RESUMO
An important property of the host innate immune response during microbial infection is its ability to control the expression of antimicrobial effector proteins, but how this occurs post-transcriptionally is not well defined. Here, we describe a critical antibacterial role for the classic antiviral gene 2'-5'-oligoadenylate synthetase 1 (OAS1). Human OAS1 and its mouse ortholog, Oas1b, are induced by interferon-γ and protect against cytosolic bacterial pathogens such as Francisella novicida and Listeria monocytogenes in vitro and in vivo. Proteomic and transcriptomic analysis showed reduced IRF1 protein expression in OAS1-deficient cells. Mechanistically, OAS1 binds and localizes IRF1 mRNA to the rough endoplasmic reticulum (ER)-Golgi endomembranes, licensing effective translation of IRF1 mRNA without affecting its transcription or decay. OAS1-dependent translation of IRF1 leads to the enhanced expression of antibacterial effectors, such as GBPs, which restrict intracellular bacteria. These findings uncover a noncanonical function of OAS1 in antibacterial innate immunity.
Assuntos
2',5'-Oligoadenilato Sintetase , Imunidade Inata , Fator Regulador 1 de Interferon , 2',5'-Oligoadenilato Sintetase/metabolismo , 2',5'-Oligoadenilato Sintetase/genética , Fator Regulador 1 de Interferon/metabolismo , Fator Regulador 1 de Interferon/genética , Animais , Humanos , Camundongos , Biossíntese de Proteínas/imunologia , Listeria monocytogenes/imunologia , Camundongos Knockout , Camundongos Endogâmicos C57BL , Listeriose/imunologia , Interferon gama/metabolismo , Interferon gama/imunologiaRESUMO
In response to viral infection, how cells balance translational shutdown to limit viral replication and the induction of antiviral components like interferons (IFNs) is not well understood. Moreover, how distinct isoforms of IFN-induced oligoadenylate synthetase 1 (OAS1) contribute to this antiviral response also requires further elucidation. Here, we show that human, but not mouse, OAS1 inhibits SARS-CoV-2 replication through its canonical enzyme activity via RNase L. In contrast, both mouse and human OAS1 protect against West Nile virus infection by a mechanism distinct from canonical RNase L activation. OAS1 binds AU-rich elements (AREs) of specific mRNAs, including IFNß. This binding leads to the sequestration of IFNß mRNA to the endomembrane regions, resulting in prolonged half-life and continued translation. Thus, OAS1 is an ARE-binding protein with two mechanisms of antiviral activity: driving inhibition of translation but also a broader, non-canonical function of protecting IFN expression from translational shutdown.
Assuntos
2',5'-Oligoadenilato Sintetase , Interferons , Oligorribonucleotídeos , Viroses , Febre do Nilo Ocidental , Animais , Humanos , Camundongos , 2',5'-Oligoadenilato Sintetase/genética , 2',5'-Oligoadenilato Sintetase/metabolismo , Nucleotídeos de Adenina , Antivirais/farmacologia , Febre do Nilo Ocidental/genética , Febre do Nilo Ocidental/metabolismo , Vírus do Nilo Ocidental/metabolismo , Vírus do Nilo Ocidental/patogenicidadeRESUMO
Innate immunity and the actions of type I and III interferons (IFNs) are essential for protection from SARS-CoV-2 and COVID-19. Each is induced in response to infection and serves to restrict viral replication and spread while directing the polarization and modulation of the adaptive immune response. Owing to the distribution of their specific receptors, type I and III IFNs, respectively, impart systemic and local actions. Therapeutic IFN has been administered to combat COVID-19 but with differential outcomes when given early or late in infection. In this perspective, we sort out the role of innate immunity and complex actions of IFNs in the context of SARS-CoV-2 infection and COVID-19. We conclude that IFNs are a beneficial component of innate immunity that has mediated natural clearance of infection in over 700 million people. Therapeutic induction of innate immunity and use of IFN should be featured in strategies to treat acute SARS-CoV-2 infection in people at risk for severe COVID-19.
