Obesity and STING1 genotype associate with 23-valent pneumococcal vaccination efficacy

Sebastian, Mathew; Hsiao, Chu; Futch, Hunter S.; Eisinger, Robert S.; Dumeny, Leanne; Patel, Seema; Gobena, Mesfin; Katikaneni, Divya S.; Cohen, Joel; Carpenter, Anne-Marie; Spiryda, Lisa Beth; Heldermon, Coy D.; Jin, Lei; Brantly, Mark

doi:10.1172/jci.insight.136141

Cited by 9 publications

(9 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Levy and colleagues (14) showed that whereas WT STING promoted MHCmatched allogeneic hematopoietic stem cell transplantationinduced graft-versus-host disease, the HAQ mice developed reduced MHCmatched graft-versus-host disease (14). Most recently, in a clinical trial (ClinicalTrials.gov ID NCT02471014), we found that HAQ individuals had poor responses to the Pneumovax 23 vaccine (15), a phenotype that we previously found in the HAQ knock-in mouse (11). Thus, the HAQ allele is defective in CDN sensing.…”

Section: Mpys Modulates Fatty Acid Metabolism and Immunementioning

confidence: 90%

See 1 more Smart Citation

MPYS Modulates Fatty Acid Metabolism and Immune Tolerance at Homeostasis Independent of Type I IFNs

Mansouri

Gogoi

Patel

et al. 2022

The Journal of Immunology

View full text Add to dashboard Cite

MPYS/STING (stimulator of IFN genes) senses cyclic dinucleotides (CDNs), generates type I IFNs, and plays a critical role in infection, inflammation, and cancer. In this study, analyzing genotype and haplotype data from the 1000 Genomes Project, we found that the R71H-G230A-R293Q (HAQ) MPYS allele frequency increased 57-fold in East Asians compared with sub-Saharan Africans. Meanwhile, the G230A-R293Q (AQ) allele frequency decreased by 98% in East Asians compared with sub-Saharan Africans. We propose that the HAQ and AQ alleles underwent a natural selection during the out-of-Africa migration. We used mouse models of HAQ and AQ to investigate the underlying mechanism. We found that the mice carrying the AQ allele, which disappeared in East Asians, had normal CDN–type I IFN responses. Adult AQ mice, however, had less fat mass than did HAQ or wild-type mice on a chow diet. AQ epididymal adipose tissue had increased regulatory T cells and M2 macrophages with protein expression associated with enhanced fatty acid oxidation. Conditional knockout mice and adoptive cell transfer indicate a macrophage and regulatory T cell–intrinsic role of MPYS in fatty acid metabolism. Mechanistically, AQ/IFNAR1−/− mice had a similar lean phenotype as for the AQ mice. MPYS intrinsic tryptophan fluorescence revealed that the R71H change increased MPYS hydrophilicity. Lastly, we found that the second transmembrane (TM) and the TM2–TM3 linker region of MPYS interact with activated fatty acid, fatty acyl–CoA. In summary, studying the evolution of the human MPYS gene revealed an MPYS function in modulating fatty acid metabolism that may be critical during the out-of-Africa migration.

show abstract

Section: Mpys Modulates Fatty Acid Metabolism and Immunementioning

confidence: 90%

“…2C). In contrast, HAQ mice have impaired anti-PPS IgM response to Pneumovax 23 (11,15). Next, we compared Prevnar 13 immunization in HAQ and AQ mice.…”

Section: Aq Knock-in Mice Respond To Cdns and Prevnar 13 Vaccinationmentioning

confidence: 99%

MPYS Modulates Fatty Acid Metabolism and Immune Tolerance at Homeostasis Independent of Type I IFNs

Mansouri

Gogoi

Patel

et al. 2022

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…We need further studies in the field. However, obese people have an advantage over lean people in terms of their immune response against 23-valent pneumococcal vaccination due to the STING activation ( 127 ).…”

Section: Cgas-sting-based Host Cell Dna Recognitionmentioning

confidence: 99%

The Trinity of cGAS, TLR9, and ALRs Guardians of the Cellular Galaxy Against Host-Derived Self-DNA

Kumar

2021

Front. Immunol.

