Assessment of Toll-like receptor 2, 4 and 9 SNP genotypes in canine sino-nasal aspergillosis (original) (raw)
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Non-synonymous genetic variation in exonic regions of canine Toll-like receptors
Canine Genetics and Epidemiology, 2014
Background: Toll-like receptors (TLRs) are pattern recognition receptors (PRRs) considered to be the primary sensors of pathogens in innate immunity. Genetic variants could be associated to differences in breed innate immune response to pathogens and thus to susceptibility to infections or autoimmune diseases. There is therefore great interest in the characterization of canine TLRs. Results: Polymorphisms in canine TLRs have been characterized by massive sequencing after enrichment of their exonic regions. DNAs from 335 dogs (seven different breeds) and 100 wolves (two different populations) were used in pools. The ratio of SNP discovery was 76.5% (in relation to CanFam 3.1); 155 out of 204 variants identified were new. Functional annotation identified 64 non-synonymous variants (43 new), 73 synonymous variants (56 new) and 67 modifier variants (57 new). 12 out of 64 non-synonymous variants are breed or wolf specific. TLR5 has been found to be the most polymorphic among canine TLRs. Finally, a TaqMan OpenArray® plate containing 64 SNPs with a possible functional effect in the protein (4 frameshifts and 60 non-synonymous codons) has been designed and validated. Conclusions: Non-synonymous genetic variation has been characterized in exonic regions of canine Toll-like Receptors. The TaqMan OpenArray® plate developed to capture the individual variability that affects protein function will allow high-throughput genotyping either to study association to infection susceptibility or even TLR evolution in the canine genome.
Polymorphisms in Toll‐Like Receptor Genes and Susceptibility to Pulmonary Aspergillosis
Journal of Infectious Diseases, 2008
Toll-like receptors (TLRs) are important components of innate immunity. We investigated the association between polymorphisms in the TLR2, TLR4, and TLR9 genes and susceptibility to noninvasive forms of pulmonary aspergillosis. A significant association was observed between allele G on Asp299Gly (TLR4) and chronic cavitary pulmonary aspergillosis (odds ratio [OR], 3.46; P ؍ .003). Susceptibility to allergic bronchopulmonary aspergillosis was associated with allele C on T-1237C (TLR9) (OR, 2.49; P ؍ .043). No particular polymorphism was associated with severe asthma with fungal sensitization. These findings reinforce the importance of innate immunity in the pathogenesis of different forms of aspergillosis.
Veterinary Immunology and Immunopathology, 2007
Idiopathic lymphoplasmacytic rhinitis (LPR) and sino-nasal aspergillosis (SNA) are among the most common causes of nasal discharge in dogs. The pathogenesis of both diseases is poorly understood. Some have proposed that LPR is a chronic inflammatory response to an inhaled irritant, pollutant or allergen, but others suggest that most cases of LPR constitute undiagnosed cases of SNA. Local immune dysfunction is thought to permit opportunist infection in canine SNA. This study investigates the nature of the local tissue immune response mounted in canine LPR and SNA in order to determine whether these diseases have similar or distinct pathogenesis. Quantitative reverse transcriptase polymerase chain reaction was carried out on RNA isolated from nasal biopsies from diseased and control dogs, using specific assays designed to amplify messenger RNA (mRNA), encoding a panel of cytokines and chemokines. SNA was associated with significantly increased expression of mRNA encoding interleukin (IL)-6, IL-8, IL-10, IL-12p19, IL-12p35, IL-12p40, IL-18, IFN-g, TNF-a, TGF-b, eotaxin-2 and all four monocyte chemoattractant proteins (MCPs) relative to controls. LPR was associated with significantly increased expression of mRNA encoding IL-5, IL-8, IL-10, IL-12p19, IL-12p40, IL-18, TNF-a, TGF-b, MCP-2 and MCP-3 relative to controls. There was significantly more expression of mRNA encoding IL-6, IL-8, IL-10, IL-12p35, IL-12p40, IL-18, IFN-g, TNF-a, TGF-b and all MCPs, and significantly less expression of IL-5 in dogs with SNA than in dogs with LPR. Thus, the profile of cytokine and chemokine gene expression in the nasal mucosa is different in dogs with LPR when compared to dogs with SNA. A partial Th2 immune response appears to be mounted in the nasal mucosa of dogs with LPR, whereas the mucosal immune response in canine SNA is of the Th1 type. Increase in IL-10 and TGF-b transcripts in dogs with SNA is thought to be implicated in the failure to clear the Aspergillus infection. These results constitute the first evidence that the pathogenesis of canine LPR and SNA is distinct. #