Assuntos
COVID-19 , Interferons , Humanos , Interferons/uso terapêutico , SARS-CoV-2 , Imunidade Inata , Movimento CelularRESUMO
Type III interferon (IFN-λ) is important for innate immune protection at mucosal surfaces and has therapeutic benefit against influenza A virus (IAV) infection. However, the mechanisms by which IFN-λ programs adaptive immune protection against IAV are undefined. Here we found that IFN-λ signaling in dendritic cell (DC) populations was critical for the development of protective IAV-specific CD8+ T cell responses. Mice lacking the IFN-λ receptor (Ifnlr1-/-) had blunted CD8+ T cell responses relative to wild type and exhibited reduced survival after heterosubtypic IAV re-challenge. Analysis of DCs revealed IFN-λ signaling directed the migration and function of CD103+ DCs for development of optimal antiviral CD8+ T cell responses, and bioinformatic analyses identified IFN-λ regulation of a DC IL-10 immunoregulatory network. Thus, IFN-λ serves a critical role in bridging innate and adaptive immunity from lung mucosa to lymph nodes to program DCs to direct effective T cell immunity against IAV.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Vírus da Influenza A/imunologia , Interferon gama/imunologia , Infecções por Orthomyxoviridae/imunologia , Receptores de Interferon/imunologia , Animais , Linhagem Celular , Cães , Feminino , Imunidade Inata/imunologia , Interleucina-10/imunologia , Células Madin Darby de Rim Canino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Interferon/genética , Receptor de Interferon gamaRESUMO
The initial response to viral infection is anticipatory, with host antiviral restriction factors and pathogen sensors constantly surveying the cell to rapidly mount an antiviral response through the synthesis and downstream activity of interferons. After pathogen clearance, the host's ability to resolve this antiviral response and return to homeostasis is critical. Here, we found that isoforms of the RNA-binding protein ZAP functioned as both a direct antiviral restriction factor and an interferon-resolution factor. The short isoform of ZAP bound to and mediated the degradation of several host interferon messenger RNAs, and thus acted as a negative feedback regulator of the interferon response. In contrast, the long isoform of ZAP had antiviral functions and did not regulate interferon. The two isoforms contained identical RNA-targeting domains, but differences in their intracellular localization modulated specificity for host versus viral RNA, which resulted in disparate effects on viral replication during the innate immune response.
Assuntos
Infecções por Alphavirus/imunologia , Interferons/genética , Isoformas de Proteínas/metabolismo , Proteínas de Ligação a RNA/metabolismo , RNA/metabolismo , Proteínas Repressoras/metabolismo , Sindbis virus/fisiologia , Infecções por Alphavirus/genética , Retroalimentação Fisiológica , Células HEK293 , Células Hep G2 , Homeostase , Humanos , Imunidade Inata , Fator Regulador 3 de Interferon/genética , Fator Regulador 3 de Interferon/metabolismo , Ligação Proteica , Isoformas de Proteínas/genética , RNA/genética , RNA Interferente Pequeno/genética , Proteínas de Ligação a RNA/genética , Proteínas Repressoras/genética , Replicação ViralRESUMO
Type I and III interferons (IFNs) drive effective antiviral functions but differentially affect tissue homeostasis. Using mouse models of severe inflammation, Broggi et al. and Major et al. report in Science that type III IFNs disrupt epithelial cell proliferation and differentiation in the lung.
Assuntos
Antivirais , Interferons , Animais , Pulmão , Camundongos , Interferon lambdaRESUMO
Type I and III interferons (IFNs) activate similar downstream signaling cascades, but unlike type I IFNs, type III IFNs (IFNλ) do not elicit strong inflammatory responses in vivo. Here, we examined the molecular mechanisms underlying this disparity. Type I and III IFNs displayed kinetic differences in expression of IFN-stimulated genes and proinflammatory responses, with type I IFNs preferentially stimulating expression of the transcription factor IRF1. Type III IFNs failed to induce IRF1 expression because of low IFNλ receptor abundance and insufficient STAT1 activation on epithelial cells and thus did not activate the IRF1 proinflammatory gene program. Rather, IFNλ stimulation preferentially induced factors implicated in tissue repair. Our findings suggest that IFN receptor compartmentalization and abundance confer a spatiotemporal division of labor where type III IFNs control viral spread at the site of the infection while restricting tissue damage; the transient induction of inflammatory responses by type I IFNs recruits immune effectors to promote protective immunity.
