Differential frequency of NKG2C/KLRC2 deletion in distinct African populations and susceptibility to Trachoma: a new method for imputation of KLRC2 genotypes from SNP genotyping data

Gonçalves, Adriana; Makalo, Pateh; Joof, Hassan; Burr, Sarah E.; Ramadhani, Athumani; Massae, Patrick; Malisa, Aiweda; Mtuy, Tara; Derrick, Tamsyn; Nabicassa, Meno; Cassama, Eunice; Houghton, Joanna; Palmer, Christine D.; Pickering, Harry; Burton, Matthew J.; Mabey, David; Bailey, Robin L.; Goodier, Martin R.; Holland, Martin J.

doi:10.1007/s00439-016-1694-2

Cited by 20 publications

(20 citation statements)

References 67 publications

(134 reference statements)

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“…The vast majority of subjects were also seropositive for EBV infection with a tendency toward increasing seroprevalence with increasing age but without any significant age‐dependent effect on EBNA‐1 IgG titres (Table ). Additionally, the overall frequencies of individuals homozygous for the NKG2C wild type gene was 44.1%; 42.6% were heterozygous and 13.2% were homozygous for the NKG2C gene deletion (an allele frequency of 34.6%) consistent with known frequency in The Gambia (Table ).…”

Section: Resultssupporting

confidence: 59%

Enhancement of cytokine‐driven NK cell IFN‐γ production after vaccination of HCMV infected Africans

et al. 2017

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Human cytomegalovirus (HCMV) infection drives the phenotypic and functional differentiation of NK cells, thereby influencing the responses of these cells after vaccination. NK cell functional differentiation is particularly advanced in African populations with universal exposure to HCMV. To investigate the impact of advanced differentiation on vaccine‐induced responses, we studied NK‐cell function before and after vaccination with Trivalent Influenza Vaccine (TIV) or diphtheria, tetanus, pertussis, inactivated poliovirus vaccine (DTPiP) in Africans with universal, lifelong HCMV exposure. In contrast to populations with lower prevalence of HCMV infection, no significant enhancement of NK‐cell responses (IFN‐γ, CD107a, CD25) occurred after in vitro re‐stimulation of post‐vaccination NK cells with TIV or DTPiP antigens compared to pre‐vaccination baseline cells. However, both vaccinations resulted in higher frequencies of NK cells producing IFN‐γ in response to exogenous IL‐12 with IL‐18, which persisted for up to 6 months. Enhanced cytokine responsiveness was restricted to less differentiated NK cells, with increased frequencies of IFN‐γ+ cells observed within CD56brightCD57−, CD56dimCD57−NKG2C− and CD56dimCD57−NKG2C+ NK‐cell subsets. These data suggest a common mechanism whereby different vaccines enhance NK cell IFN‐γ function in HCMV infected donors and raise the potential for further exploitation of NK cell “pre‐activation” to improve vaccine effectiveness.

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Section: Resultssupporting

confidence: 59%

Enhancement of cytokine‐driven NK cell IFN‐γ production after vaccination of HCMV infected Africans

et al. 2017

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“…The CD94 and NKG2C transcripts KLRC1 and KLRC3 had among the greatest decreases in fold-change of expression and the highest predictive power in identifying cases among CMV+ infants. The NKG2C receptor is encoded by the KLRC2 gene, heterozygous and homozygous deletion of which is present in a significant proportion of individuals across different populations 41 . KLRC2…”

Section: T-cell Activation Associates With Lower Mycobacterial Antigementioning

confidence: 99%

“…deletion is associated with reduced numbers of mature NK cells and increased susceptibility to HIV infection, certain autoimmune conditions and cancer [41][42][43] .…”

