthermore, IL-6 was able to block HBV infection in hepatocytes by inhibiting expression of HBV receptor in the human liver, i.e., the bile acid transporter Na (+)/taurocholate co-transporting polypeptide (Bouezzedine et al., 2015), and effectively disrupted epigenetic control of the nuclear cccDNA mini-chromosome, inhibiting HBV transcription (Palumbo et al., 2015) and the expression of hepatocyte nuclear transcription factors 1 and 4 alpha (Hosel et al., 2009). However, experimental scientific evidence also suggests potential negative consequences that increased levels of IL-6 might have on the cellular immune response against viruses. In this context different potential mechanisms involving this cytokine might affect viral clearance, ultimately favoring the establishment of a viral persistent state in infected hosts. First, in-vitro secretion of IL-6 by activated splenocytes, as a consequence of stimulation of toll like receptor 1/2 by the agonist P3C, inhibited effector CD8 T-cell responses by impairing the production of interferon gamma (IFN-γ) when compared with similarly activated and stimulated splenocytes from IL-6−/− mice (Wu et al., 2015). Similar results were obtained providing an exogenous source of IL-6, confirming the ability of IL-6 to negatively regulate effector CD8 T-cell response after T cell activation. This inhibition was orchestrated through the STAT3 signaling pathway producing the upregulation of suppressor of cytokine signaling (SOCS3) that reduces the STAT4 phosphorylation pathway induced by IL-12, which is essential for effector CD8-T cell differentiation (Wu et al., 2015). Furthermore, in vivo blockage of IL-6 using a monoclonal antibody during acute infection in mice with murine leukemia virus resulted in reduced viral loads, and increased production of IFN-γ and the serine protease granzyme B (essential to produce apoptosis in target cells; Wu et al., 2015). Second, the synergistic interaction between IL-6 and interleukin 17 (IL-17) have been associated with viral persistence and exacerbated clinical outcome during infection with Theiler's murine encephalomyelitis virus (TMEV). Genetically engineered mice carrying a human IL-6 transgene have excessive production of IL-6, leading to increased production of Th17 cells during an immune response. The IL-6 and IL-17 synergistic interaction leads to induction of anti-apoptotic molecules (Bcl-2 and Bcl-xL) inhibiting the destruction of TMEV-infected cells by virus-specific CD8+ T-cells, therefore favoring virus survival (Hou et al., 2014). Also, inhibition of apoptosis by IL-17 seems to be associated with the ability of this cytokine to block the Fas-FasL pathway (Hou et al., 2009). Interestingly, the induction of immunopathology, prevention of Th1 cells, and the inhibition of IL-2 and IFN-γ production have been mentioned as potential detrimental factors induced by Th17 cells during viral infections caused by influenza virus, Mouse hepatitis virus, hepatitis C virus, herpes simplex virus, and coxsackie virus B3 (Martinez et al., 2012). The last potential mechanism links IL-6 with the negative co-stimulator molecules programmed cell death one (PD-1) and its ligand (PDL-1). Under normal conditions, PD-1 and PDL-1 prevent autoimmunity by inducing T-cell regulation and maintaining self-tolerance (Bardhan et al., 2016). However, during chronic viral infections, T-cell ligation of PD-1 by PDL-1, expressed on infected cells, alters immunity against viruses by preventing T-cell generation and expansion (Bardhan et al., 2016). Experimental evidence evaluating the induction of PD-1 and PDL-1 after infection with TMEV in normal and transgenic IL-6 mice showed that the excessive production of IL-6 displayed by transgenic mice after infection positively correlates with increased up-regulation of PD-1 and PDL-1 molecules in the central nervous system, and consequently with reduced CD8+ cytolytic function (Jin et al., 2013). Interestingly, PD-1 and PDL-1 up-regulation appeared to be the result of the cooperative action between IL-6 and interferon type I, with IL-6 essential to the expression of maximum levels of PDL-1 (Jin et al., 2013). Evidence from clinical studies in humans and animals have also linked the increased systemic levels of IL-6 with the exacerbation of clinical outcomes involving viral pathogens. In this context, increased levels of IL-6 in serum has been reported in human patients chronically affected with Andes virus (Angulo et al., 2017), influenza virus (Zheng et al., 2017), HBV (Torre et al., 1994), hepatitis C virus (Spanakis et al., 2002), human immunodeficiency virus (HIV; Borges et al., 2015), Crimean-Congo hemorrhagic fever virus (Ergonul et al., 2017), and Chikungunya virus (Chirathaworn et al., 2013). Similar results