Assuntos
Fator Regulador 1 de Interferon/imunologia , Interferon Tipo I/imunologia , Interferons/imunologia , Animais , Linhagem Celular , Células Epiteliais/imunologia , Humanos , Inflamação/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator de Transcrição STAT1/imunologia , Interferon lambdaRESUMO
The RNA-editing enzyme ADAR1 is essential for the suppression of innate immune activation and pathology caused by aberrant recognition of self-RNA, a role it carries out by disrupting the duplex structure of endogenous double-stranded RNA species1,2. A point mutation in the sequence encoding the Z-DNA-binding domain (ZBD) of ADAR1 is associated with severe autoinflammatory disease3-5. ZBP1 is the only other ZBD-containing mammalian protein6, and its activation can trigger both cell death and transcriptional responses through the kinases RIPK1 and RIPK3, and the protease caspase 8 (refs. 7-9). Here we show that the pathology caused by alteration of the ZBD of ADAR1 is driven by activation of ZBP1. We found that ablation of ZBP1 fully rescued the overt pathology caused by ADAR1 alteration, without fully reversing the underlying inflammatory program caused by this alteration. Whereas loss of RIPK3 partially phenocopied the protective effects of ZBP1 ablation, combined deletion of caspase 8 and RIPK3, or of caspase 8 and MLKL, unexpectedly exacerbated the pathogenic effects of ADAR1 alteration. These findings indicate that ADAR1 is a negative regulator of sterile ZBP1 activation, and that ZBP1-dependent signalling underlies the autoinflammatory pathology caused by alteration of ADAR1.
Assuntos
Adenosina Desaminase , Doenças do Sistema Imunitário , Inflamação , Mutação , Proteínas de Ligação a RNA , Adenosina Desaminase/genética , Adenosina Desaminase/metabolismo , Animais , Caspase 8/genética , Caspase 8/metabolismo , Morte Celular , Deleção de Genes , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/metabolismo , Doenças do Sistema Imunitário/patologia , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Mamíferos/genética , Proteínas Quinases/deficiência , Proteínas Quinases/genética , RNA de Cadeia Dupla/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/deficiência , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Transdução de SinaisRESUMO
IFNL3, which encodes interferon-λ3 (IFN-λ3), has received considerable attention in the hepatitis C virus (HCV) field, as many independent genome-wide association studies have identified a strong association between polymorphisms near IFNL3 and clearance of HCV. However, the mechanism underlying this association has remained elusive. In this study, we report the identification of a functional polymorphism (rs4803217) in the 3' untranslated region (UTR) of IFNL3 mRNA that dictated transcript stability. We found that this polymorphism influenced AU-rich element (ARE)-mediated decay (AMD) of IFNL3 mRNA, as well as the binding of HCV-induced microRNAs during infection. Together these pathways mediated robust repression of the unfavorable IFNL3 polymorphism. Our data reveal a previously unknown mechanism by which HCV attenuates the antiviral response and indicate new potential therapeutic targets for HCV treatment.
Assuntos
Elementos Ricos em Adenilato e Uridilato/genética , Interleucinas/genética , MicroRNAs/genética , Polimorfismo de Nucleotídeo Único , Estabilidade de RNA/genética , Regiões 3' não Traduzidas/genética , Sequência de Bases , Linhagem Celular Tumoral , Citometria de Fluxo , Genótipo , Células Hep G2 , Hepacivirus/fisiologia , Hepatite C/genética , Hepatite C/virologia , Interações Hospedeiro-Patógeno , Humanos , Interferons , Interleucinas/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Dados de Sequência Molecular , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Homologia de Sequência do Ácido NucleicoRESUMO
Hosts have evolved diverse strategies to respond to microbial infections, including the detection of pathogen-encoded proteases by inflammasome-forming sensors such as NLRP1 and CARD8. Here, we find that the 3CL protease (3CLpro) encoded by diverse coronaviruses, including Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), cleaves a rapidly evolving region of human CARD8 and activates a robust inflammasome response. CARD8 is required for cell death and the release of pro-inflammatory cytokines during SARS-CoV-2 infection. We further find that natural variation alters CARD8 sensing of 3CLpro, including 3CLpro-mediated antagonism rather than activation of megabat CARD8. Likewise, we find that a single nucleotide polymorphism (SNP) in humans reduces CARD8's ability to sense coronavirus 3CLpros and, instead, enables sensing of 3C proteases (3Cpro) from select picornaviruses. Our findings demonstrate that CARD8 is a broad sensor of viral protease activities and suggests that CARD8 diversity contributes to inter- and intraspecies variation in inflammasome-mediated viral sensing and immunopathology.
