scholarly journals Integrin Alpha E (CD103) Limits Virus-Induced IFN-I Production in Conventional Dendritic Cells

2021 ◽  
Vol 11 ◽  
Author(s):  
Vikas Duhan ◽  
Vishal Khairnar ◽  
Simo Kitanovski ◽  
Thamer A. Hamdan ◽  
Andrés D. Klein ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Vesicular Stomatitis Virus ◽  
Immune Activation ◽  
Genome Wide Association Study ◽  
Innate Immune ◽  
Akt Phosphorylation ◽  
Genome Wide ◽  
A Genome ◽  
Cell Type Specific ◽  
Vesicular Stomatitis

Early and strong production of IFN-I by dendritic cells is important to control vesicular stomatitis virus (VSV), however mechanisms which explain this cell-type specific innate immune activation remain to be defined. Here, using a genome wide association study (GWAS), we identified Integrin alpha-E (Itgae, CD103) as a new regulator of antiviral IFN-I production in a mouse model of vesicular stomatitis virus (VSV) infection. CD103 was specifically expressed by splenic conventional dendritic cells (cDCs) and limited IFN-I production in these cells during VSV infection. Mechanistically, CD103 suppressed AKT phosphorylation and mTOR activation in DCs. Deficiency in CD103 accelerated early IFN-I in cDCs and prevented death in VSV infected animals. In conclusion, CD103 participates in regulation of cDC specific IFN-I induction and thereby influences immune activation after VSV infection.

scholarly journals Tumor Necrosis Factor-Mediated Survival of CD169 + Cells Promotes Immune Activation during Vesicular Stomatitis Virus Infection

2017 ◽  
Vol 92 (3) ◽  
Author(s):  
Prashant V. Shinde ◽  
Haifeng C. Xu ◽  
Sathish Kumar Maney ◽  
Andreas Kloetgen ◽  
Sukumar Namineni ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Virus Infection ◽  
Vesicular Stomatitis Virus ◽  
Virus Replication ◽  
Immune Activation ◽  
Tumor Necrosis ◽  
Severe Disease ◽  
Innate Immune ◽  
Vesicular Stomatitis ◽  
Necrosis Factor

ABSTRACT Innate immune activation is essential to mount an effective antiviral response and to prime adaptive immunity. Although a crucial role of CD169 + cells during vesicular stomatitis virus (VSV) infections is increasingly recognized, factors regulating CD169 + cells during viral infections remain unclear. Here, we show that tumor necrosis factor is produced by CD11b + Ly6C + Ly6G + cells following infection with VSV. The absence of TNF or TNF receptor 1 (TNFR1) resulted in reduced numbers of CD169 + cells and in reduced type I interferon (IFN-I) production during VSV infection, with a severe disease outcome. Specifically, TNF triggered RelA translocation into the nuclei of CD169 + cells; this translocation was inhibited when the paracaspase MALT-1 was absent. Consequently, MALT1 deficiency resulted in reduced VSV replication, defective innate immune activation, and development of severe disease. These findings indicate that TNF mediates the maintenance of CD169 + cells and innate and adaptive immune activation during VSV infection. IMPORTANCE Over the last decade, strategically placed CD169 + metallophilic macrophages in the marginal zone of the murine spleen and lymph nodes (LN) have been shown to play a very important role in host defense against viral pathogens. CD169 + macrophages have been shown to activate innate and adaptive immunity via “enforced virus replication,” a controlled amplification of virus particles. However, the factors regulating the CD169 + macrophages remain to be studied. In this paper, we show that after vesicular stomatitis virus infection, phagocytes produce tumor necrosis factor (TNF), which signals via TNFR1, and promote enforced virus replication in CD169 + macrophages. Consequently, lack of TNF or TNFR1 resulted in defective immune activation and VSV clearance.

scholarly journals Genome-wide heritability analysis of severe malaria resistance reveals evidence of polygenic inheritance

2019 ◽  
Vol 29 (1) ◽  
pp. 168-176
Author(s):  
Delesa Damena ◽  
Emile R Chimusa
Keyword(s):  
Severe Malaria ◽  
Genome Wide Association Study ◽  
Allelic Frequency ◽  
Relationship Matrix ◽  
Summary Statistics ◽  
Cell Type ◽  
Polygenic Inheritance ◽  
Genome Wide ◽  
A Genome ◽  
Cell Type Specific

Abstract Background: Estimating single nucleotide polymorphism (SNP)-heritability (h2g) of severe malaria resistance and its distribution across the genome might shed new light in to the underlying biology. Method: We investigated h2g of severe malaria resistance from a genome-wide association study (GWAS) dataset (sample size = 11 657). We estimated the h2g and partitioned in to chromosomes, allele frequencies and annotations using the genetic relationship-matrix restricted maximum likelihood approach. We further examined non-cell type-specific and cell type-specific enrichments from GWAS-summary statistics. Results: The h2g of severe malaria resistance was estimated at 0.21 (se = 0.05, P = 2.7 × 10−5), 0.20 (se = 0.05, P = 7.5 × 10−5) and 0.17 (se = 0.05, P = 7.2 × 10−4) in Gambian, Kenyan and Malawi populations, respectively. A comparable range of h2g [0.21 (se = 0.02, P < 1 × 10−5)] was estimated from GWAS-summary statistics meta-analysed across the three populations. Partitioning analysis from raw genotype data showed significant enrichment of h2g in genic SNPs while summary statistics analysis suggests evidences of enrichment in multiple categories. Supporting the polygenic inheritance, the h2g of severe malaria resistance is distributed across the chromosomes and allelic frequency spectrum. However, the h2g is disproportionately concentrated on three chromosomes (chr 5, 11 and 20), suggesting cost-effectiveness of targeting these chromosomes in future malaria genomic sequencing studies. Conclusion: We report for the first time that the heritability of malaria resistance is largely ascribed by common SNPs and the causal variants are overrepresented in protein coding regions of the genome. Further studies with larger sample sizes are needed to better understand the underpinning genetics of severe malaria resistance.

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