View full text Add to dashboard Cite

The immune system has evolved to protect the host from the pathogens and allergens surrounding their environment. The immune system develops in such a way to recognize self and non-self and develops self-tolerance against self-proteins, nucleic acids, and other larger molecules. However, the broken immunological self-tolerance leads to the development of autoimmune or autoinflammatory diseases. Pattern-recognition receptors (PRRs) are expressed by immunological cells on their cell membrane and in the cytosol. Different Toll-like receptors (TLRs), Nod-like receptors (NLRs) and absent in melanoma-2 (AIM-2)-like receptors (ALRs) forming inflammasomes in the cytosol, RIG (retinoic acid-inducible gene)-1-like receptors (RLRs), and C-type lectin receptors (CLRs) are some of the PRRs. The DNA-sensing receptor cyclic GMP–AMP synthase (cGAS) is another PRR present in the cytosol and the nucleus. The present review describes the role of ALRs (AIM2), TLR9, and cGAS in recognizing the host cell DNA as a potent damage/danger-associated molecular pattern (DAMP), which moves out to the cytosol from its housing organelles (nucleus and mitochondria). The introduction opens with the concept that the immune system has evolved to recognize pathogens, the idea of horror autotoxicus, and its failure due to the emergence of autoimmune diseases (ADs), and the discovery of PRRs revolutionizing immunology. The second section describes the cGAS-STING signaling pathway mediated cytosolic self-DNA recognition, its evolution, characteristics of self-DNAs activating it, and its role in different inflammatory conditions. The third section describes the role of TLR9 in recognizing self-DNA in the endolysosomes during infections depending on the self-DNA characteristics and various inflammatory diseases. The fourth section discusses about AIM2 (an ALR), which also binds cytosolic self-DNA (with 80–300 base pairs or bp) that inhibits cGAS-STING-dependent type 1 IFN generation but induces inflammation and pyroptosis during different inflammatory conditions. Hence, this trinity of PRRs has evolved to recognize self-DNA as a potential DAMP and comes into action to guard the cellular galaxy. However, their dysregulation proves dangerous to the host and leads to several inflammatory conditions, including sterile-inflammatory conditions autoinflammatory and ADs.

show abstract

“…In contrast, AQ and Q293 are only found in Africans [ 51 ]. In a recent clinical trial, Sebastian M. et al showed that HAQ carriers had low anti-PPS antibodies production in response to Pneumovax ® 23 immunization (ClinicalTrials.gov: NCT02471014) [ 90 ]. The result is in line with the previous data from a HAQ knock-in mouse mode [ 51 ].…”

Section: Confounding Factors In Cdn Adjuvanticity In Humansmentioning

confidence: 99%

“…Accumulating evidence in humans [ 90 , 91 , 100 , 101 ] and mouse models [ 50 , 51 , 102 ] indicated that the HAQ and H232 alleles are impaired in the STING function. CDN-adjuvanted vaccines aim to protect the general public from the pandemic and endemic.…”

Section: Future Of Cdn Vaccine Adjuvantsmentioning

confidence: 99%

The Age of Cyclic Dinucleotide Vaccine Adjuvants

2020

Self Cite

View full text Add to dashboard Cite

As prophylactic vaccine adjuvants for infectious diseases, cyclic dinucleotides (CDNs) induce safe, potent, long-lasting humoral and cellular memory responses in the systemic and mucosal compartments. As therapeutic cancer vaccine adjuvants, CDNs induce potent anti-tumor immunity, including cytotoxic T cells and NK cells activation that achieve durable regression in multiple mouse models of tumors. Clinical trials are ongoing to fulfill the promise of CDNs (ClinicalTrials.gov: NCT02675439, NCT03010176, NCT03172936, and NCT03937141). However, in October 2018, the first clinical data with Merck’s CDN MK-1454 showed zero activity as a monotherapy in patients with solid tumors or lymphomas (NCT03010176). Lately, the clinical trial from Aduro’s CDN ADU-S100 monotherapy was also disappointing (NCT03172936). The emerging hurdle in CDN vaccine development calls for a timely re-evaluation of our understanding on CDN vaccine adjuvants. Here, we review the status of CDN vaccine adjuvant research, including their superior adjuvant activities, in vivo mode of action, and confounding factors that affect their efficacy in humans. Lastly, we discuss the strategies to overcome the hurdle and advance promising CDN adjuvants in humans.

show abstract

Obesity and STING1 genotype associate with 23-valent pneumococcal vaccination efficacy

Cited by 9 publications

References 31 publications

MPYS Modulates Fatty Acid Metabolism and Immune Tolerance at Homeostasis Independent of Type I IFNs

MPYS Modulates Fatty Acid Metabolism and Immune Tolerance at Homeostasis Independent of Type I IFNs

The Trinity of cGAS, TLR9, and ALRs Guardians of the Cellular Galaxy Against Host-Derived Self-DNA

The Age of Cyclic Dinucleotide Vaccine Adjuvants

Contact Info

Product

Resources

About