Assuntos
COVID-19 , Picornaviridae , Humanos , Inflamassomos/metabolismo , Picornaviridae/genética , Picornaviridae/metabolismo , SARS-CoV-2/metabolismo , Inibidores de Proteases , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas Adaptadoras de Sinalização CARD/metabolismoRESUMO
From the initial sensing of viral nucleotides by pattern recognition receptors, through the induction of type I and III interferons (IFN), upregulation of antiviral effector proteins, and resolution of the inflammatory response, each step of innate immune signaling is under tight control. Though innate immunity is often associated with broad regulation at the level of gene transcription, RNA-centric post-transcriptional processes have emerged as critical mechanisms for ensuring a proper antiviral response. Here, we explore the diverse RNA regulatory mechanisms that modulate the innate antiviral immune response, with a focus on RNA sensing by RIG-I-like receptors (RLR), interferon (IFN) and IFN signaling pathways, viral pathogenesis, and host genetic variation that contributes to these processes. We address the post-transcriptional interactions with RNA-binding proteins, non-coding RNAs, transcript elements, and modifications that control mRNA stability, as well as alternative splicing events that modulate the innate immune antiviral response.
Assuntos
Fatores de Restrição Antivirais/imunologia , Imunidade Inata , RNA Viral , Viroses/imunologia , Humanos , Interferons , RNA Viral/genética , Receptores de Reconhecimento de Padrão/genéticaRESUMO
Immunopathology and intestinal stem cell (ISC) loss in the gastrointestinal (GI) tract is the prima facie manifestation of graft-versus-host disease (GVHD) and is responsible for significant mortality after allogeneic bone marrow transplantation (BMT). Approaches to prevent GVHD to date focus on immune suppression. Here, we identify interferon-λ (IFN-λ; interleukin-28 [IL-28]/IL-29) as a key protector of GI GVHD immunopathology, notably within the ISC compartment. Ifnlr1-/- mice displayed exaggerated GI GVHD and mortality independent of Paneth cells and alterations to the microbiome. Ifnlr1-/- intestinal organoid growth was significantly impaired, and targeted Ifnlr1 deficiency exhibited effects intrinsic to recipient Lgr5+ ISCs and natural killer cells. PEGylated recombinant IL-29 (PEG-rIL-29) treatment of naive mice enhanced Lgr5+ ISC numbers and organoid growth independent of both IL-22 and type I IFN and modulated proliferative and apoptosis gene sets in Lgr5+ ISCs. PEG-rIL-29 treatment improved survival, reduced GVHD severity, and enhanced epithelial proliferation and ISC-derived organoid growth after BMT. The preservation of ISC numbers in response to PEG-rIL-29 after BMT occurred both in the presence and absence of IFN-λ-signaling in recipient natural killer cells. IFN-λ is therefore an attractive and rapidly testable approach to prevent ISC loss and immunopathology during GVHD.
Assuntos
Transplante de Medula Óssea , Citocinas/farmacologia , Gastroenteropatias , Doença Enxerto-Hospedeiro , Interleucinas/farmacocinética , Transdução de Sinais , Animais , Citocinas/imunologia , Gastroenteropatias/tratamento farmacológico , Gastroenteropatias/genética , Gastroenteropatias/imunologia , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/imunologia , Interleucinas/imunologia , Camundongos , Camundongos Knockout , Receptores de Interferon/genética , Receptores de Interferon/imunologia , Índice de Gravidade de Doença , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Transplante HomólogoRESUMO
Interleukin (IL)-4 and IL-13 are related cytokines with well-known specific roles in type 2 immune response. However, their effects on neutrophils are not completely understood. For this, we studied human primary neutrophil responses to IL-4 and IL-13. Neutrophils are dose-dependently responsive to both IL-4 and IL-13 as indicated by signal transducer and activator of transcription 6 (STAT6) phosphorylation upon stimulation, with IL-4 being more potent inducer of STAT6. IL-4-, IL-13- and Interferon (IFN)-γ-stimulated gene expression in highly purified human neutrophils induced both overlapping and unique gene expression in highly purified human neutrophils. IL-4 and IL-13 specifically regulate several immune-related genes, including IL-10, tumor necrosis factor (TNF) and leukemia inhibitory factor (LIF), while type1 immune response-related IFN-γ induced gene expression related for example, to intracellular infections. In analysis of neutrophil metabolic responses, oxygen independent glycolysis was specifically regulated by IL-4, but not by IL-13 or IFN-γ, suggesting specific role for type I IL-4 receptor in this process. Our results provide a comprehensive analysis of IL-4, IL-13 and IFN-γ -induced gene expression in neutrophils while also addressing cytokine-mediated metabolic changes in neutrophils.