Section: T-cell Activation Associates With Lower Mycobacterial Antigementioning

confidence: 99%

Cytomegalovirus infection is a risk factor for TB disease in Infants

Müller

Matsumiya

Snowden

et al. 2017

Preprint

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Immune activation is associated with increased risk of tuberculosis (TB) disease in infants. We performed a case-control analysis to identify drivers of immune activation and disease risk. Among 49 infants who developed TB disease over the first two years of life, and 129 matched controls who remained healthy, we found the cytomegalovirus (CMV) stimulated IFN-γ response at age 4-6 months to be associated with CD8+ T-cell activation (Spearman’s rho, p=6×10−8). A CMV specific IFN-γ response was also associated with increased risk of developing TB disease (Conditional Logistic Regression, p=0.043, OR 2.2, 95% CI 1.02-4.83), and shorter time to TB diagnosis (Log Rank Mantel-Cox p=0.037). CMV positive infants who developed TB disease had lower expression of natural killer cell associated gene signatures and a lower frequency of CD3-CD4-CD8-lymphocytes. We identified transcriptional signatures predictive of risk of TB disease among CMV ELISpot positive (AUROC 0.98, accuracy 92.57%) and negative (AUROC 0.9, accuracy 79.3%) infants; the CMV negative signature validated in an independent infant study (AUROC 0.71, accuracy 63.9%). Understanding and controlling the microbial drivers of T cell activation, such as CMV, could guide new strategies for prevention of TB disease in infants.

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“…In HCMV positive infants who progressed to TB disease in the South African cohort there was lower expression of CD94 and NKG2C (KLRD1 and KLRC3) transcripts and lower frequency of NK cells 5 . The NKG2C receptor is encoded by the KLRC2 gene which is deleted in approximately 10% of individuals 40 . The KLRC2 gene deletion is associated with lower numbers of mature NK cells and increased risk of HIV infection and disease progression 41, 42 , as well as with susceptibility to autoimmune conditions and cancer 40 .…”

Section: Human Cytomegalovirus Infectionmentioning

confidence: 99%

“…The NKG2C receptor is encoded by the KLRC2 gene which is deleted in approximately 10% of individuals 40 . The KLRC2 gene deletion is associated with lower numbers of mature NK cells and increased risk of HIV infection and disease progression 41, 42 , as well as with susceptibility to autoimmune conditions and cancer 40 . Susceptibility to TB in this infant population may be due to loss of control of CMV infection due to KLRC2 gene defects in some individuals.…”

Section: Human Cytomegalovirus Infectionmentioning

confidence: 99%

The convergent epidemiology of tuberculosis and human cytomegalovirus infection

Cobelens¹,

Nagelkerke

Fletcher

2018

F1000Res

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Although several factors are known to increase the risk of tuberculosis, the occurrence of tuberculosis disease in an infected individual is difficult to predict. We hypothesize that active human cytomegalovirus infection due to recent infection, reinfection or reactivation plays an epidemiologically relevant role in the aetiology of tuberculosis by precipitating the progression from latent tuberculosis infection to disease. The most compelling support for this hypothesis comes from the striking similarity in age-sex distribution between the two infections, important because the age-sex pattern of tuberculosis disease progression has not been convincingly explained. Cytomegalovirus infection and tuberculosis have other overlapping risk factors, including poor socio-economic status, sexual contact, whole blood transfusion and solid organ transplantation. Although each of these overlaps could be explained by shared underlying risk factors, none of the epidemiological observations refute the hypothesis. If this interaction would play an epidemiologically important role, important opportunities would arise for novel approaches to controlling tuberculosis.

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Differential frequency of NKG2C/KLRC2 deletion in distinct African populations and susceptibility to Trachoma: a new method for imputation of KLRC2 genotypes from SNP genotyping data

Cited by 20 publications

References 67 publications

Enhancement of cytokine‐driven NK cell IFN‐γ production after vaccination of HCMV infected Africans

Enhancement of cytokine‐driven NK cell IFN‐γ production after vaccination of HCMV infected Africans

Cytomegalovirus infection is a risk factor for TB disease in Infants

The convergent epidemiology of tuberculosis and human cytomegalovirus infection

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