COVID-19 researchGene: KLF2
Evidence Summary from Illumina curation team (Alison Coffey and Julie Taylor): KLF2 is a member of the Kruppel-like factor (KLF) family of zinc finger transcription factors that function in cell differentiation, quiescence, and homeostasis. It also plays a regulatory role in inflammation-related pathways (Jha and Das 2017). Richardson et al. (2012) showed that KLF2 acts as a host factor that modulates CCR5 expression in CD4 T cells and influences susceptibility to infection with CCR5-dependent HIV-1 strains. Huang et al. (2017) showed through both network analyses and experimental results that KLF2 plays a central role in regulating many genes associated with acute respiratory distress syndrome (ARDS) identified by GWAS and that overexpression of KLF2 in vivo in mice could mitigate lung injury and expression of inflammatory genes, including that induced by influenza A virus.
PMID 17141159: Lee et al. (2006) - KLF2 deficient mice die in prenatal stage due to vascular defects, highlighting its crucial role in embryonic development. Lethal high-output heart failure, as found in the KO mice, was also observed in zebrafish embryos after morpholino inhibition of the Klf2 ortholog klf2a. CD4+ T cells from KLF2-deficient mice expressed multiple inflammatory chemokine receptors, suggesting that loss of KLF2 leads to redirection of naïve T cells to nonlymphoid sites (Sebzda et al., 2008).
PMID 19592277: Weinreich et al. (2009) - Demonstrated upregulation of the chemokine receptor CXCR3 on KLF2-deficient T cells (Fig. 1). KLF2-deficient T cells also overproduced IL-4 (Fig. 5).
PMID 22988032: Richardson et al. (2012) - Tested whether the abundance of KLF2 after T cell activation regulates CCR5 expression and, thus, susceptibility of a T cell to CCR5-dependent HIV-1 strains (R5). Introduced small interfering RNA targeting KLF2 expression and demonstrated that reduced KLF2 expression also resulted in less CCR5 (Fig. 3). Introduction of KLF2 under control of a heterologous promoter could restore CCR5 expression and R5 susceptibility to CD3/28 costimulated T cells and some transformed cell lines (Fig. 5, 6). KLF2 is a host factor that modulates CCR5 expression in CD4 T cells and influences susceptibility to R5 infection.
PMID 29125549: (review) Jha and Das (2017) - KLF2 also plays a critical regulatory role in various inflammatory diseases and their pathogenesis.
PMID 27855271: Huang et al. (2017) - Animal and in vitro models of acute lung injury were used to characterize KLF2 expression and its downstream effects responding to influenza A virus (A/WSN/33 [H1N1]), tumor necrosis factor-α, LPS, mechanical stretch/ventilation, or microvascular flow to examine the role of the gene in endothelial barrier disruption and cytokine storm in experimental lung injury. Pulmonary Klf2 was down-regulated by inflammation induced by influenza A/WSN/H1N1 virus (H1N1) infection, LPS administration, or LPS administration followed by high tidal volume ventilation in vivo (Fig. 1). It was also down-regulated by pathologic stretch and inflammatory stimuli (Fig. 2). Knockdown of endogenous KLF2 reduces Rac1 activation in human pulmonary microvascular cells, whereas adenovirus-mediated transduction with KLF2 promoted Rac1 activation (Fig. 3). Computational predictive pathway analysis suggested that KLF2 acts to regulate ARDS-associated GWAS genes, including ACE, NAD(P)H, NQO1, SERPINE1/PAI-1, TNF, and NF-kappaB. Expression studies in mice confirmed this regulatory role (Fig. 8). Overexpression of KLF2 in vivo in mice could also mitigate lung injury and expression of inflammatory genes (Fig. 7).
Created: 28 May 2020, 3:21 p.m. | Last Modified: 28 May 2020, 3:21 p.m.
Panel Version: 0.348
Identified through an OMIM search for potential viral susceptibility genes, and subsequently triaged/reviewed by Illumina curation team.
Created: 28 May 2020, 12:36 p.m. | Last Modified: 28 May 2020, 12:36 p.m.
Panel Version: 0.336
gene: KLF2 was added gene: KLF2 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Green Mode of inheritance for gene: KLF2 was set to Unknown