Association of Genetic Polymorphisms in DC-SIGN, Toll-Like Receptor 3, and Tumor Necrosis Factor α Genes and the Lewis-Negative Phenotype With Chikungunya Infection and Disease in Nicaragua

Abstract

Background Chikungunya infections range from subclinical infection to debilitating arthralgia and to chronic inflammatory rheumatism. Tumor necrosis factor (TNF) α, DC-SIGN (dendritic cell–specific intercellular adhesion molecule 3–grabbing nonintegrin), Toll-like receptor (TLR) 3, and blood groups have been directly or indirectly implicated in the susceptibility and pathogenesis of chikungunya. Methods To test the hypothesis that polymorphisms in genes coding for these molecules determine clinical outcomes of chikungunya infection, a retrospective case-control study was performed in León, Nicaragua. The study included 132 case patients and 132 controls, matched for age, sex and neighborhood. Case patients had clinical symptoms of chikungunya, which was diagnosed by means of polymerase chain reaction. Controls were individuals not reporting abrupt presentation of clinical chikungunya-like symptoms. Polymorphisms were identified by TaqMan single-nucleotide polymorphism genotyping assays. Results After adjustment for sociodemographic risk factors, chikungunya disease was associated with polymorphism in DC-SIGN and TLR3 genes (odds ratios, 5.2 and 3.3, respectively), and TNF-α with reduced persistent joint pain (0.24). Persistent joint pain was also associated with age, female sex and other comorbid conditions. Most interestingly, the Lewis-negative phenotype was strongly associated with both symptomatic chikungunya and immunoglobulin G seropositivity (odds ratios, 2.7, and 3.3, respectively). Conclusion This study identified polymorphisms in DC-SIGN, TLR3, and TNF-α genes as well as Lewis-negative phenotype as risk factors for chikungunya infection and disease progression.

Immunopathogenesis of Different Emerging Viral Infections: Evasion, Fatal Mechanism, and Prevention

“…Genetic variants in IL6R, TLR3, and DC-SIGN genes were associated with susceptibility and/or severity of DF (75). Genetic polymorphisms of DC-SIGN, TLR3 and TNF-a genes are also risk factors for the susceptibility and disease progression of Chikungunya infection (76). Interferon-inducible transmembrane protein 3 (IFITM3) gene is associated with susceptibility to severe influenza (77), and the variant with higher TMPRSS2 expression confers a higher risk to susceptibility of human A(H7N9) influenza and severity of A (H1N1)09 influenza (78).…”

“…The viruses enter the lung epithelial cells and induce innate immunity with production of interferons which limit viral replication before adaptive immunity. In different virus-host interactions, the virulent antigen(s) of the viruses (112), or host genetic variants (74)(75)(76)(77)(78), could impair the innate immune response and cause proinflammation or immunosuppression, followed by altered hyperinflammation with skewed Th17 reaction (113,114). The viral RNA of SARS-CoV-1 and SARS-CoV-2 cannot only be detected in respiratory secretions but also in urine, feces, tears, and blood (115,116).…”

Chikungunya and Zika Viruses: Co-Circulation and the Interplay between Viral Proteins and Host Factors

“…It serves as an attachment factor for various types of viruses, including alphavirus (CHIKV [ 37 ]), flavivirus (DENV [ 172 ], JEV [ 173 ], HCV [ 174 ], WNV [ 175 ], and ZIKV [ 37 ]), filovirus (EBOV [ 176 ]), herpesvirus (CMV/HHV-5 [ 175 ], and Kaposi’s sarcoma herpes virus [ 177 ]), orthomyxovirus (influenza virus [ 178 ]), retrovirus (human immunodeficiency virus 1 (HIV-1) and HIV-2 [ 179 , 180 ]), and coronavirus (human coronavirus 229E [ 181 ], SARS-CoV and SARS-CoV-2 [ 175 , 182 , 183 , 184 ]). Polymorphism in DC-SIGN was reported as a risk factor for CHIKV infection and pathology [ 185 ]. This phenomenon is based on an alteration of the CD209 promoter gene (A/G (rs4804803) at position 336) and the greater frequency of this genotype in Chikungunya-infected patients compared to healthy controls [ 171 , 186 ].…”

Phosphatidylserine within the Viral Membrane Enhances Chikungunya Virus Infectivity in a Cell-type Dependent Manner

“…Virus-cell attachment is an essential step in viral invasion of the host cell. Matrix remodeling associated 8 (MXRA8) (22), glycosaminoglycans (GAGs) such as heparan sulfate (HS) (23–26), C-type lectins including DC-SIGN (27, 28), prohibitin 1 (PHB-1) (29) and phosphatidylserine (PS) receptors such as TIM-1 (30–32) or CD300a (33) have all been implicated in promoting CHIKV entry. The role of MXRA8 in CHIKV pathogenesis has recently been investigated in vivo (22, 34).…”

“…The copyright holder for this preprint this version posted January 15, 2022. ; https://doi.org/10.1101/2022.01.14.476428 doi: bioRxiv preprint (HS) (23)(24)(25)(26), C-type lectins including DC-SIGN (27,28), prohibitin 1 (PHB-1) (29) and phosphatidylserine (PS) receptors such as TIM-1 (30)(31)(32) or CD300a (33) have all been implicated in promoting CHIKV entry. The role of MXRA8 in CHIKV pathogenesis has recently been investigated in vivo (22,34).…”