Human genetic variation in
            <i>VAC14</i>
            regulates
            <i>Salmonella</i>
            invasion and typhoid fever through modulation of cholesterol

Alvarez, Monica I; Glover, Luke C; Luo, Peter; Wang, Liuyang; Theusch, Elizabeth; Oehlers, Stefan H.; Walton, Eric M; Tram, Trinh Thi Bich; Kuang, Yu‐Lin; Rotter, Jerome I.; McClean, Colleen M.; Chinh, Nguyen Tran; Medina, Marisa W.; Tobin, David M.; Dunstan, Sarah J.; Ko, Dennis C.

doi:10.1073/pnas.1706070114

Cited by 46 publications

(58 citation statements)

References 109 publications

(100 reference statements)

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“…Examination of SPI-1’s role in SarA translocation is more complex due to the requirement of SPI-1 for entry into non-phagocytic cells (Collazo and Galan, 1997), including LCLs (Alvarez et al, 2017). Therefore, we utilized S. Typhi (which does not contain SarA and therefore does not induce IL-10) to trigger macropinocytosis in the LCLs and co-infected with S .…”

Section: Resultsmentioning

confidence: 99%

Salmonella Activation of STAT3 Signaling by SarA Effector Promotes Intracellular Replication and Production of IL-10

et al. 2018

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Salmonella enterica is an important foodborne pathogen that uses secreted effector proteins to manipulate host pathways to facilitate survival and dissemination. Different S. enterica serovars cause disease syndromes ranging from gastroenteritis to typhoid fever and vary in their effector repertoire. We leveraged this natural diversity to identify stm2585, here designated sarA (Salmonella anti-inflammatory response activator), as a Salmonella effector that induces production of the anti-inflammatory cytokine IL-10. RNA-seq of cells infected with either ΔsarA or wild-type S. Typhimurium revealed that SarA activates STAT3 transcriptional targets. Consistent with this, SarA is necessary and sufficient for STAT3 phosphorylation, STAT3 inhibition blocks IL-10 production, and SarA and STAT3 interact by co-immunoprecipitation. These effects of SarA contribute to intracellular replication in vitro and bacterial load at systemic sites in mice. Our results demonstrate the power of using comparative genomics for identifying effectors and that Salmonella has evolved mechanisms for activating an important anti-inflammatory pathway.

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Section: Resultsmentioning

confidence: 99%

Salmonella Activation of STAT3 Signaling by SarA Effector Promotes Intracellular Replication and Production of IL-10

et al. 2018

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“…We reasoned that functional annotations might provide clues to further putatively causal variants among our list of most associated regions. To assess this, we annotated all imputed variants with information indicative of functional importance, including location and predicted function within genes 26 , chromatin state 27–29 and transcriptional activity 28,30,31 across cell types, status as an eQTL 31–33 , and association evidence from other traits 34–37 . This analysis revealed a number of potentially functional variants with evidence of association ( Table S4 ).…”

Section: Resultsmentioning

confidence: 99%

New insights into malaria susceptibility from the genomes of 17,000 individuals from Africa, Asia, and Oceania

