Dengue is the most important viral disease transmitted to humans by the bite of the Aedes aegypti mosquito in most tropical and subtropical countries of the world [1] [2] . There are an estimated 50 to 100 million cases of dengue fever worldwide every year [3] . Isolated for the first time in 1925 in Burkina Faso, the country recorded 79,867 suspected cases including 34,687 probable cases and 349 deaths in 2023 [4] [5] . Dengue virus (DENV) is a single-stranded RNA virus of positive polarity of 10.7 Kb, belonging to the genus Flavivirus [6] .

There are 5 serotypes of the virus which are genetically related but antigenically distinct, classified as DENV 1 to 5 [7] . DENV 1, 2, 3 and 4 are each capable of causing self-limiting fevers to fatal states. Infection with any of the four viral serotypes confers protective immunity against reinfection with the same serotype only, while subsequent infection with other serotypes can result in severe dengue [6] . DENV 5, isolated in 2013, follows a purely sylvatic cycle [7] . The main target cells of DENV in vitro are monocytes, macrophages and dendritic cells [8] . Generally, dengue can be asymptomatic or cause mild illness during a primary infection. However, a second infection can be fatal [9] [10] . Environmental factors, the serotype/genotype of the dengue virus, the immune response and the genetic make-up of the host are considered to influence the development of the clinical manifestations of dengue, as well as the severity of the disease [11] [12] . And the host immune response has been highlighted as a genetic marker of the disease with the production and release of several pro-inflammatory, antiviral and immunoregulatory cytokines [11] [13] . The host immune response is primarily determined by the recognition of the virus by the host cells and the subsequent antiviral response. Th1 cells are typically associated with an acute phase of fever, while Th2 cells are expressed throughout the infection, leading to endothelial cell dysfunction and causing plasma leakage. The activation of T lymphocytes triggers a cytokine cascade. During DENV infection, these cytokines can be secreted by macrophages and monocytes [7] .

Previous studies shown that cytokines have a significant impact on the severity of dengue fever, including alpha tumor necrosis factor (TNF-α), interleukin 6 (IL6), interleukin 10 (IL10), interleukin 17 (IL17) and gamma interferons (IFN-γ) [10] [12] [14] . In addition, single-nucleotide polymorphisms (SNPs) in the genes for these cytokines have contributed significantly to our understanding of pathophysiology and the role of host genetics in dengue infection [15] [16] . Serum concentrations of TNF-α, IL6, IL2, and INF-γ are elevated during the first three days of infection of DENV, while high levels of IL10, IL5, and IL4 appear later. The interaction of these cytokines, which can either increase or decrease their production, may be responsible for triggering the inflammatory process in infectious diseases [7] .

Interleukin 10 (IL10) plays a pleiotropic immune and inflammatory regulatory role in infectious diseases and is produced by monocytes, macrophages, dendritic cells, regulatory T cells (Tregs) [13] [17] . IL10 contains three distinct SNPs in its promoter region, at nucleotide positions 1082, 819, 592 [17] . In the pathogenesis of DENV, IL-10 has immunomodulatory activity, resulting in persistent viral infection, promoting inflammation and disease severity [12] . Polymorphisms of the IL10 gene could influence the Antibody-Dependent Enhancement reaction (ADE) [3] .

Given that cytokine production is influenced by genetic polymorphisms and that different genetic variants have been associated with dengue disease, it would be relevant to investigate the potential role of cytokine genetic polymorphisms, in the pathogenesis of dengue.

The aim of our study was to evaluate the role of interleukin 10 (IL-10) gene polymorphisms rs1800872 and rs1800896 in the pathogenesis of dengue fever and to assess their involvement in the progression of infection to severe forms of the disease in a Burkinabe population.

IL-10 is a major anti-inflammatory cytokine, essential in controlling the host immune response by regulating the production of several pro-inflammatory cytokines. It has been associated with several diseases and is considered an important immunoregulatory mediator produced by monocytes, dendritic cells and T and B lymphocytes [12] [14] . IL-10 is also likely to be regulated at transcriptional level by several polymorphisms, including 819 and 1082 [12] .

The aim of our study was to evaluate the involvement of IL10 gene polymorphisms in the pathogenesis of dengue disease and its progression to severe forms in a Burkinabe population. In the present study, the different IL10 polymorphisms showed that IL10-592 and IL10-1082 were statistically associated with DF and even progression from DF to the severe DS form.