have been reported in pigs and ponies infected with VSV and influenza virus, respectively, where the virulence of different strains might be positively correlated with both local and systemic detection of IL-6 (Wattrang et al., 2003; Velazquez-Salinas et al., 2018). Additionally, transcriptome analysis of persistently infected pharyngeal tissues collected from cattle with foot and mouth disease virus showed a local increase of IL-6 expression (Pacheco et al., 2015), suggesting that overexpression of IL-6 might be a possible mechanism favoring persistence of some viruses. Similarly, in HIV-infected individuals increased levels of IL-6 positively correlated with levels of residual viremia, while in ectocervical tissues, the presence of IL-6 was correlated with enhanced transcriptional levels of HIV-1 (Rollenhagen and Asin, 2011). In conclusion, there is plentiful evidence supporting a significant role of IL-6 during viral infections. However, certain scenarios create disparity of IL-6 production that may be detrimental to the cellular immune response during viral infections. Two different hypotheses may be considered to explain the change in IL-6 production during the immune response to viral infection: (i) the increased ability of some viral strains to overcome the immune response using a variety of evasion strategies (Beachboard and Horner, 2016), and consequently up-regulate the production of IL-6 as a result of increased viral loads, and (ii) polymorphisms in the IL-6 gene promoter stimulating overexpression of IL-6 during the immune response, a fact that has been shown to correlate with HBV progression (Lan et al., 2015). This last hypothesis might explain clinical reports correlating IL-6 overexpression with exacerbation of clinical outcomes in a sub-group of individuals during an outbreak caused by a single virus strain. Interestingly, this is consistent with experimental evidence in transgenic IL-6 mice (discussed below). Experimental evidence supports the observation 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 (Figure 1). 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 (Shin and Wherry, 2007; Bardhan et al., 2016). Increased levels of IL-6 might also exacerbate the immunopathology during chronic infections by increasing inflammation followed by cytokine secretion and cellular recruitment as described during autoimmune diseases (Srirangan and Choy, 2010). In fact, this condition of increased inflammation may be an advantage for some viruses by providing new cellular targets for subsequent viral infections (Pingen et al., 2016). Figure 1 Overexpression of IL-6 and its potential negative consequences on the viral immune response. Current scientific evidence supports different scenarios where imbalance on the IL-6 production after viral infection can affect viral clearance, promoting viral persistence and chronic infections. (A) IL-6 might favor Th2 polarization by stimulating STAT3 pathway, and consequently increasing the production of IL-4, and the suppressor of cytokine signaling one protein (SOCS-1). SOCS-1 affects STAT 1 phosphorylation, impairing IFNγ production by decreasing IFNγ self-loop stimulation. (B) IL-6 might impair cytolysis by inducing the production of SOCS-3, affecting phosphorylation of STAT 4, and consequently impairing IFNγ production, an essential IFN type II interferon molecule to promote CD8 and NK cells activation. (C) IL-6 might promote infected cell survival by inducing apoptosis. Overexpression of this cytokine increments Th17 polarization, increasing IL-17 production in the cellular environment. IL-17 pathway induce the production of the anti-apoptotic B-cell lymphoma 2 (Bcl-2) and B-cell lymphoma extra-large (Bcl-xL) proteins, which prevent mitochondrion to produce the cytochrome complex protein (Cyt-c) after stimulation by the pro-apoptotic molecule protease Granzyme B, impairing the production of active apoptotic caspase molecules. An additional scenario includes the production of the programmed death ligand 1 protein (PD-L1) by the concerted action of IFN type I and IL-6. Matching between PD-L1 and programed death protein 1 (PD-1) switches off apoptosis mediated by CD8 T cells. An interesting question arises regarding the potential of some viruses to selectively up-regulate IL-6 levels as a possible immune evasion strategy. Although right now there is no scientific evidence to support the causal relationship between IL-6 levels and virulence, it could open new lines of research considering the capability of other intracellular microorganisms, like Mycobacterium tuberculosis, to induce overexpression of IL-6 to inhibit the autophagy process in infected cells (Dutta et al., 2012) Further work is necessary to clarify the exact role of IL-6 during virus