Association of TLR variants with susceptibility to Plasmodium vivax malaria and parasitemia in the Amazon region of Brazil

Costa, Allyson Guimarães; Ramasawmy, Rajendranath; Ibiapina, Hiochelson Najibe Santos; Sampaio, Vanderson de Souza; Xabregas, Lilyane Amorim; Brasil, Larissa W.; Tarragô, Andréa Monteiro; Almeida, Anne Cristine Gomes de; Kuehn, Andrea; Vítor-Silva, Sheila; Melo, Gisely Cardoso de; Siqueira, André Machado; Lacerda, Marcus Vinícius Guimarães; Malheiro, Adriana

doi:10.1371/journal.pone.0183840

Cited by 21 publications

(20 citation statements)

References 69 publications

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“…The MAF of TLR9 −1237A/G and −1486A/G SNPs are 15.3 and 17.4% for the first SNP and 38.5 and 33.3% for the second in patients and controls, respectively. Similar high MAF for these SNPs were observed in other studies in the Amazonas ( 37 , 40 ).…”

Section: Discussionsupporting

confidence: 89%

“…Other studies in Brazil showed higher MAF varying from 4.6 to 7.0% ( 37 , 38 , 46 ). However, one study of case-controls of malaria from the Amazonas observed similar MAF to ours indicating the frequency is a reflex of the local population ( 40 ).…”

Section: Discussionsupporting

confidence: 85%

“…This study observed MAF for SNP 1805T/G of TLR1 of 25.0 and 27.0% in TB patients and controls, respectively. Previous studies of other infectious diseases in Brazil showed frequencies varying between 11.0 and 40.0% ( 37 – 40 ). Frequency of the MAF in other populations such as Spain, Turkey, and Nepal are 30.0, 43.0, and 6.0%, respectively ( 28 , 41 , 42 ).…”

Section: Discussionmentioning

confidence: 93%

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Toll-Like Receptor-1 Single-Nucleotide Polymorphism 1805T/G Is Associated With Predisposition to Multibacillary Tuberculosis

et al. 2018

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Tuberculosis (TB), caused by mycobacterial species of the Mycobacterium tuberculosis complex, is a serious global health issue. Brazil is among the 22 countries with the highest number of TB cases, and the state of Amazonas has the highest incidence of TB cases in the country. Toll-like receptors (TLRs) are important pattern recognition receptors of the innate immunity and play a key role in orchestrating an effective immune response. We investigated whether the single-nucleotide polymorphisms (SNPs) 1805T/G TLR1, 2258G/A TLR2, 896A/G and 1196C/T of TLR4, 745T/C TLR6, and −1237A/G and −1486A/G of TLR9 are associated with the predisposition to TB and/or bacillary load. The SNPs genotyping was performed by nucleotide sequencing in 263 TB patients and 232 healthy controls residing in the state of Amazonas. Alleles and genotypes frequencies were similar between patients and healthy individuals for most of the investigated SNPs. Stratification of the TB patients according to their bacillary load showed that the genotype 1805TT TLR1 (rs5743618) was prevalent among paucibacillary patients [odds ratio (OR) = 0.38; 95% confidence interval (CI) = 0.19–0.76; p = 0.009] while the genotype 1805TG was common among multibacillary patients (OR = 3.72; CI = 1.65–8.4; p = 0.004). Comparison of demographic characteristics of patients to controls showed that TB is strongly associated with smoking (OR = 6.55; 95% CI = 3.2–13.6; p < 0.0001); alcohol use disorder (OR = 7.14; 95% CI = 3.7–13.9; p < 0.0001); and male gender (OR = 3.66; 95% CI = 2.52–5.3; p < 0.0001). Multivariate logistic regression demonstrated that alcoholism (OR = 2.93; 95% CI = 1.05–8.16; p = 0.03) and the 1805G allele (OR = 2.75; 95% CI = 1.33–5.7; p = 0.006) are predictive variables for multibacillary TB. Altogether, we suggest that the TLR1 1805G allele may be a relevant immunogenetic factor for the epidemiology of TB together with environmental, sociodemographic, and behavioral factors.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 93%

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Toll-Like Receptor-1 Single-Nucleotide Polymorphism 1805T/G Is Associated With Predisposition to Multibacillary Tuberculosis

et al. 2018

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“…On the other hand, the TLR9 variant −1237C/C correlates with acute parasitemia during a P. vivax infection [81]. An endoplasmic reticulum resident protein, UNC93B1, is critical for host resistance to T. cruzi and T. gondii [80,82].…”

