Association of the IFNG +874T/A Polymorphism with Symptomatic COVID-19 Susceptibility.

Tumor necrosis factor (TNF) and interferon-gamma (IFNγ) are important inflammatory mediators in the development of cytokine storm syndrome (CSS). Single nucleotide polymorphisms (SNPs) regulate the expression of these cytokines, making host genetics a key factor in the prognosis of COVID-19. In this study, we investigated the associations of the TNF -308G/A and IFNG +874T/A polymorphisms with COVID-19. We analyzed the frequencies of the two polymorphisms in the control groups (CG: TNF -308G/A, n = 497; IFNG +874T/A, n = 397), a group of patients with COVID-19 (CoV, n = 222) and among the subgroups of patients with nonsevere (n = 150) and severe (n = 72) COVID-19. We found no significant difference between the genotypic and allelic frequencies of TNF -308G/A in the groups analyzed; however, both the frequencies of the high expression genotype (TT) (CoV: 13.51% vs. CG: 6.30%; p = 0.003) and the *T allele (CoV: 33.56% vs. CG: 24. 81%; p = 0.001) of the IFNG +874T/A polymorphism were higher in the COVID-19 group than in the control group, with no differences between the subgroups of patients with nonsevere and severe COVID-19. The *T allele of IFNG +874T/A (rs2430561) is associated with susceptibility to symptomatic COVID-19. These SNPs provided valuables clues about the potential mechanism involved in the susceptibility to developing symptomatic COVID-19.

Severe COVID-19 and long COVID are associated with high expression of STING, cGAS and IFN-α.

The cGAS-STING pathway appears to contribute to dysregulated inflammation during coronavirus disease 2019 (COVID-19); however, inflammatory factors related to long COVID are still being investigated. In the present study, we evaluated the association of cGAS and STING gene expression levels and plasma IFN-α, TNF-α and IL-6 levels with COVID-19 severity in acute infection and long COVID, based on analysis of blood samples from 148 individuals, 87 with acute COVID-19 and 61 in the post-COVID-19 period. Quantification of gene expression was performed by real-time PCR, and cytokine levels were quantified by ELISA and flow cytometry. In acute COVID-19, cGAS, STING, IFN-α, TNF-α, and IL-6 levels were higher in patients with severe disease than in those with nonsevere manifestations (p < 0.05). Long COVID was associated with elevated cGAS, STING and IFN-α levels (p < 0.05). Activation of the cGAS-STING pathway may contribute to an intense systemic inflammatory state in severe COVID-19 and, after infection resolution, induce an autoinflammatory disease in some tissues, resulting in long COVID.

Polymorphisms in the MBL2 gene are associated with the plasma levels of MBL and the cytokines IL-6 and TNF-α in severe COVID-19.

Introduction: Mannose-binding lectin (MBL) promotes opsonization, favoring phagocytosis and activation of the complement system in response to different microorganisms, and may influence the synthesis of inflammatory cytokines. This study investigated the association of MBL2 gene polymorphisms with the plasma levels of MBL and inflammatory cytokines in COVID-19. Methods: Blood samples from 385 individuals (208 with acute COVID-19 and 117 post-COVID-19) were subjected to real-time PCR genotyping. Plasma measurements of MBL and cytokines were performed by enzyme-linked immunosorbent assay and flow cytometry, respectively. Results: The frequencies of the polymorphic MBL2 genotype (OO) and allele (O) were higher in patients with severe COVID-19 (p< 0.05). The polymorphic genotypes (AO and OO) were associated with lower MBL levels (p< 0.05). IL-6 and TNF-α were higher in patients with low MBL and severe COVID-19 (p< 0.05). No association of polymorphisms, MBL levels, or cytokine levels with long COVID was observed. Discussion: The results suggest that, besides MBL2 polymorphisms promoting a reduction in MBL levels and therefore in its function, they may also contribute to the development of a more intense inflammatory process responsible for the severity of COVID-19.

Cytokine Profiles Associated With Acute COVID-19 and Long COVID-19 Syndrome.

