Biology subjects

Muller, M.

Publications and source records attributed to Muller, M..

39 records · Page 3Linked to original sources

bioRxiv2019

Congenital Zika Syndrome is associated with maternal genetic background

BackgroundHost factors that influence Congenital Zika Syndrome (CZS) outcome remain elusive. Interferons have been reported as the main antiviral factor in Zika and other flavivirus infections. MethodsWe accessed samples from Zika pregnancies, conducted a case-control study to verify whether interferon alfa receptor 1 (IFNAR1) and interferon lambda 2 and 4 (IFNL2/4) single nucleotide polymorphisms (SNPs) contribute to CZS newborn outcome and we characterized placenta gene expression profile at term. FindingsNewborns carrying CG/CC genotypes of rs2257167 in IFNAR1 presented higher risk of developing CZS (OR=3.73; IC=1.36-10.21; Pcorrected=0.02646). No association between IFNL SNPs and CZS was observed. Placenta from CZS cases displayed lower levels of IFNL2 and ISG15 along with higher IFIT5. The rs2257167 CG/CC placentas also demonstrated high levels of IFIT5 and inflammation-related genes. InterpretationWe found CZS to be related with exacerbated type I IFN and insufficient type III IFN in placenta at term, forming an unbalanced response modulated by the IFNAR1 rs2257167 genotype. These findings shed light on the host-pathogen interaction focusing on the genetically regulated type I / type III IFN axis that could lead to better management of Zika and other TORCH (Toxoplasma, Others, Rubella, Cytomegalovirus, Herpes) congenital infections. FundingThis work was supported by the Instituto Oswaldo Cruz (Rio de Janeiro, Brazil) and by the Instituto de Tecnologia em Imunobiologicos (Rio de Janeiro, Brazil). Research in contextO_ST_ABSEvidence before this studyC_ST_ABSLevels of type I and type III interferons are genetically controlled and decisively regulate outcome of spontaneous viral infections or response to antiviral treatment. Hepatitis C virus, Yellow Fever and Zika virus belong to the Flaviviridae family and elicit similar host immune responses. Congenital Zika Syndrome presents well-known risk factors, mainly the first trimester of pregnancy as well as social and nutritional factors, however, these do not entirely explain abnormal outcomes. Added value of this studyWe conducted a case-control study to evaluate SNPs in type I and III interferon genes using samples from newborns and mothers who had zika infection during pregnancy. We have shown that newborn interferon type I background contributes to the development of abnormal CSZ. This specific genetic makeup regulates placental immunological responses and prevents an exacerbated type I, and lack of type III, interferon response in syndromic cases. Implications of all the available evidenceOur study suggests an important factor regulating the host-pathogen interaction during Zika virus (ZIKV) infections in humans. During pregnancy, genetic variations play a role in balancing tissue-specific type I and III interferons during ZIKV congenital infection influencing fetal neurological damage. Custom pharmacological interventions could be used to modulate immunity and inflammation towards protective responses. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=104 SRC="FIGDIR/small/715862v3_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@ee554forg.highwire.dtl.DTLVardef@122c773org.highwire.dtl.DTLVardef@547695org.highwire.dtl.DTLVardef@13543db_HPS_FORMAT_FIGEXP M_FIG C_FIG

genetics↗

bioRxiv2018

C19ORF66 broadly escapes viral-induced endonuclease cleavage and restricts Kaposi Sarcoma Associated Herpesvirus (KSHV)

One striking characteristic of certain herpesviruses is their ability to induce rapid and widespread RNA decay in order to gain access to host resources. This phenotype is induced by viral endoribonucleases, including SOX in KSHV, muSOX in MHV68, BGLF5 in EBV and vhs in HSV-1. Here, we performed comparative RNA-seq upon expression of these herpesviral endonucleases in order to characterize their effect on the host transcriptome. Consistent with previous reports, we found that approximately two thirds of transcripts are downregulated in cells expressing any of these viral endonucleases. Among transcripts spared from degradation, we uncovered a cluster of transcripts that systematically escape degradation from all tested endonucleases. Among these escapees, we identified C19ORF66 and reveal that like the previously identified escapees, this transcript is protected from degradation by its 3UTR. We then show that C19ORF66, a known anti-viral protein, is a potent KSHV restriction factor, suggesting that its ability to escape viral cleavage may be an important component of the host response to viral infection. Collectively, our comparative approach is a powerful tool to pinpoint key regulators of the viral-host interplay and led us to uncover a novel KSHV regulator.

microbiology↗

bioRxiv2017

Nuclease escape elements protect messenger RNA against cleavage by multiple viral endonucleases

During lytic Kaposis sarcoma-associated herpesvirus (KSHV) infection, the viral endonu-clease SOX promotes widespread degradation of cytoplasmic messenger RNA (mRNA). However, select mRNAs, including the transcript encoding interleukin-6 (IL-6), escape SOX-induced cleavage. IL-6 escape is mediated through a 3 UTR RNA regulatory element that overrides the SOX targeting mechanism. Here, we reveal that this protective RNA element functions to broadly restrict cleavage by a range of homologous and non-homologous viral endonucleases. However, it does not impede cleavage by cellular endonucleases. The IL-6 protective sequence may be representative of a larger class of nuclease escape elements, as we identified a similar protective element in the GADD45B mRNA. The IL-6 and GADD45B-derived elements display similarities in their sequence, putative structure, and several associated RNA binding proteins. However, the overall composition of their ribonucleoprotein complexes appears distinct, leading to differences in the breadth of nucleases restricted. These findings highlight how RNA elements can selectively control transcript abundance in the background of widespread virus-induced mRNA degradation.\n\nAUTHOR SUMMARYThe ability of viruses to control the host gene expression environment is crucial to promote viral infection. Many viruses express factors that reduce host gene expression through widespread mRNA decay. However, some mRNAs escape this fate, like the transcript encoding the immunoregulatory cytokine IL-6 during KSHV infection. IL-6 escape relies on an RNA regulatory element located in its 3UTR and involves the recruitment of a protective protein complex. Here, we show that this escape extends beyond KSHV to a variety of related and unrelated viral endonucleases. However, the IL-6 element does not protect against cellular endonucleases, revealing for the first time a virus-specific nuclease escape element. We identified a related escape element in the GADD45B mRNA, which displays several similarities with the IL-6 element. However, these elements assemble a largely distinct complex of proteins, leading to differences in the breadth of their protective capacity. Collectively, these findings reveal how a putative new class of RNA elements function to control RNA fate in the background of widespread mRNA degradation by viral endonucleases.

molecular biology↗