The SIGLEC14 null allele is associated with Mycobacterium tuberculosis- and BCG-induced clinical and immunologic outcomes
Introduction
Mycobacterium tuberculosis (Mtb) is a leading infectious cause of morbidity and mortality worldwide. In 2014 there were an estimated 9.4 million incident cases of tuberculosis (TB) disease and 1.5 million deaths [1]. There are substantial differences in individual susceptibility to tuberculosis [2], [3], [4]. Evidence from twins, Mendelian studies in children, genome wide linkage studies, candidate gene association studies, and genome-wide association studies suggest that human genetic factors mediate susceptibility to TB disease [5], [6], [7], [8], [9], [10]. The human innate immune system is critical in the early response to Mtb and the effector mechanisms that kill the bacillus [2], [5], [11]. Macrophages are a major reservoir of Mtb and the success of the bacterium depends in part on its ability to circumvent macrophage killing mechanisms [12], [13]. The host genetic factors that influence the macrophage response to Mtb are not well understood.
Sialic acid-binding immunoglobulin-like lectins (Siglecs) are a family of cell-surface transmembrane receptors that contain an amino-terminal sialic acid-binding site and are expressed on many immune cells including macrophages [14], [15]. All host cells express sialic acids on their surface and recognition of these “Self Associated Molecular Patterns” by Siglecs allows host immune cells to distinguish between self and non-self [16], [17], [18]. Consistent with their role in the inhibition of an inappropriate autoimmune inflammatory response, most Siglecs have cytoplasmic domains that contain immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and induce immunosuppressive signaling events through interaction with tyrosine phosphatases such as SHP1 and SHP2. A smaller number of Siglecs associate with an immunoreceptor tyrosine-based activation motif (ITAM) via DAP12 and induce an activation signal through interaction with spleen tyrosine kinase (SYK) [17], [19]. Some pathogenic organisms are able to bind host Siglecs. Siglecs mediate capture of HIV by dendritic cells [20] and entry of varicella zoster virus into oligodendroglial cells [21] while certain bacteria are able to induce Siglec signaling in a sialic acid-dependent [22], [23], [24] or sialic acid-independent manner [25]. The cell envelope of Mtb contains a variety of glycoconjugates [26], though it is not known whether Mtb is able to bind to Siglec molecules or induce Siglec signaling.
SIGLEC5 and SIGLEC14 encode two human Siglec molecules that are expressed on host innate immune cells including granulocytes and macrophages; Siglec-5 is also expressed on B-cells at lower levels [27]. The two genes share more than 99% sequence homology in the exons encoding their ligand-binding domains [28] but have opposing intracellular signaling effects due to the presence of an ITIM in the cytoplasmic domain of Siglec-5 and an ITAM in the cytoplasmic domain of the Siglec-14/DAP12 complex [27], [29]. The two molecules have been postulated to represent a paired receptor system, in which the inhibitory effect of Siglec-5 is counterbalanced by the activating effect of Siglec-14 [28], [29], [30]. Some individuals lack expression of Siglec-14 due to a SIGLEC14 deletion polymorphism between the two genes on chromosome 19. The deletion, termed the SIGLEC14 null allele, eliminates Siglec-14 protein expression but simultaneously places a SIGLEC5-like gene fusion product under the control of the SIGLEC14 promoter [27], [28], [29]. Macrophages of null allele homozygotes express only the inhibitory Siglec-5-like molecule while macrophages of wild-type homozygotes express only the activating Siglec-14. Macrophages of heterozygotes express both Siglec-5 and Siglec-14 [27], [31].
Given the central role of macrophages in controlling Mtb infection and the impact of the SIGLEC14 genotype on myeloid cell function, we hypothesized that the SIGLEC14 null allele influences TB susceptibility in humans. We examined a South African pediatric cohort with TB disease and two Vietnamese adult cohorts, one with pulmonary TB (PTB) and the other with TB meningitis (TBM). We also evaluated SIGLEC14-dependent ex-vivo T-cell cytokine responses to Bacillus Calmette Guerin (BCG) vaccination to determine if the molecule plays a role in the development of the adaptive immune response. Lastly, we compared Mtb replication in a monocyte cell line overexpressing either the inhibitory Siglec-5 or the activating Siglec-14. We hypothesized that the SIGLEC14 null allele is associated with Mtb replication in monocytes, T-cell responses to BCG, and clinical susceptibility to TB in children and adults.
Section snippets
Vietnamese adult cohort
HIV-uninfected adults (age > 15 years) with PTB were recruited in Ho Chi Minh City, Vietnam, from a network of district tuberculosis clinics or from the Pham Ngoc Thach Hospital for Tuberculosis and Lung Diseases. Subjects had positive sputum smears for acid-fast bacilli and also met the following criteria: no history of previous tuberculosis treatment, no evidence of extrapulmonary or miliary tuberculosis, and negative HIV testing.