infections and the potential role of this cytokine to be used as a biomarker of viral virulence. Additional work exploring the potential therapeutic use of blocking IL-6 or different products affected by its activity might provide insight into controlling persistent viral infections. Caution is warranted for these kinds of studies, considering the conflicting effects of this interleukin during the progression of different viral infections. It is possible that the apparent contradictory function of IL-6 may depend on diverse triggering events that can be directly linked to the characteristics inherent to each virus infection. The pleiotropism of IL-6 function might stem from different viral stimuli activating distinct patterns of effector host mechanisms and their corresponding consequences. Author Contributions LV-S, AV-R, LR, and MB conceived, designed, and wrote this manuscript. Conflict of Interest Statement The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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              Severe acute respiratory syndrome (SARS) coronavirus-induced lung epithelial cytokines exacerbate SARS pathogenesis by modulating intrinsic functions of monocyte-derived macrophages and dendritic cells.

              Severe acute respiratory syndrome (SARS), which is caused by a novel coronavirus (CoV), is a highly communicable disease with the lungs as the major pathological target. Although SARS likely stems from overexuberant host inflammatory responses, the exact mechanism leading to the detrimental outcome in patients remains unknown. Pulmonary macrophages (Mphi), airway epithelium, and dendritic cells (DC) are key cellular elements of the host innate defenses against respiratory infections. While pulmonary Mphi are situated at the luminal epithelial surface, DC reside abundantly underneath the epithelium. Such strategic locations of these cells within the airways make it relevant to investigate their likely impact on SARS pathogenesis subsequent to their interaction with infected lung epithelial cells. To study this, we established highly polarized human lung epithelial Calu-3 cells by using the Transwell culture system. Here we report that supernatants harvested from the apical and basolateral domains of infected Calu-3 cells are potent in modulating the intrinsic functions of Mphi and DC, respectively. They prompted the production of cytokines by both Mphi and DC and selectively induced CD40 and CD86 expression only on DC. However, they compromised the abilities of the DC and Mphi in priming naïve T cells and phagocytosis, respectively. We also identified interleukin-6 (IL-6) and IL-8 as key SARS-CoV-induced epithelial cytokines capable of inhibiting the T-cell-priming ability of DC. Taken together, our results provide insights into the molecular and cellular bases of the host antiviral innate immunity within the lungs that eventually lead to an exacerbated inflammatory cascades and severe tissue damage in SARS patients.
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                Author and article information

                Journal
                Malays J Med Sci
                Malays J Med Sci
                Malaysian Journal of Medical Sciences
                The Malaysian Journal of Medical Sciences : MJMS
                Penerbit Universiti Sains Malaysia
                1394-195X
                2180-4303
                March 2020
                30 April 2020
                : 27
                : 2
                : 165-169
                Affiliations
                [1 ]Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia
                [2 ]Department of Pathology, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia
                [3 ]Department of Pharmacology, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia
                [4 ]Brain and Behaviour Cluster, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia
                Author notes
                Correspondence: Dr Mohd Zulkifli Mustafa, Lecturer and Neuroscientist, PhD (Universiti Sains Malaysia), MD (Veterinary Medicine) (Universiti Putra Malaysia) Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia, Tel: +09 7676300, E-mail: zulkifli.mustafa@ 123456usm.my
                Article
                17mjms27022020_le
                10.21315/mjms2020.27.2.17
                7409568
                32788852
                17117c67-ed71-4661-8997-1f77b3850719
                © Penerbit Universiti Sains Malaysia, 2020

                This work is licensed under the terms of the Creative Commons Attribution (CC BY) ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 25 March 2020
                : 02 April 2020
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