Assuntos
Interleucina-13 , Interleucina-4 , Humanos , Citocinas/metabolismo , Interferon gama/metabolismo , Interleucina-13/farmacologia , Interleucina-13/metabolismo , Interleucina-4/farmacologia , Interleucina-4/metabolismo , Neutrófilos/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
miRNAs play an important role in fine-tuning host immune homeostasis and responses through the regulation of mRNA stability and translation. Studies have demonstrated that miRNA-mediated regulation of gene expression has a profound impact on immune cell development, function, and response to invading pathogens. As we continue to examine the mechanisms by which miRNAs maintain the balance between robust protective host immune responses and dysregulated responses that promote immune pathology, careful consideration of the complexity of post-transcriptional immune regulation is needed. Distinct tissue- and stimulus-specific RNA-RNA and RNA-protein interactions can modulate the functions of a given miRNA. Thus, new challenges emerge in the identification of post-transcriptional coregulatory modules and the genetic factors that impact miRNA function.
Assuntos
MicroRNAs/imunologia , Processamento Pós-Transcricional do RNA/imunologia , Regiões 3' não Traduzidas/imunologia , Animais , Variação Genética/imunologia , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Estabilidade de RNA/imunologia , RNA Longo não Codificante/imunologia , RNA Mensageiro/química , RNA Mensageiro/imunologia , Proteínas de Ligação a RNA/imunologia , Proteínas de Ligação a RNA/metabolismoRESUMO
Gene expression programs undergo constant regulation to quickly adjust to environmental stimuli that alter the physiological status of the cell, like cellular stress or infection. Gene expression is tightly regulated by multilayered regulatory elements acting in both cis and trans. Posttranscriptional regulation of the 3' untranslated region (UTR) is a powerful regulatory process that determines the rate of protein translation from mRNA. Regulatory elements targeting the 3' UTR include microRNAs, RNA-binding proteins, and long noncoding RNAs, which dramatically alter the immune response. We provide an overview of our current understanding of posttranscriptional regulation of immune gene expression. The focus of this review is on regulatory elements that target the 3' UTR. We delineate how the synergistic or antagonistic interactions of posttranscriptional regulators determine gene expression levels and how dysregulation of 3' UTR-mediated posttranscriptional control associates with human diseases.
Assuntos
Regiões 3' não Traduzidas/genética , Regulação da Expressão Gênica/genética , Processamento Pós-Transcricional do RNA/genética , RNA Mensageiro/genética , Humanos , MicroRNAs/genética , Poliadenilação/genética , RNA Longo não Codificante/genética , Proteínas de Ligação a RNA/genética , Sequências Reguladoras de Ácido Nucleico/genéticaRESUMO
The HLA-C locus is distinct relative to the other classical HLA class I loci in that it has relatively limited polymorphism, lower expression on the cell surface, and more extensive ligand-receptor interactions with killer-cell immunoglobulin-like receptors. A single nucleotide polymorphism (SNP) 35 kb upstream of HLA-C (rs9264942; termed -35) associates with control of HIV, and with levels of HLA-C messenger RNA transcripts and cell-surface expression, but the mechanism underlying its varied expression is unknown. We proposed that the -35 SNP is not the causal variant for differential HLA-C expression, but rather is marking another polymorphism that directly affects levels of HLA-C. Here we show that variation within the 3' untranslated region (UTR) of HLA-C regulates binding of the microRNA hsa-miR-148 to its target site, resulting in relatively low surface expression of alleles that bind this microRNA and high expression of HLA-C alleles that escape post-transcriptional regulation. The 3' UTR variant associates strongly with control of HIV, potentially adding to the effects of genetic variation encoding the peptide-binding region of the HLA class I loci. Variation in HLA-C expression adds another layer of diversity to this highly polymorphic locus that must be considered when deciphering the function of these molecules in health and disease.