HIV-negative adults with TBM were recruited from 1997 through
Association of the SIGLEC14 null allele with protection from tuberculosis disease in Vietnam
Using a case-population study design in Vietnamese adults, we genotyped the SIGLEC14 null allele in 378 cord blood controls and 773 cases of TB disease (Table 1). The TB disease cohort was comprised of 380 cases of PTB without extrapulmonary involvement and 393 cases of TBM (together, labeled ‘AllTb’). The allele was in Hardy-Weinberg equilibrium in the control population (χ2 p = 0.60). The SIGLEC14 null allele was more common than the wild-type allele in the Vietnamese population, with a null
Discussion
In Vietnamese adults, we found that the SIGLEC14 null allele was associated with protection from disease in the combined PTB and TBM cohort. The protection was strongest in the TBM subgroup. In South African children, the null allele showed a borderline association with increased BCG-specific IL-2 and IL-17 responses following BCG vaccination. Our in-vitro analysis showed that overexpression of either Siglec-5 or Siglec-14 led to increased Mtb replication in monocytes.
While the presence of the
Acknowledgements
We would like to thank the participants in the study. We would also like to thank the immunology and clinical teams at the SATVI research site in Worchester and the Hospital for Tropical Diseases and Pham Ngoc Thac Hospital in Vietnam for obtaining informed consent and collecting and processing blood from the study participants. This research was supported by NIH 5T32HL007287 (ADG), NIH K24 AI089794 (TRH), NIH NO1-AI-70022 (Tuberculosis Research Unit) (TRH, WAH), the Burroughs Wellcome
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Roles of Siglecs in neurodegenerative diseases
2023, Molecular Aspects of MedicineCitation Excerpt :In this case, the fusion between SIGLEC14 and SIGLEC5 results in the deletion of the genomic segment encoding the Siglec-14-unique polypeptide, and the resulting SIGLEC14–SIGLEC5 fusion gene yields a protein that is identical to Siglec-5 in amino acid sequence (Yamanaka et al., 2009). The frequency of this “SIGLEC14 null” allele in human populations ranges from moderate (∼0.2 in Europeans) to high (∼0.7 in East Asians), possibly reflecting balancing selection by different pathogens (Ali et al., 2014; Angata et al., 2013; Graustein et al., 2017). Many recent GWAS/GWAX incorporate the information of eQTL and splicing QTL (sQTL) as part of the study design to narrow down candidate “causal” polymorphisms.
Discovery, classification, evolution and diversity of Siglecs
2023, Molecular Aspects of MedicineCitation Excerpt :The frequency of SIGLEC14 null allele differs depending on the human population–generally high in Asia and low in Europe–suggesting the presence of some regional selective pressure that favors or disfavors the null allele (Yamanaka et al., 2009). We have found associations between SIGLEC14 null allele and clinical conditions induced by bacterial pathogens, such as exacerbation of chronic obstructive pulmonary disease (COPD) (Angata et al., 2013), pre-term delivery of infant in the presence of GBS infection (Ali et al., 2014), and meningitis in the presence of Mycobacterium tuberculosis infection (Graustein et al., 2017) (Table 3). It should be noted that the null allele appears to be beneficial in some situations (e.g., exacerbation of COPD) but disadvantageous in others (e.g., GBS infection), implying that the polymorphism may be maintained by balancing selection.
Common determinants of severe Covid-19 infection are explicable by SARS-CoV-2 secreted glycoprotein interaction with the CD33-related Siglecs, Siglec-3 and Siglec-5/14
2020, Medical HypothesesCitation Excerpt :There are recognised functional consequences. Adults with the Siglec-14 null allele are at reduced risk for infective exacerbation of COPD [18] and may be less susceptible to severe tuberculosis [19]. Conversely Siglec-14 null women are at increased risk of premature delivery If infected with GBS [17].
Genetics and evolution of tuberculosis pathogenesis: New perspectives and approaches
2020, Infection, Genetics and EvolutionCitation Excerpt :Two studies have also examined the association between genetic variants and BCG vaccine induced production of cytokines that are known to be an important part of the response to BCG vaccination. One study found that SIGLEC14 variants were associated with increased BCG-induced IL-2 and IL-17 production in South African children(Graustein et al., 2017). The other found that variants in HSP90B1 (a chaperone protein for multiple toll-like receptors) were associated with higher BCG-induced IL-2 production in South African children(Graustein et al., 2018).
Are humans prone to autoimmunity? Implications from evolutionary changes in hominin sialic acid biology
2017, Journal of AutoimmunityCitation Excerpt :While the homology and expression patterns of CD33rSiglecs found on immune cells varies between different evolutionary lineages, human ancestors appear to have accumulated a large number of fixed and polymorphic changes in these genes that likely predated the origin of our species in Africa. Space does not allow for a detailed discussion of all these genomic events and their potential functional consequences, which are discussed in recent reviews and papers [34,77–81], but it is likely that they are altering the immune reactivity of individuals and that combinations of these polymorphisms are contributing to relative propensities to autoimmune disease. Careful population studies are needed to address this issue further.