Genetic Variation of Innate Immune Genes in HIV-Infected African Patients With or Without Oropharyngeal Candidiasis

Abstract Inflammaging refers to low-grade, chronically activated innate immunity that has deleterious effects on healthy lifespan. However, little is known about the intrinsic signaling pathway that elicits innate immune genes during aging. Here using Drosophila melanogaster, we profile the microRNA targetomes in young and aged animals, and reveal Dawdle (Daw), an activin-like ligand of the TGF-β pathway, as a physiological target of microRNA-252 (miR-252). We show that miR-252 cooperates with Forkhead box O (FoxO), a conserved transcriptional factor implicated in aging, to repress Daw. Unopposed Daw triggers hyper activation of innate immune genes coupled with a decline in organismal survival. Using adult muscle tissues, single-cell sequencing analysis describes that Daw and its downstream innate immune genes are expressed in distinct cell types, suggesting a cell non-autonomous mode of regulation. We further determine the genetic cascade by which Daw signaling leads to increased Kenny/IKKγ protein, which in turn activates Relish/NF-κB protein and consequentially innate immune genes. Finally, transgenic increase of miR-252 and FoxO pathway factors in wild-type Drosophila extends lifespan and mitigates the induction of innate immune genes in aging. Together, we propose that miR-252 and FoxO promote healthy longevity by cooperative inhibition on Daw mediated inflammaging.

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Modulatory upregulation of an insulin peptide gene by different pathogens in C. elegans

10.1101/238568 ◽

2017 ◽

Author(s):

Song-Hua Lee ◽

Shizue Omi ◽

Nishant Thakur ◽

Clara Taffoni ◽

Jérôme Belougne ◽

...

Keyword(s):

Gene Expression ◽

Insulin Signaling ◽

Kinase Inhibitor ◽

Innate Immune ◽

Immune Genes ◽

C Elegans ◽

Intestinal Infections ◽

Innate Immune Genes ◽

Peptide Gene ◽

Complex Manner

ABSTRACTWhen an animal is infected, its innate immune response needs to be tightly regulated across tissues and coordinated with other aspects of organismal physiology. Previous studies with Caenorhabditis elegans have demonstrated that insulin-like peptide genes are differentially expressed in response to different pathogens. They represent prime candidates for conveying signals between tissues upon infection. Here, we focused on one such gene, ins-11 and its potential role in mediating cross-tissue regulation of innate immune genes. While diverse bacterial intestinal infections can trigger the up-regulation of ins-11 in the intestine, we show that epidermal infection with the fungus Drechmeria coniospora triggers an upregulation of ins-11 in the epidermis. Using the Shigella virulence factor OpsF, a MAP kinase inhibitor, we found that in both cases, ins-11 expression is controlled cell autonomously by p38 MAPK, but via distinct transcription factors, STA-2/STAT in the epidermis and HLH-30/TFEB in the intestine. We established that ins-11, and the insulin signaling pathway more generally, are not involved in the regulation of antimicrobial peptide gene expression in the epidermis. The up-regulation of ins-11 in the epidermis does, however, affect intestinal gene expression in a complex manner, and has a deleterious effect on longevity. These results support a model in which insulin signaling, via ins-11, contributes to the coordination of the organismal response to infection, influencing the allocation of resources in an infected animal.

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CF Monocyte Derived Macrophages Have an Attenuated Response to Extracellular Vesicles Secreted by Airway Epithelial Cells

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00621.2020 ◽

2021 ◽

Author(s):

Katja Koeppen ◽

Amanda B Nymon ◽

Roxanna Barnaby ◽

Zhongyou Li ◽

Thomas H Hampton ◽

...

Keyword(s):

Immune Response ◽

Epithelial Cells ◽

Bacterial Infection ◽

Extracellular Vesicles ◽

Cell Types ◽

Airway Epithelial Cells ◽

Innate Immune ◽

Airway Epithelial ◽

Immune Genes ◽

Innate Immune Genes

Mutations in CFTR alter macrophage responses, for example, by reducing their ability to phagocytose and kill bacteria. Altered macrophage responses may facilitate bacterial infection and inflammation in the lungs, contributing to morbidity and mortality in cystic fibrosis (CF). Extracellular vesicles (EVs) are secreted by multiple cell types in the lungs and participate in the host immune response to bacterial infection, but the effect of EVs secreted by CF airway epithelial cells (AEC) on CF macrophages is unknown. This report examines the effect of EVs secreted by primary AEC on monocyte derived macrophages (MDM) and contrasts responses of CF and WT MDM. We found that EVs generally increase pro-inflammatory cytokine secretion and expression of innate immune genes in MDM, especially when EVs are derived from AEC exposed to Pseudomonas aeruginosa, and that this effect is attenuated in CF MDM. Specifically, EVs secreted by P. aeruginosa exposed AEC induced immune response genes and increased secretion of pro-inflammatory cytokines, chemoattractants and chemokines involved in tissue repair by WT MDM, but these effects were less robust in CF MDM. We attribute attenuated responses by CF MDM to differences between CF and WT macrophages because EVs secreted by CF AEC or WT AEC elicited similar responses in CF MDM. Our findings demonstrate the importance of AEC EVs in macrophage responses and show that the Phe508del mutation in CFTR attenuates the innate immune response of MDM to EVs.