Examining the genotypic distribution of IL10-592 polymorphisms, we found that the AA genotype (46.81% of DF cases and 53.57% in DS cases, with a p-value < 0.001) could be associated with the risk of developing DS, while the CA heterozygote (32.98%s of DF cases and 21.43% in DS cases, with a p-value < 0.001) could confer resistance in the progression to the DS form; and homozygous CC (20.21% of DF cases and 25.00% in DS cases, with a p-value < 0.001) would tend not to favor DF infection.

The GG genotype of the IL10-1082 gene could be a predisposing factor for DF and even progression to DS (52.69% DF and 58.06% DS). Whereas the AA genotype (19.35% DS/DF with p-value < 0.001) could be a protective factor against progression to DS. Gyeltshen et al. obtained a frequency of GG genotype associated with higher plasma levels of IL10-1082 [16] . According to the virus serotypes circulating in the study population, we obtained equal frequencies of AA and CA genotypes (24.14%) in serotype DENV1, which was the most frequently encountered. Serotype DENV4 was also present in the Burkinabe population, and the AA genotype of IL10-592 and the GG genotype of IL10-1082 were present at 3.45%. The study by Féitosa et al. in Brazil also shows an association of high IL10 levels with DENV1 infections [18] . The association of AG + AA mutant genotypes (47.31% of DF cases and 41.94% of DS cases; OR = 1.707; CI [1.020 - 1.873] with p-value = 0.040) of the IL10-1082 gene could confer slight protection against DS.

The allele C allele of IL10-592 is proportionally predominant in dengue cases with all CA+AA mutated genotypes, compared with the wild-type AA genotype, which would be a factor slowing down progression to DS (79.79% of DF cases and 75.00% in DS cases; OR = 0.378; CI [0.212 - 0.664] with a p-value = 0.001). Also, the A allele of IL10-1082 (OR = 1.521 CI [1.046 - 2.215], p-value = 0.027) was associated with the development of dengue and would not be indifferent in the progression to the DS form; this may be in line with the study of cytokine polymorphism frequencies in a population from Western Europe, Africa, Asia, the Middle East and South America, which obtained high frequencies of the IL10-1082 A allele, and also with the study on a Bhutanese population which found a frequency of the IL10-592 C allele at 53.86% [16] [17] .

Our results are in line with a large number of studies that have shown the association of the IL10 gene with dengue fever. Such as those obtained in Indonesia, which obtained higher IL10 levels in DF than in DS [10] ; in Cuba, which found that SNPs-1082 (G/A), and -592 (C/A) were associated with DHF risk [14] ; in Sri Lanka, which confirmed the association between the same genotypes and DHF, suggesting a risk factor for the development of DS, while alternative combinations were associated with protection against dengue hemorrhagic fever [11] ; and also in Brazil, which obtained a distribution of IL10-1082 genotypes [18] .

Knowing that one study had associated these genotypes with low IL10-expression we can suggest with other authors that dengue-associated genotypes could be responsible for the ineffective immune response and resulting severity [7] [11] [14] .

The results of this study showed a statistically significant association of IL10-592, IL-1082 gene polymorphisms in dengue virus infection in the Burkinabe population, and also their implications in disease progression to severe forms of the disease. Despite the studies carried out to understand the pathogenesis of dengue disease, questions remain as to how many genes contribute to susceptibility to dengue, and to what extent these genes interact with each other to cause severe disease. Further studies with other genes and also with the involvement of other arboviruses, particularly in cases of co-infections, in different population groups are essential for a complete understanding of the genetic associations with dengue infections.

We would like to thanks The World Academy of Sciences and the Swedish International Development Cooperation Agency (Sida) for funding this research through the grant No. 17-403 RG/BIO/AF/AC_I–FR3240297757. We thank also the UNESCO chaire in “Génie génétique et Biologie Moléculaire” for the technical support.

See ethical approval.

The datasets used and/or analyzed during the current study are available from the corresponding authors on reasonable request.

Conceptualization, data curation, formal analysis, methodology, writing—original draft, writing—review and editing by ASAT, FT, JS and FWD.

FWD, ASAT, FT, LT, SOTB, TWCO, RAO, PDI, MS, PSD and JS contributed for the samples analysis, validation, review and editing the manuscript.

FWD mobilized the funding for the study.

All authors read and approved the final version of the manuscript.