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After a chikungunya outbreak in Salvador, Brazil, we performed a cross-sectional, community-based study of 1,776 inhabitants to determine chikungunya virus (CHIKV) seroprevalence, identify factors associated with exposure, and estimate the symptomatic infection rate. From November 2016 through February 2017, we collected sociodemographic and clinical data by interview and tested serum samples for CHIKV IgG. CHIKV seroprevalence was 11.8% (95% CI 9.8%-13.7%), and 15.3% of seropositive persons reported an episode of fever and arthralgia. Infections were independently and positively associated with residences served by unpaved streets, a presumptive clinical diagnosis of chikungunya, and recall of an episode of fever with arthralgia in 2015-2016. Our findings indicate that the chikungunya outbreak in Salvador may not have conferred sufficient herd immunity to preclude epidemics in the near future. The unusually low frequency of symptomatic disease points to a need for further longitudinal studies to better investigate these findings.

The immunopathogenesis of chikungunya virus (CHIKV) infection and the role of acute-phase immune response on joint pain persistence is not fully understood. We investigated the profile of serum chemokine and cytokine in CHIKV-infected patients with acute disease, compared the levels of these biomarkers to those of patients with other acute febrile diseases (OAFD) and healthy controls (HC), and evaluated their role as predictors of chronic arthralgia development. Chemokines and cytokines were measured by flow Cytometric Bead Array. Patients with CHIKV infection were further categorized according to duration of arthralgia (≤ 3 months vs >3 months), presence of anti-CHIKV IgM at acute-phase sample, and number of days of symptoms at sample collection (1 vs 2-3 vs ≥4). Patients with acute CHIKV infection had significantly higher levels of CXCL8, CCL2, CXCL9, CCL5, CXCL10, IL-1β, IL-6, IL-12, and IL-10 as compared to HC. CCL2, CCL5, and CXCL10 levels were also significantly higher in patients with CHIKV infection compared to patients with OAFD. Patients whose arthralgia lasted > 3 months had increased CXCL8 levels compared to patients whose arthralgia did not (p3 months. Patients with chikungunya and OAFD had similar cytokine kinetics for IL-1β, IL-12, TNF, IFN-γ, IL-2, and IL-4, although the levels were lower for CHIKV patients. This study suggests that chemokines may have an important role in the immunopathogenesis of chronic chikungunya-related arthralgia.

Several variants involved in the expression of proteins related to immunopathological mechanisms have been associated with dengue, but few specifically related to severe dengue. In addition, children are a group with a high incidence and mortality rate due to dengue. Several immunopathological processes developed specifically in children affected with severe dengue partially explain this risk condition. This case-control retrospective study aimed to examine the association of variants in CD209, NFKBIA, IL12B, and IL1B genes with severe dengue. These genes encode proteins involved in one of the main pathways of the immune response against dengue virus infection. The study population included affected children and householding controls from Brazil. Genotyping was performed with Real-Time TaqMan assays, and the association analysis was performed with conditional logistic regressions. We found the IL1B rs1143634 genotypes carrying the T allele to be associated with susceptibility to severe dengue in children. The lower circulating levels of IL-1β associated with carrying the T allele of the IL1B rs1143634 suggest a role of this cytokine in the impairment of the immune response and plasma leakage, and, consequently, in the development of severe dengue.

Dengue is a major worldwide problem in tropical and subtropical areas; it is caused by four different viral serotypes, and it can manifest as asymptomatic, mild, or severe. Many factors interact to determine the severity of the disease, including the genetic profile of the infected patient. However, the mechanisms that lead to severe disease and eventually death have not been determined, and a great challenge is the early identification of patients who are more likely to progress to a worse health condition. Studies performed in regions with cyclic outbreaks such as Cuba, Brazil, and Colombia have demonstrated that African ancestry confers protection against severe dengue. Highlighting the host genetics as an important factor in infectious diseases, a large number of association studies between genetic polymorphisms and dengue outcomes have been published in the last two decades. The most widely used approach involves case-control studies with candidate genes, such as the HLA locus and genes for receptors, cytokines, and other immune mediators. Additionally, a Genome-Wide Association Study (GWAS) identified SNPs associated with African ethnicity that had not previously been identified in case-control studies. Despite the increasing number of publications in America, Africa, and Asia, the results are quite controversial, and a meta-analysis is needed to assess the consensus among the studies. SNPs in the MICB, TNF, CD209, FcγRIIA, TPSAB1, CLEC5A, IL10 and PLCE1 genes are associated with the risk or protection of severe dengue, and the findings have been replicated in different populations. A thorough understanding of the viral, human genetic, and immunological mechanisms of dengue and how they interact is essential for effectively preventing dengue, but also managing and treating patients.

