High Producing Tumor Necrosis Factor Alpha Gene Alleles in Protection against Severe Manifestations of Dengue

Sam, Sing‐Sin; Teoh, Boon‐Teong; Chinna, Karuthan; AbuBakar, Sazaly

doi:10.7150/ijms.8988

Cited by 25 publications

(16 citation statements)

References 59 publications

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“…Other researchers have reported that cross‐reactive heterotypic antibodies from a preceding DENV infection may play important roles in development of severe dengue . This is consistent with the finding that most individuals with severe dengue have previously been exposed to dengue . In contrast, cross‐protective mAbs between two different viruses isolated from patients with dengue reportedly confer protection against Zika virus .…”

supporting

confidence: 83%

Sera of patients with systemic lupus erythematosus cross‐neutralizes dengue viruses

Zainal

Tan

Johari

et al. 2018

Microbiology and Immunology

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Dengue is the most prevalent mosquito‐borne disease in Southeast Asia, where the incidence of systemic lupus erythematosus (SLE) is approximately 30 to 53 per 100,000. Severe dengue, however, is rarely reported among individuals with SLE. Here, whether sera of patients with SLE cross‐neutralize dengue virus (DENV) was investigated. Serum samples were obtained from individuals with SLE who were dengue IgG and IgM serology negative. Neutralization assays were performed against the three major DENV serotypes. Of the dengue serology negative sera of individuals with SLE, 60%, 61% and 52% of the sera at 1/320 dilution showed more than 50% inhibition against dengue type‐1 virus (DENV‐1), DENV‐2 and DENV‐3, respectively. The neutralizing capacity of the sera was significantly greater against DENV‐1 (P < 0.001) and DENV‐3 (P < 0.01) than against DENV‐2 (P < 0.05). Neutralization against the DENV correlated with dengue‐specific IgG serum titers below the cut‐off point for dengue positivity. Depletion of total IgG from the sera of patients with SLE resulted in significant decreases of up to 80% in DENV inhibition, suggesting that IgG plays an important role. However, some of the SLE sera was still able to neutralize DENV, even with IgG titers <0.1 OD absorbance. Our findings suggest that sera of patients with SLE contain IgG, and possibly other type of antibodies, that can cross‐neutralize DENV, which may explain the rarity of severe dengue in individuals with SLE. Further studies, are needed to further substantiate this finding and to elucidate the specific neutralizing epitopes recognized by the sera of individuals with SLE.

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supporting

confidence: 83%

Sera of patients with systemic lupus erythematosus cross‐neutralizes dengue viruses

Zainal

Tan

Johari

et al. 2018

Microbiology and Immunology

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“…This would suggest that its degradation alters not only the mRNA export but also the expression of Nup98dependent genes such as CDK9, RNAPII, and HLA-DRA, which in turn regulate the expression of TNF-alpha, inducible IL-6, and IFN-gamma 62 . All these cytokines are relevant during flavivirus infection 63 and its abundance has to be evaluated after transfection with WT and mutant viral proteases.…”

Section: Discussionmentioning

confidence: 99%

The Nonstructural Proteins 3 and 5 from Flavivirus Modulate Nuclear-Cytoplasmic Transport and Innate Immune Response Targeting Nuclear Proteins