Assuntos
Regulação da Expressão Gênica , Infecções por HIV/genética , Infecções por HIV/imunologia , HIV/imunologia , Antígenos HLA-C/genética , MicroRNAs/genética , Regiões 3' não Traduzidas/genética , Alelos , Sequência de Bases , Linhagem Celular , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/imunologia , Genes Reporter/genética , Infecções por HIV/terapia , Humanos , Polimorfismo de Nucleotídeo Único/genética , Carga ViralRESUMO
Synthetic oligonucleotides (ODN) expressing CpG motifs mimic the ability of bacterial DNA to trigger the innate immune system via TLR9. Plasmacytoid dendritic cells (pDCs) make a critical contribution to the ensuing immune response. This work examines the induction of antiviral (IFN-ß) and pro-inflammatory (IL-6) cytokines by CpG-stimulated human pDCs and the human CAL-1 pDC cell line. Results show that interferon regulatory factor-5 (IRF-5) and NF-κB p50 are key co-regulators of IFN-ß and IL-6 expression following TLR9-mediated activation of human pDCs. The nuclear accumulation of IRF-1 was also observed, but this was a late event that was dependant on type 1 IFN and unrelated to the initiation of gene expression. IRF-8 was identified as a novel negative regulator of gene activation in CpG-stimulated pDCs. As variants of IRF-5 and IRF-8 were recently found to correlate with susceptibility to certain autoimmune diseases, these findings are relevant to our understanding of the pharmacologic effects of "K" ODN and the role of TLR9 ligation under physiologic, pathologic, and therapeutic conditions.
Assuntos
Células Dendríticas/imunologia , Fatores Reguladores de Interferon/imunologia , Interferon beta/biossíntese , Interleucina-6/biossíntese , Subunidade p50 de NF-kappa B/imunologia , Linhagem Celular , Células Dendríticas/metabolismo , Imunofluorescência , Regulação da Expressão Gênica/imunologia , Humanos , Immunoblotting , Imunoprecipitação , Fatores Reguladores de Interferon/metabolismo , Interferon beta/imunologia , Interleucina-6/imunologia , Subunidade p50 de NF-kappa B/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Receptor Toll-Like 9/imunologiaRESUMO
Asthma is a complex disease for which genetic predisposition has been widely documented. Considerable evidence supports the hypothesis that polymorphisms in the muscarinic-cholinergic (CHRM) genes could be involved in asthma pathogenesis, bronchial hyperresponsiveness, and mucus secretion. To determine whether single nucleotide polymorphisms (SNPs) or haplotypes in CHRM1, CHRM2, or CHRM3 are associated with asthma in Mexican pediatric population. We performed a case-control study including 398 pediatric cases with asthma and 450 healthy controls. We analyzed 19 SNPs distributed among these three genes. Two of the seven SNPs located in CHRM2, the 3' untranslated region rs8191992 and rs6962027, differed significantly in allele frequencies between patients with asthma and healthy controls [odds ratio (OR) 1.42, 95 % confidence interval (95 % CI) 1.14-1.77, P = 0.001, and OR 1.50, 95 % CI 1.21-1.87, P = 0.0002, respectively]. Statistical significance remained after multiple comparison corrections (P = 0.003 and P = 0.005, respectively). The haplotypes AA and TT, containing both major and minor alleles from rs8191992 and rs6962027, also differed between cases and controls. The haplotype AA occurred at a lower frequency in cases (OR 0.67, 95 % CI 0.53-0.85, P = 0.001) whereas the haplotype TT was overrepresented in cases compared to controls (28 vs 21 %, respectively; OR 1.46, 95 % CI 1.15-1.85, P = 0.002). No association was observed between CHRM1 or CHRM3 SNPs or haplotypes and asthma. CHRM2 polymorphisms are implicated in the genetic etiology of asthma.