The duration and severity of COVID-19 are related to age, comorbidities, and cytokine synthesis. This study evaluated the impact of these factors on patients with clinical presentations of COVID-19 in a Brazilian cohort. A total of 317 patients diagnosed with COVID-19 were included; cases were distributed according to clinical status as severe (n=91), moderate (n=56) and mild (n=170). Of these patients, 92 had acute COVID-19 at sample collection, 90 had already recovered from COVID-19 without sequelae, and 135 had sequelae (long COVID syndrome). In the acute COVID-19 group, patients with the severe form had higher IL-6 levels (p=0.0260). In the post-COVID-19 group, there was no significant difference in cytokine levels between groups with different clinical conditions. In the acute COVID-19 group, younger patients had higher levels of TNF-α, and patients without comorbidities had higher levels of TNF-α, IL-4 and IL-2 (p<0.05). In contrast, patients over age 60 with comorbidities had higher levels of IL-6. In the post-COVID-19 group, subjects with long COVID-19 had higher levels of IL-17 and IL-2 (p<0.05), and subjects without sequelae had higher levels of IL-10, IL-6 and IL- 4 (p<0.05). Our results suggest that advanced age, comorbidities and elevated serum IL-6 levels are associated with severe COVID-19 and are good markers to differentiate severe from mild cases. Furthermore, high serum levels of IL-17 and IL-2 and low levels of IL-4 and IL-10 appear to constitute a cytokine profile of long COVID-19, and these markers are potential targets for COVID-19 treatment and prevention strategies.

Moderate endemicity of the human T-lymphotropic virus infection in the metropolitan region of Belém, Pará, Brazil. / Moderada endemicidade da infecção pelo vírus linfotrópico-T humano na região metropolitana de Belém, Pará, Brasil.

INTRODUCTION: The spread of the HTLV infection in families living in the metropolitan area of Belém, Pará, Brazil, and the lack of studies in the general population requires studies to better understand its prevalence in the region. METHODS: An anti-HTLV-1/HTLV-2 antibodies test was carried out on random adults in public places in Belém between November 2014 and November 2015. A proviral DNA test detected if the person was infected, and then a clinical evaluation and an intrafamilial investigation were carried out. RESULTS: Of the 1059 individuals being investigated, 21 (2.0%) had seroreagent samples, 15 (1.4%) had HTLV-1, 5 (0.5%) had HTLV-2, and proviral DNA was undetectable in one case. The mean age of the infected people (57.2) was higher than that of those that were uninfected (46.2) (p = 0.0010). The prevalence of infection increased with age, especially in individuals with a family income equal to or less than a minimum wage. Intrafamilial transmission seems to have occurred in all of the families being studied. Among the patients with HTLV-1, 30% (3/10) already had some symptom related to the infection. DISCUSSION: The increase in prevalence rates according to age may be due to late seroconversion of a previously acquired infection, or the cumulative risk of new infections, especially in women. CONCLUSION: There was a moderate prevalence of the HTLV infection among adult individuals from the metropolitan area of Belém, with a predominance of HTLV-1. This infection was associated with low income and increasingly older women. It also presented intrafamily spread and negligence in the diagnosis of associated diseases.

INTRODUÇÃO: A disseminação da infecção pelo vírus linfotrópico-T humano (HTLV) em famílias da área metropolitana de Belém, Pará, Brasil, e a ausência de estudos na população em geral requisitam investigações que esclareçam melhor a sua prevalência na região. METODOLOGIA: Foi realizada pesquisa de anticorpos anti-HTLV-1/HTLV-2 em indivíduos adultos transeuntes de logradouros públicos de Belém, entre novembro de 2014 e novembro de 2015. A infecção foi confirmada por pesquisa de DNA proviral e foi realizada avaliação clínica e investigação intrafamiliar dos infectados. RESULTADOS: Dos 1.059 indivíduos investigados, 21 (2,0%) apresentaram amostras sororeagentes, 15 (1,4%) confirmados para HTLV-1, 5 (0,5%) para HTLV-2 e o DNA proviral foi indetectável em 1 caso. A média de idade dos infectados (57,2) foi maior que a dos não infectados (46,2) (p = 0,0010). A infecção aumentou com a idade e se destacou nos indivíduos com renda familiar menor ou igual a um salário mínimo. A transmissão intrafamiliar parece ter ocorrido em todas as famílias investigadas. Dentre os portadores de HTLV-1, 30% (3/10) já apresentavam algum sintoma relacionado à infecção. DISCUSSÃO: O aumento da infecção de acordo com a idade pode ocorrer por soroconversão tardia de infecção pré-adquirida ou pelo risco cumulativo de novas infecções, sobretudo em mulheres. CONCLUSÃO: A infecção por HTLV demonstrou moderada prevalência na população estudada, com predomínio do HTLV-1. Essa mostrou-se associada à baixa renda e ao aumento da idade das mulheres. Também apresentou disseminação intrafamiliar e negligência no diagnóstico das doenças associadas.

Low genetic diversity of the Human T-cell Lymphotropic Virus (HTLV-1) in an endemic area of the Brazilian Amazon basin.