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Association Of Polymorphisms In Known And Novel Innate Immune Genes With Gram Negative Bacteremia

10.1164/ajrccm-conference.2011.183.1_meetingabstracts.a3869 ◽

2011 ◽

Cited By ~ 1

Author(s):

Ivana V. Yang ◽

Laura A. Warg ◽

Scott Alper ◽

David A. Schwartz

Keyword(s):

Innate Immune ◽

Gram Negative ◽

Immune Genes ◽

Gram Negative Bacteremia ◽

Innate Immune Genes

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Responses of some innate immune‐genes involved in the toll‐pathway in black tiger shrimp ( Penaeus monodon ) to Vibrio harveyi infection and on exposure to ligands in vitro

Journal of the World Aquaculture Society ◽

10.1111/jwas.12723 ◽

2020 ◽

Vol 51 (6) ◽

pp. 1419-1429 ◽

Cited By ~ 1

Author(s):

Anand Deepika ◽

Krishnan Sreedharan ◽

Kooloth Valappil Rajendran

Keyword(s):

Vibrio Harveyi ◽

Penaeus Monodon ◽

Innate Immune ◽

Toll Pathway ◽

Immune Genes ◽

Black Tiger Shrimp ◽

Tiger Shrimp ◽

Innate Immune Genes

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Genomic architecture of haddock (Melanogrammus aeglefinus) shows expansions of innate immune genes and short tandem repeats

BMC Genomics ◽

10.1186/s12864-018-4616-y ◽

2018 ◽

Vol 19 (1) ◽

Cited By ~ 15

Author(s):

Ole K. Tørresen ◽

Marine S. O. Brieuc ◽

Monica H. Solbakken ◽

Elin Sørhus ◽

Alexander J. Nederbragt ◽

...

Keyword(s):

Short Tandem Repeats ◽

Tandem Repeats ◽

Innate Immune ◽

Melanogrammus Aeglefinus ◽

Immune Genes ◽

Genomic Architecture ◽

Innate Immune Genes ◽

Haddock Melanogrammus Aeglefinus ◽

Short Tandem

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Human polymorphisms in GSDMD alter the inflammatory response

Journal of Biological Chemistry ◽

10.1074/jbc.ra119.010604 ◽

2020 ◽

Vol 295 (10) ◽

pp. 3228-3238 ◽

Cited By ~ 2

Author(s):

Joseph K. Rathkey ◽

Tsan S. Xiao ◽

Derek W. Abbott

Keyword(s):

Cell Death ◽

Genetic Variation ◽

Posttranslational Modifications ◽

Apoptotic Cell ◽

Gene Families ◽

Inflammasome Activation ◽

Caspase Cleavage ◽

Immune Genes ◽

Functional Consequences ◽

Innate Immune Genes

Exomic studies have demonstrated that innate immune genes exhibit an even higher degree of variation than the majority of other gene families. However, the phenotypic implications of this genetic variation are not well understood, with effects ranging from hypomorphic to silent to hyperfunctioning. In this work, we study the functional consequences of this variation by investigating polymorphisms in gasdermin D, the key pyroptotic effector protein. We find that, although SNPs affecting potential posttranslational modifications did not affect gasdermin D function or pyroptosis, polymorphisms disrupting sites predicted to be structurally important dramatically alter gasdermin D function. The manner in which these polymorphisms alter function varies from conserving normal pyroptotic function to inhibiting caspase cleavage to disrupting oligomerization and pore formation. Further, downstream of inflammasome activation, polymorphisms that cause loss of gasdermin D function convert inflammatory pyroptotic cell death into immunologically silent apoptotic cell death. These findings suggest that human genetic variation can alter mechanisms of cell death in inflammation.

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Molecular evolution in immune genes across the avian tree of life

Parasitology Open ◽

10.1017/pao.2019.3 ◽

2019 ◽

Vol 5 ◽

Cited By ~ 1

Author(s):

Diana C. Outlaw ◽

V. Woody Walstrom ◽

Haley N. Bodden ◽

Chuan-yu Hsu ◽

Mark Arick ◽

...

Keyword(s):

Purifying Selection ◽

Tree Of Life ◽

Innate Immune ◽

Phylogenetic Study ◽

Significant Differential Expression ◽

Immune Genes ◽

Treatment Groups ◽

Show Evidence ◽

Differential Gene ◽

Innate Immune Genes

Abstract All organisms encounter pathogens, and birds are especially susceptible to infection by malaria parasites and other haemosporidians. It is important to understand how immune genes, primarily innate immune genes which are the first line of host defense, have evolved across birds, a highly diverse group of tetrapods. Here, we find that innate immune genes are highly conserved across the avian tree of life and that although most show evidence of positive or diversifying selection within specific lineages or clades, the number of sites is often proportionally low in this broader context of putative constraint. Rather, evidence shows a much higher level of negative or purifying selection in these innate immune genes – rather than adaptive immune genes – which is consistent with birds' long coevolutionary history with pathogens and the need to maintain a rapid response to infection. We further explored avian responses to haemosporidians by comparing differential gene expression in wild birds (1) uninfected with haemosporidians, (2) infected with Plasmodium and (3) infected with Haemoproteus (Parahaemoproteus). We found patterns of significant differential expression with some genes unique to infection with each genus and a few shared between ‘treatment’ groups, but none that overlapped with the genes included in the phylogenetic study.

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