Outbreaks of the Zika, dengue, and chikungunya viruses, especially in the Americas, pose a global threat due to their rapid spread and difficulty controlling the vector. Extreme phenotypes are often observed, from asymptomatic to severe clinical manifestations, which are well-studied in dengue. Host variations are also important contributors to disease outcomes, and many case-control studies have associated single nucleotide polymorphisms (SNPs) with severe dengue. Here, we found that the TC genotype and T-carriers for SNP rs1285933 in the C-type lectin superfamily member 5 (CLEC5A) gene was associated with severe dengue in a Northern Brazilian population (OR=2.75 and p-value=0.01, OR=2.11 and p-value=0.04, respectively). We also tested the functional effect of the CLEC5A protein and found that it is upregulated on the surface of human monocytes after in vitro dengue infection. CLEC5A was correlated with viral load inside the monocytes (Spearman r=0.55, p=0.008) and TNF production in culture supernatants (Spearman r=0.72, p=0.03). Analysis of mRNA in blood samples from DENV4-infected patients exhibiting mild symptoms showed that CLEC5A mRNA expression is correlated with TNF (r=0.67, p=0.0001) and other immune mediators. Monocytes from rs1285933 TT/TC individuals showed lower CLEC5A expression compared to CC genotypes. However, in these cells, CLEC5A was not correlated with TNF production. In summary, we confirmed that CLEC5A is genetically associated with dengue severity outcome, playing a central role during the immune response triggered by a dengue viral infection, and rs1285933 is a relevant SNP that is able to regulate signaling pathways after interactions between the dengue virus and CLEC5A receptors.

In Mycobacterium tuberculosis (MTB) infection, the complex interaction of host immune system and the mycobacteria is associated with levels of cytokines production that play a major role in determining the outcome of the disease. Several single-nucleotide polymorphisms (SNPs) in cytokine genes have been associated with tuberculosis (TB) outcome. The aim of this study was to evaluate the association between previously reported SNPs IL2-330 T>G (rs2069762); IL4-590 C>T (rs2243250); IL6-174 G>C (rs1800795); IL10-592 A>C (rs1800872); IL10-1082 G>A (rs1800896); IL17A -692 C>T (rs8193036); IL17A -197 G>A (rs2275913); TNF -238 G>A (rs361525); TNF -308 G>A (rs1800629) and IFNG +874 T>A (rs2430561) and pulmonary TB (PTB) susceptibility. We conducted a case-control study in individuals from Southern Brazil who were recruited between February 2012 and October 2013 in a high incidence TB city. We performed a multiplex genotyping assay in 191 patients with PTB and 175 healthy subjects. Our results suggest a decreased risk for PTB development associated with the IL17A -197A allele (OR = 0.29; p = 0.04), AA genotype (OR = 0.12; p = 0.04) and A carrier (AG/AA) (OR = 0.29; p = 0.004) and IL6 -174C carrier (CC/CG) (OR = 0.46; p = 0.04). We could not properly analyze IL17A -692 C>T (rs8193036) and IFNG +874T>A due to genotypic inconsistencies and found no evidence of association for the IL2, IL4, IL10 and TNF polymorphisms and PTB. In conclusion, our results show a protective effect of IL17 and IL6 polymorphisms on PTB outcome in Southern Brazilian population.

Dengue is an arthropod-borne emerging viral disease with high morbidity and mortality risk in tropical countries like Brazil. Clinical manifestations are vast, ranging from asymptomatic to most severe forms of dengue such as shock. Previous data have shown that host genetics play a role in disease susceptibility and severity. Herein, we have tested the association of single nucleotide polymorphisms (SNPs) at TNF, IL10, MIF, DCSIGN, CLEC5A, NOD2, CCR5 and MRC1 as candidate genes using a matched case–control study design including 88 severe children cases of dengue patients and 335 healthy unrelated subjects that was also separated in IgG+ and IgG− controls. We demonstrated that the TT genotype of CLEC5A SNP (rs1285933 C>T) is associated with dengue severity (OR = 2.25; p = 0.03) and that GG genotype of −336G>A DCSIGN (CD209) SNP is associated with protection to severe dengue (OR = 0.12; p = 0.04). Both comparisons were borderline significant when cases were compared with IgG+ controls subgroup. Nevertheless, genotype–phenotype correlation was also assessed using serum levels of TNF from infected patients at the onset of dengue fever, and CT/TT carriers in CLEC5A secreted higher levels of TNF than CC individuals in 5–7 days of infection. No significant difference was observed in TNF levels between genotypes GG versus AG/AA at DCSIGN promoter. Next, we performed a meta-analysis retrieving results from the literature for −336G>A DCSIGN and −308G>A TNF SNPs demonstrating that the consensus estimates of these SNPs indicated no association with dengue severity (when compared to Dengue fever) in the overall analysis. But, a subgroup analysis in the −336G>A DCSIGN, the G allele was associated with severe dengue susceptibility in Asians (ORallele = 2.77; p = 0.0001; ORcarriers = 2.99; p = 0.0001) and protection in Brazilians (ORallele=0.66; p=0.013). In summary, our results suggest that genetic variations at CLEC5A increase the risk and regulate TNF secretion in dengue severity among Brazilians. Also, combined data of the literature suggest population-specific effect of the −336 DCSIGN SNP more prominent in Asians and in a different direction than Brazilians.