Tissue Antigens, 2011
Inflammatory bowel disease (IBD) is thought to be the most common cause of vomiting and diarrhoea in dogs. Although IBD can occur in any canine breed, certain breeds are more susceptible. We have previously shown that polymorphisms in the TLR4 and TLR5 (toll-like receptor) genes are significantly associated with IBD in German Shepherd dogs (GSDs). In order to allow for the development of novel diagnostics and therapeutics suitable for all dogs suffering from IBD, it would be useful to determine if the described polymorphisms are also significantly associated with IBD in other breeds. Therefore, the aim of this study was to investigate whether polymorphisms in the canine TLR4 and TLR5 genes are associated with IBD in other non-GSD canine breeds. The significance of the previously identified non-synonymous single nucleotide polymorphisms (SNPs) in the TLR4 (T23C, G1039A, A1571T and G1807A) and TLR5 genes (G22A, C100T and T1844C) were evaluated in a casecontrol study using a SNaPSHOT multiplex reaction. Sequencing information from 85 unrelated dogs with IBD consisting of 38 different breeds was compared with a breedmatched control group consisting of 162 unrelated dogs. Indeed, as in the GSD IBD population, the two TLR5 SNPs (C100T and T1844C) were found to be significantly protective for IBD in other breeds (P = 0.023 and P = 0.0195 respectively). Our study suggests that the two TLR5 SNPs, C100T and T1844C could play a role in canine IBD as these were found to be protective factors for this disease in 38 different canine breeds. Thus, targeting TLR5 in the canine system may represent a suitable way to develop new treatment for IBD in dogs.
Revista da Sociedade Brasileira de Medicina Tropical
Invasive aspergillosis is a common fungal infection in immunocompromised individuals. Some studies have shown that toll-like receptor and dectin-1 genetic polymorphisms may alter signaling pathways, thus increasing an individual's susceptibility to invasive aspergillosis. We investigated the pertinent literature to determine whether polymorphisms in the genes encoding toll-like receptors and dectin-1 increase the susceptibility to invasive aspergillosis. This study systematically reviewed the literature using the databases PubMed/PMC, Scopus, and Web of Science using the keywords invasive aspergillosis, polymorphism, Toll-like, and Dectin-1. From the initial search, 415 studies were found and according to our inclusion and exclusion criteria, eight studies were selected. Several studies described single-nucleotide polymorphisms (SNPs) that are associated with a greater susceptibility to invasive aspergillosis. These SNPs were found in the genes that encode toll-like receptors 1,...
Toll-like receptors in domestic animals
Cell and Tissue Research, 2011
Toll-like receptors are pattern recognition receptors with which hosts recognize pathogen-associated molecular patterns (PAMP). This recognition process is translated rapidly into a meaningful defense reaction. This form of innate host defense is preserved in the animal kingdom: invertebrates heavily depend on it; higher vertebrates also have an adaptive immune system. Both adaptive and innate immune systems are intertwined in that the former also depends on an intact innate recognition and response system. Members of the TLR system cover recognition of parasitic, bacterial or viral germs. Due to the constraints imposed by the necessity to recognize PAMP and to interact with downstream signaling mole-cules, the TLR system is relatively conserved in evolution. Nevertheless, subtle species differences have been reported for several mammalian TLR members. Examples of this will be given. In all mammalian species investigated, part of the coding sequence is available for the most important TLR members, thus allowing study of expression of these TLR members in various tissues by reverse-transcription polymerase chain reaction in its classical (RT-PCR) and quantitative real time RT-PCR (qRT-PCR) form. In some species, the whole coding sequences of the most important or even all TLR members are known. This allows construction of cDNA and transfection of common host cells, thus permitting functional studies. Extensive investigations were devoted to the study of non-synonymous single nucleotide polymorphisms. In a few cases, expression of a given amino acid in the extracellular (ligandbinding) portion of TLR members could be associated with infectious diseases. This will be discussed below.
