Polymorphisms in CARD8 and NLRP3 are associated with extrapulmonary TB and poor clinical outcome in active TB in Ethiopia

Ebba Abate,Maria Lerm,Deepti Verma,Mats Fredrikson,Peter Söderkvist,Robert Blomgran,Meseret Belayneh,Olle Stendahl,Thomas Schön

doi:10.1038/s41598-019-40121-8

Abstract

Innate immunity is a first line defense against Mycobacterium tuberculosis infection where inflammasome activation and secretion of the pro-inflammatory cytokine IL-1beta, plays a major role. Thus, genetic polymorphisms in innate immunity-related genes such as CARD8 and NLRP3 may contribute to the understanding of why most exposed individuals do not develop infection. Our aim was to investigate the association between polymorphisms in CARD8 and NLRP3 and active tuberculosis (TB) as well as their relationship to treatment outcome in a high-endemic setting for TB. Polymorphisms in CARD8 (C10X) and NLRP3 (Q705K) were analysed in 1190 TB patients and 1990 healthy donors (HD). There was a significant association between homozygotes in the CARD8 polymorphism and extrapulmonary TB (EPTB), which was not the case for pulmonary TB or HDs. Among TB-patients, there was an association between poor treatment outcome and the NLRP3 (Q705K) polymorphism. Our study shows that inflammasome polymorphisms are associated with EPTB and poor clinical outcome in active TB in Ethiopia. The practical implications and determining causal relationships on a mechanistic level needs further study.

Highlights

One peculiar feature of tuberculosis (TB) is that relatively few individuals become infected even after long-term household exposure[1,2]
The recessive model showed a significantly higher presence of homozygotes in CARD8 (C10X) in extrapulmonary TB (EPTB) (19.9% 69/347) compared to pulmonary TB (PTB) (odds ratio (OR): 1.8 (1.3–2.6); 12.0%; 91/759, p < 0.001) or healthy donors (HD) (OR: 1.4 (1.05–1.9); 15.1%; 296/1964, p = 0.024; Table 3)
The main result of this large-scale study on inflammasome polymorphisms in Ethiopia is an association between homozygotes in CARD8 (C10X) and EPTB as well as an association to an impaired TB treatment outcome in carriers of the NLRP3 (Q705K) polymorphism

Summary

Introduction

One peculiar feature of tuberculosis (TB) is that relatively few individuals become infected even after long-term household exposure[1,2]. In Crohn’s disease and rheumatoid arthritis (RA), a hyperactive inflammasome contributes to an excessive inflammatory response[6,7]. In these cases, single nucleotide polymorphisms (SNPs) leading to a constitutively active NLRP3 inflammasome contribute to the disease manifestations. NLRP3 activation leads to the recruitment of the adaptor ASC,which binds to NLRP3, and through its caspase recruitment domain (CARD). The Q705K polymorphism in NLRP3 has shown to be a gain-of-function SNP leading to enhanced IL1-beta release[5]. Caspase recruitment domain-containing protein 8 (CARD8), was recently shown to be a specific suppressor of NLRP3/ASC/procaspase −1 protein assembly, thereby inhibiting NLRP3-inflammasome activation[9]. Gain-of-function polymorphisms in the NLRP3 inflammasome resulting from gene polymorphisms such as NLRP3 (Q705K) and loss-of-function in relation to CARD8 (C10X) are associated to RA and Crohn’s disease, and some evidence for a combined effect of these polymorphisms have been described[6,7]

Objectives

Methods

Results

Conclusion