Clarke

Kivinen

et al. 2019

Preprint

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We conducted a genome-wide association study of host resistance to severe Plasmodium falciparum malaria in over 17,000 individuals from 11 malariaendemic countries, undertaking a wide ranging analysis which identifies five replicable associations with genome-wide levels of evidence. Our findings include a newly implicated variant on chromosome 6 associated with risk of cerebral malaria, and the discovery of an erythroid-specific transcription start site underlying the association in ATP2B4. Previously reported HLA associations cannot be replicated in this dataset. We estimate substantial heritability of severe malaria (h 2 ~ 23%), of which around 10% is explained by the currently identified associations. Our dataset will provide a major building block for future research on the genetic determinants of disease in these diverse human populations.a single set of estimated haplotypes for 17,960 individuals at the set of over 1.5M SNPs genome-wide that passed our quality control process (Methods). This dataset includes 6,888 individuals from Mali, Burkina Faso, Ghana, Nigeria, Cameroon, Tanzania, Vietnam and Papua New Guinea that have not previously been included in meta-analysis, as well as previously reported data from The Gambia, Malawi and Kenya 9,10 , and thus reflects the haplotype diversity of a substantial portion of the malaria-endemic world.A reference panel enriched for African DNA improves imputation accuracy across the genome The ethnically diverse nature of our study provides challenges for genomic inference, including for our ability to impute genotypes at potentially relevant untyped loci 11 . To address this, we sequenced the genomes of 773 individuals from ten ethnic groups in east and west Africa (specifically from the Gambia, Burkina Faso, Cameroon and Tanzania), including 207 family trios (Figure 1). We combined genotypes at single nucleotide polymorphisms (SNPs) in these data with Phase 3 of the 1000 Genomes Project to form an imputation reference panel which covers most common genetic variation 12 and in which two-fifths of the donor families are of African ancestry (1,203 of 3,046 individuals). In principle, the additional representation of African DNA in this panel should lead to improvements in imputation accuracy for African study populations, and we found that this was indeed the case, with use of our panel leading to a large increase in accuracy relative to panels used in our previous GWAS 9-11 and a more modest improvement relative to using the 1000 Genomes Phase 3 panel alone (Figure S1). Imputation of Vietnamese individuals, and those from Papua New Guinea (PNG) which is substantially diverged from any reference panel population (Figure 1d), were less affected by the inclusion of these additional haplotypes.We specifically examined imputation of malaria-protective alleles in the HBB gene, which have previously been found difficult to impute 9,11 . The SNP encoding the sickle cell mutation (rs334, chr11:5248232) was imputed with r>0.9 in all African populations, as compared with genotype...

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“…Furthermore, effects of the proteins sopB and sopE are necessary for Salmonella to induce its own entrance. 27 We have reported that, similar to epithelial cell infection, Salmonella Typhimurium promotes its own entry into spleen mouse B cells in a process dependent on SPI-1 genes. 24 It has also been shown that this entry process can be mediated by the BCR.…”

Section: Spi-5 Encodes a Series Of Proteins Responsible For Enteropatmentioning

confidence: 98%

“…It is well established that B cells are targets of Salmonella infection. [22][23][24][25][26][27][28] In murine models, we observed that Salmonella…”

Section: Spi-5 Encodes a Series Of Proteins Responsible For Enteropatmentioning

confidence: 99%

Beyond the antibody: B cells as a target for bacterial infection

García-Gil

Lopez-Bailon

Ortiz-Navarrete

2019

Journal of Leukocyte Biology

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It is well established that B cells play an important role during infections beyond antibody production. B cells produce cytokines and are APCs for T cells. Recently, it has become clear that several pathogenic bacterial genera, such as Salmonella, Brucella, Mycobacterium, Listeria, Francisella, Moraxella, and Helicobacter, have evolved mechanisms such as micropinocytosis induction, inflammasome down‐regulation, inhibitory molecule expression, apoptosis induction, and anti‐inflammatory cytokine secretion to manipulate B cell functions influencing immune responses. In this review, we summarize our current understanding of B cells as targets of bacterial infection and the mechanisms by which B cells become a niche for bacterial survival and replication away from extracellular immune responses such as complement and antibodies.

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Human genetic variation in VAC14 regulates Salmonella invasion and typhoid fever through modulation of cholesterol

Cited by 46 publications

References 109 publications

Salmonella Activation of STAT3 Signaling by SarA Effector Promotes Intracellular Replication and Production of IL-10

Salmonella Activation of STAT3 Signaling by SarA Effector Promotes Intracellular Replication and Production of IL-10

New insights into malaria susceptibility from the genomes of 17,000 individuals from Africa, Asia, and Oceania

Beyond the antibody: B cells as a target for bacterial infection

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