Association of Toll-Like Receptor Polymorphisms With Nasal Polyposis
Nasal polyposis is a disease characterized with chronic inflammation of the nasal mucosa. Toll-like receptors (TLRs) are defined as essential receptors of the innate immune system and may play in the development of nasal polyposis. A total of 71 patients with nasal polyposis and 74 healthy controls were included in this study. Three single-nucleotide polymorphisms (SNPs); TLR2 (2258 A>G), TLR4 (896 A>G), and TLR4 (1196 C>T) were analyzed in all patients. The degree of pair-wise linkage disequilibrium and the genotype and haplotype analyses were conducted using regression in this logistic model and the Multifactor Dimensionality Reduction (MDR) software package was used to construct all possible interactions among different genotype variants belonging to the TLR gene. There was significant difference in genotype and allele frequencies of the TLR4 (1196 C>T) polymorphism between the nasal polyposis and control groups (0.017). Also, it was observed that the probability of nasal polyposis was 62.7% in the presence of TLR4 (1196 C>T) polymorphism with asthma (P ¼ .007). As a conclusion, this study showed that TLR4 and TLR2 polymorphisms were predisposing factors for nasal polyposis. Further functional studies investigating the consequences of loss of TLR function are needed.
The role of toll-like receptor polymorphisms in susceptibility to canine distemper virus
Mammalian Biology
Canine distemper virus (CDV) is a global multi-host pathogen of wildlife. Toll-like receptors (TLR) are key recognition structures of the innate immune system. To investigate host susceptibility to CDV, the presence of non-synonymous single nucleotide polymorphisms (SNPs) in the coding regions of TLR 2, 3, 4, 7 and 8 genes were investigated in two recent CDV outbreaks in South Africa. The first case consisted of five lions (Panthera leo), diagnosed with CDV. Four of the lions died following exposure to the virus. The second case consisted of six African wild dogs (Lycaon pictus) with CDV and one surviving African wild dog. TLR diversity showed a higher rate of polymorphism in the African wild dogs within each of the TLR loci compared to lions. A single amino acid change (Met527Thr) within the leucine rich repeat of TLR2 was observed in the single surviving lioness. This alteration resulted in a non-polar to polar group change, potentially influencing the expression and function of TLR2. No specific amino acid alterations could be associated with CDV susceptibility in the African wild dogs. This study provides a critical starting point in elucidating the mechanism involved in host immunity and therefore susceptibility towards CDV infection.
Toll-Like Receptor-4 Gene (Asp299Gly) polymorphism in allergic conjunctivitis
Egyptian Journal of Immunology, 2022
Allergic conjunctivitis (AC) is an allergic reaction that causes inflammation of the conjunctiva. Toll-like receptors (TLRs) are essential innate immune receptors that contribute to developing various allergic diseases. This case-control study aims to determine the correlation between TLR-4 gene (Asp299Gly) polymorphism and AC incidence and severity. The study included 70 AC patients and 70 non-allergic controls. All included subjects were subjected to a skin prick test, total immunoglobulin E (IgE) measurement, and TLR-4 gene (Asp299Gly) polymorphism detection by PCR restriction fragment length polymorphism (PCR-RFLP) technique. AC patients had significantly higher total IgE levels than controls (P ≤ 0.001). The frequency of the wild-type AA and heterozygous AG genotype were significantly lower in AC patients compared to controls (60 % vs. 80 % and 8.6% vs. 12.9 %, respectively). In contrast, the homozygous mutant GG genotype was significantly more prevalent among AC patients than controls (31.4 % vs. 7.1 %). Furthermore, the wild AA genotype was strongly associated with mild disease (68.2%); nonetheless, the homozygous mutant GG genotype was linked to severe disease (53.8%). The heterozygous AG genotype was only found in moderate AC patients (17.1%). AC patients with the mutant G allele may be more likely to have a severe course of AC.
Allergic rhinitis and genetic components: focus on Toll-like receptors (TLRs) gene polymorphism
The Application of Clinical Genetics, 2010
Allergic rhinitis represents a global health issue affecting 10% to 25% of the population worldwide. Over the years, studies have found that allergic diseases, including allergic rhinitis, are associated with immunological responses to antigens driven by a Th2-mediated immune response. Because Toll-like receptors (TLRs) are involved in both innate and adaptive immune responses to a broad variety of antigens, the association between polymorphisms of TLRs and allergic diseases has been the focus in many animal and human studies. Although the etiology of allergic rhinitis is still unknown, extensive research over the years has confirmed that the underlying causes of allergic diseases are due to many genetic and environmental factors, along with the interactions among them, which include gene-environment, gene-gene, and environment-environment interactions. Currently, there is great inconsistency among studies mainly due to differences in genetic background and unique gene-environment interactions. This paper reviews studies focusing on the association between TLR polymorphisms and allergic diseases, including allergic rhinitis, which would help researchers better understand the role of TLR polymorphisms in the development of allergic rhinitis, and ultimately lead to more efficient therapeutic interventions being developed.