Section: Other Protozoansmentioning

confidence: 99%

TLR-Mediated Host Immune Response to Parasitic Infectious Diseases

Aguirre-Garcı́a¹,

Rojas-Bernabé²,

Gómez-García³

et al. 2020

Toll-Like Receptors

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Toll-like receptors (TLRs) are important for the host immune response to a variety of pathogens, including bacteria, viruses, fungi, and parasites. These receptors become activated upon recognizing pathogen-associated molecular patterns (PAMPs) and thus initiate the innate immune response to the corresponding pathogen. A key aspect of TLRs is their activation of signaling that leads to cytokine production and an inflammatory response. Additionally, TLRs act as the bridge between innate and acquired immunity, enhancing phagocytosis and the process of killing parasites. We herein focus on how parasites (protozoans and helminths) and their derived products have the capability of stimulating or evading the host response by triggering or inhibiting TLR activation. Parasites often develop successful survival strategies that imply interference with the host immune response. Accordingly, many of these organisms have molecules that modulate inflammation and other aspects of host immunity. Taking advantage of such mechanisms, there are some anti-inflammatory therapies based on human infection with helminths. Helminths and protozoans influence the activity of various TLRs, especially TLR2, TLR4, and TLR9. A better understanding of the role of TLRs and their parasite-derived ligands should certainly provide new therapeutic tools for combatting various parasitic and inflammatory diseases.

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“…It has been shown that binding to IE and recognition of Plasmodium moieties such as the glycosylphosphatidylinositol anchors (GPI) or hemozoin-DNA complexes can be mediated by several TLRs, providing sensor redundancy in the immuno-detection of blood stage parasites (48, 49, 153). A number of reports suggest that variants in different TLRs and their adaptor molecules are associated with control of parasite load (TLR9, rs187084), susceptibility to severe disease (TLR1, rs4833095), resilience to fatal disease (TIRAP S180L) and susceptibility to severe disease, including poor pregnancy outcomes (TLR4, rs4986790) (136, 154–160) (Supplementary Table 1). Together these studies convey the notion that recognition of Plasmodium- derived molecules by innate receptors contribute to the host response in different steps of the natural course of malaria likely by linking with pro-inflammatory responses, such as interferon production (131).…”

Section: Innate Sensors (Tlrs and Related Genes)mentioning

confidence: 99%

Genetics of Malaria Inflammatory Responses: A Pathogenesis Perspective

Penha‐Gonçalves

2019

Front. Immunol.

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Despite significant progress in combating malaria in recent years the burden of severe disease and death due to Plasmodium infections remains a global public health concern. Only a fraction of infected people develops severe clinical syndromes motivating a longstanding search for genetic determinants of malaria severity. Strong genetic effects have been repeatedly ascribed to mutations and allelic variants of proteins expressed in red blood cells but the role of inflammatory response genes in disease pathogenesis has been difficult to discern. We revisited genetic evidence provided by inflammatory response genes that have been repeatedly associated to malaria, namely TNF, NOS2, IFNAR1, HMOX1, TLRs, CD36, and CD40LG. This highlighted specific genetic variants having opposing roles in the development of distinct malaria clinical outcomes and unveiled diverse levels of genetic heterogeneity that shaped the complex association landscape of inflammatory response genes with malaria. However, scrutinizing genetic effects of individual variants corroborates a pathogenesis model where pro-inflammatory genetic variants acting in early infection stages contribute to resolve infection but at later stages confer increased vulnerability to severe organ dysfunction driven by tissue inflammation. Human genetics studies are an invaluable tool to find genes and molecular pathways involved in the inflammatory response to malaria but their precise roles in disease pathogenesis are still unexploited. Genome editing in malaria experimental models and novel genotyping-by-sequencing techniques are promising approaches to delineate the relevance of inflammatory response gene variants in the natural history of infection thereby will offer new rational angles on adjuvant therapeutics for prevention and clinical management of severe malaria.

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Association of TLR variants with susceptibility to Plasmodium vivax malaria and parasitemia in the Amazon region of Brazil

Cited by 21 publications

References 69 publications

Toll-Like Receptor-1 Single-Nucleotide Polymorphism 1805T/G Is Associated With Predisposition to Multibacillary Tuberculosis

Toll-Like Receptor-1 Single-Nucleotide Polymorphism 1805T/G Is Associated With Predisposition to Multibacillary Tuberculosis

TLR-Mediated Host Immune Response to Parasitic Infectious Diseases

Genetics of Malaria Inflammatory Responses: A Pathogenesis Perspective

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