Cervantes-Salazar

Gutiérrez-Escolano

Reyes-Ruiz

et al. 2018

Preprint

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Viruses hijack cellular proteins and components to be replicated in the host cell and to evade the immune response. Although flaviviruses have a cytoplasmic replicative cycle, some viral proteins such as the capsid (C) and the RNA dependent RNA polymerase, NS5, can reach the nucleus of the infected cells.Considering the important roles of NS5 in viral replication and in the control of the immune response, and its striking presence in the nucleus, the possible functions of this protein in some mechanisms orchestrated by the nucleus was analyzed. We isolated and identified nuclear proteins that interact with NS5; one of them, the DEAD-box RNA helicase DDX5 is relocated to the cytoplasm and degraded during infection with DENV, which correlates with its function in IFN dependent response.Since DDX5 and many other proteins are relocated from the nucleus to the cytoplasm during flavivirus infection, the integrity and function of the main regulator of the nuclear-cytoplasmic transport, the nuclear pore complex (NPC) was evaluated. We found that during DENV and ZIKV infection nucleoporins (NUPs) such as TPR, Nup153, Nup98, and Nup62 were cleavaged/degraded. The protease NS2B-NS3 induces NUPs degradation and it causes a dramatic inhibition of mature mRNAs export to the cytoplasm but not the export of DDX5 protein, which is dependent on NS5. Here we describe for the first time that the NS3 and NS5 proteins from flavivirus play novel functions hijacking the NPC and some nuclear proteins relevant in triggering immune response pathways, inducing a favorable environment for viral replication. IMPORTANCEViruses, as intracellular obligate parasites, hijack cellular components to enter and replicate in infected cells. Remarkably, in many cases, viruses hijack molecules with crucial functions for the cells. Here it is described how RNA viruses such as DENV and ZIKV, with a cytoplasmic replicative cycle, use NS3 and NS5, two of their unique non-structural proteins with enzymatic activity, to modulate nuclearcytoplasmic transport. We found that NS3 disrupts the nuclear pore complex, the main regulator in nuclear-cytoplasmic transport, causing a strong reduction in the the fatty acids synthase to the RC and viral infection increases the activity of the HMG CoA reductase (limiting enzyme in the cholesterol synthesis pathway). The activation of the HMG CoA reductase is a consequence of the inhibition of the molecule considered as the cellular metabolism controller, the AMP-dependent kinase (AMPK) 3 .Although there is an evident hijack of relevant cytoplasmic cell proteins, components and organelles during flaviviral infection, the hijack of nuclear components and the effect in cellular expression is poorly understood. Even though flaviviral infection takes place in the cytoplasm, two viral proteins are also located in the nuclei of infected cells; one is the C protein and the other, the NS5 protein. NS5 is the largest and most conserved viral protein (105 kDa and 900 amino acids) 4, 5 which contains three domains: the RNA dependent RNA...

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“…Functional assays have shown that transient suppression of TNF-α production during the early period of ADE infection in THP-1 cells promoted the initiation of DENV replication [39]. These results were contradicted in another work, where TNF-α at high and medium concentration inhibited DENV replication in human dendritic cells, a primary DENV target cells (cited in [40]). The promoter -308A allele has been related to enhanced TNF-α gene transcriptional activity [41], and different studies have associated it with diverse dengue phenotypes or failed to do so: protective against development of DHF/DSS in Malaysia [40]; not associated in Mexico [42]; dominant model marginally protective against DF in Brazil [43]; risk factor for DHF in Venezuela [44] and Cuba [45].…”

Section: Introductionmentioning

confidence: 95%

Population genetics-informed meta-analysis in seven genes associated with risk to dengue fever disease

Oliveira

Saraiva

Cavadas

et al. 2018

Infection, Genetics and Evolution

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Population genetics theory predicted that rare frequent markers would be the main contributors for heritability of complex diseases, but meta-analyses of genome-wide association studies are revealing otherwise common markers, present in all population groups, as the identified candidate genes. In this work, we applied a population-genetics informed meta-analysis to 10 markers located in seven genes said to be associated with dengue fever disease. Seven markers (in PLCE1, CD32, CD209, OAS1 and OAS3 genes) have high-frequency and the other three (in MICB and TNFA genes) have intermediate frequency. Most of these markers have high discriminatory power between population groups, but their frequencies follow the rules of genetic drift, and seem to have not been under strong selective pressure. There was a good agreement in directional consistency across trans-ethnic association signals, in East Asian and Latin American cohorts, with heterogeneity generated by randomness between studies and especially by low sample sizes. This led to confirm the following significant associations: with DF, odds ratio of 0.67 for TNFA-rs1800629-A; with DHF, 0.82 for CD32-rs1801274-G; with DSS, 0.55 for OAS3-rs2285933-G, 0.80 for PLCE1-rs2274223-G and 1.32 for MICB-rs3132468-C. The overall genetic risks confirmed sub-Saharan African populations and descendants as the best protected against the severer forms of the disease, while Southeast and Northeast Asians are the least protected ones. European and close neighbours are the best protected against dengue fever, while, again, Southeast and Northeast Asians are the least protected ones. These risk scores provide important predictive information for the largely naïve European and North American regions, as well as for Africa where misdiagnosis with other hemorrhagic diseases is of concern.

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High Producing Tumor Necrosis Factor Alpha Gene Alleles in Protection against Severe Manifestations of Dengue

Cited by 25 publications

References 59 publications

Sera of patients with systemic lupus erythematosus cross‐neutralizes dengue viruses

Sera of patients with systemic lupus erythematosus cross‐neutralizes dengue viruses

The Nonstructural Proteins 3 and 5 from Flavivirus Modulate Nuclear-Cytoplasmic Transport and Innate Immune Response Targeting Nuclear Proteins

Population genetics-informed meta-analysis in seven genes associated with risk to dengue fever disease

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