The Human T-cell Lymphotropic Virus (HTLV-1) is a Deltaretrovírus that was first isolated in the 1970s, and associated with Adult T-cell Leucemia-Lymphoma (ATLL), and subsequently to Tropical Spastic Paraparesis-Myelopathy (TSP/HAM). The genetic diversity of the virus varies among geographic regions, although its mutation rate is very low (approximately 1% per thousand years) in comparison with other viruses. The present study determined the genetic diversity of HTLV-1 in the metropolitan region of Belém, in northern Brazil. Blood samples were obtained from patients at the UFPA Tropical Medicine Nucleus between January 2010 and December 2013. The DNA was extracted and the PX region of the HTLV was amplified using nested PCR. The positive samples were then digested using the Taq1 enzyme for the identification and differentiation of the HTLV-1 and HTLV-2. The 5'LTR region of the positive HTLV-1 samples were amplified by nested PCR, and then sequenced genetically. The phylogenetic analysis of the samples was based on the maximum likelihood method and the evolutionary profile was analyzed by the Bayesian approach. Overall, 78 samples tested positive for HTLV-1, and 44 were analyzed here. The aA (cosmopolitan-transcontinental) subtype was recorded in all the samples. The following evolutionary rates were recorded for the different subtypes-a: 2.10-3, b: 2.69. 10-2, c: 6.23. 10-2, d: 3.08. 10-2, e: 6. 10-2, f: 1.78. 10-3, g: 2.2. 10-2 mutations per site per year. The positive HTLV-1 samples tested in the present study were characterized by their low genetic diversity and high degree of stability.

Moderada endemicidade da infecção pelo vírus linfotrópico-T humano na região metropolitana de Belém, Pará, Brasil / Moderate endemicity of the human T-lymphotropic virus infection in the metropolitan region of Belém, Pará, Brazil

RESUMO: Introdução: A disseminação da infecção pelo vírus linfotrópico-T humano (HTLV) em famílias da área metropolitana de Belém, Pará, Brasil, e a ausência de estudos na população em geral requisitam investigações que esclareçam melhor a sua prevalência na região. Metodologia: Foi realizada pesquisa de anticorpos anti-HTLV-1/HTLV-2 em indivíduos adultos transeuntes de logradouros públicos de Belém, entre novembro de 2014 e novembro de 2015. A infecção foi confirmada por pesquisa de DNA proviral e foi realizada avaliação clínica e investigação intrafamiliar dos infectados. Resultados: Dos 1.059 indivíduos investigados, 21 (2,0%) apresentaram amostras sororeagentes, 15 (1,4%) confirmados para HTLV-1, 5 (0,5%) para HTLV-2 e o DNA proviral foi indetectável em 1 caso. A média de idade dos infectados (57,2) foi maior que a dos não infectados (46,2) (p = 0,0010). A infecção aumentou com a idade e se destacou nos indivíduos com renda familiar menor ou igual a um salário mínimo. A transmissão intrafamiliar parece ter ocorrido em todas as famílias investigadas. Dentre os portadores de HTLV-1, 30% (3/10) já apresentavam algum sintoma relacionado à infecção. Discussão: O aumento da infecção de acordo com a idade pode ocorrer por soroconversão tardia de infecção pré-adquirida ou pelo risco cumulativo de novas infecções, sobretudo em mulheres. Conclusão: A infecção por HTLV demonstrou moderada prevalência na população estudada, com predomínio do HTLV-1. Essa mostrou-se associada à baixa renda e ao aumento da idade das mulheres. Também apresentou disseminação intrafamiliar e negligência no diagnóstico das doenças associadas.

ABSTRACT: Introduction: The spread of the HTLV infection in families living in the metropolitan area of Belém, Pará, Brazil, and the lack of studies in the general population requires studies to better understand its prevalence in the region. Methods: An anti-HTLV-1/HTLV-2 antibodies test was carried out on random adults in public places in Belém between November 2014 and November 2015. A proviral DNA test detected if the person was infected, and then a clinical evaluation and an intrafamilial investigation were carried out. Results: Of the 1059 individuals being investigated, 21 (2.0%) had seroreagent samples, 15 (1.4%) had HTLV-1, 5 (0.5%) had HTLV-2, and proviral DNA was undetectable in one case. The mean age of the infected people (57.2) was higher than that of those that were uninfected (46.2) (p = 0.0010). The prevalence of infection increased with age, especially in individuals with a family income equal to or less than a minimum wage. Intrafamilial transmission seems to have occurred in all of the families being studied. Among the patients with HTLV-1, 30% (3/10) already had some symptom related to the infection. Discussion: The increase in prevalence rates according to age may be due to late seroconversion of a previously acquired infection, or the cumulative risk of new infections, especially in women. Conclusion: There was a moderate prevalence of the HTLV infection among adult individuals from the metropolitan area of Belém, with a predominance of HTLV-1. This infection was associated with low income and increasingly older women. It also presented intrafamily spread and negligence in the diagnosis of associated diseases.