A5085513802- Viral Infections and Immunology Research
- Mosquito-borne diseases and control
- interferon and immune responses
- Animal Disease Management and Epidemiology
- Viral Infections and Vectors
- Viral Infectious Diseases and Gene Expression in Insects
- RNA Research and Splicing
- Viral gastroenteritis research and epidemiology
- RNA modifications and cancer
- RNA and protein synthesis mechanisms
- Animal Virus Infections Studies
- Insect symbiosis and bacterial influences
- Drug Transport and Resistance Mechanisms
- Herpesvirus Infections and Treatments
- RNA regulation and disease
- Peroxisome Proliferator-Activated Receptors
- Virus-based gene therapy research
- Ubiquitin and proteasome pathways
- Plant Virus Research Studies
- Endoplasmic Reticulum Stress and Disease
- Genetics, Bioinformatics, and Biomedical Research
- Metabolism and Genetic Disorders
- HIV Research and Treatment
- Cytomegalovirus and herpesvirus research
- Hepatitis C virus research
University of Cambridge
2015-2024
Addenbrooke's Hospital
2015-2024
The Pirbright Institute
2021-2024
SUNY Downstate Health Sciences University
2011-2021
Imperial College London
2006-2013
State University of New York
2011-2012
Trinity College Dublin
2009
University of California, San Francisco
2006-2007
San Francisco VA Medical Center
2007
University of Milan
2007
Abstract Ribosomal recruitment of cellular mRNAs depends on binding eIF4F to the mRNA’s 5′-terminal ‘cap’. The minimal ‘cap0’ consists N7-methylguanosine linked first nucleotide via a 5′-5′ triphosphate (ppp) bridge. Cap0 is further modified by 2′-O-methylation next two riboses, yielding ‘cap1’ (m7GpppNmN) and ‘cap2’ (m7GpppNmNm). However, some viral RNAs lack 2′-O-methylation, whereas others contain only ppp- at their 5′-end. Interferon-induced proteins with tetratricopeptide repeats...
Inherited microcephaly exposes Zika culprit Microcephaly has been the terrifying hallmark of recent outbreak virus (ZIKV) in Americas. How damages brain development fetus is enigmatic. Chavali et al. found that congenital microcephaly, mutations a neural precursor protein, Musashi-1 (MSI1), impede RNA binding to stem cell targets, resulting abnormal (see Perspective by Griffin). MSI1 also binds ZIKV amplify viral replication cells. This interaction could put pregnant woman at risk giving...
The interferon-induced proteins with tetratricopeptide repeats (IFITs) are a family of antiviral conserved throughout all vertebrates. IFIT1 binds tightly to non-self RNA, particularly capped transcripts lacking methylation on the first cap-proximal nucleotide, and inhibits their translation by out-competing cellular initiation apparatus. This exerts immense selection pressure cytoplasmic RNA viruses maintain mechanisms that protect messenger from recognition. However, it is becoming...
Interferon-induced proteins with tetratricopeptide repeats (IFITs) are highly expressed during the cell-intrinsic immune response to viral infection. IFIT1 inhibits translation by binding directly 5′ end of foreign RNAs, particularly those non-self cap structures, precluding recruitment cap-binding eukaryotic initiation factor 4F and ribosome recruitment. The presence imposes a requirement on viruses that replicate in cytoplasm maintain mechanisms avoid its restrictive effects. Interaction...
The establishment of a virus infection is the result pathogen's ability to replicate in hostile environment generated by host's immune system. Here, we found that ISG15 restricts Dengue and Zika viruses' replication through stabilization its binding partner USP18. expression was necessary control DV driven both autocrine paracrine type one interferon (IFN-I) signaling. Moreover, USP18 competes with NS5-mediated STAT2 degradation, major mechanism for flavivirus infection. Strikingly,...
The 3C protease (3C(pro)) from foot-and-mouth disease virus (FMDV), the causative agent of a widespread and economically devastating domestic livestock, is potential target for antiviral drug design. We have determined structure new crystal form FMDV 3C(pro), chymotrypsin-like cysteine protease, which reveals features that are important catalytic activity. In particular, we show surface loop was disordered in previous structures adopts beta-ribbon conformationally similar to equivalent...
Foot-and-mouth disease virus (FMDV), a positive sense, single-stranded RNA virus, causes highly contagious in cloven-hoofed livestock. Like other picornaviruses, FMDV has conserved 2C protein assigned to the superfamily 3 helicases group of AAA+ ATPases that predicted N-terminal membrane-binding amphipathic helix attached main ATPase domain. In infected cells, is involved formation membrane vesicles, where it co-localizes with viral replication complexes, but its precise role not been...
The 5'-untranslated regions (5' UTRs) of picornavirus genomes contain an internal ribosomal entry site (IRES) that promotes the end-independent initiation translation. Picornavirus IRESs are classified into four structurally distinct groups, each with different factor requirements. Here, we identify a fifth IRES class in members Kobuvirus, Salivirus, and Paraturdivirus genera Picornaviridae: Aichi virus (AV), bovine kobuvirus (BKV), canine (CKoV), mouse (MKoV), sheep (SKV), salivirus A...
Members of the Flaviviridae family, including dengue virus (DENV) and yellow fever virus, cause serious disease in humans, whilst maternal infection with Zika (ZIKV) can induce microcephaly newborns. Following infection, flaviviral RNA genomes are translated to produce viral replication machinery but must then serve as a template for transcription new genomes. However, ribosome polymerase proceed opposite directions along RNA, risking collisions abortive replication. Whilst generally linear,...
On most eukaryotic mRNAs, initiation codon selection involves base-by-base inspection of 5' UTRs by scanning ribosomal complexes. Although the factors 4A/4B/4G can mediate through medium-stability hairpins, more stable structures additionally requires DHX29, a member superfamily 2 DEAH/RNA helicase A (RHA) family that binds to 40S subunits and possesses 40S-stimulated nucleoside triphosphatase (NTPase) activity. Here, sequence alignment structural modeling indicated DHX29 comprises unique...
Flaviviruses, including dengue virus and Zika virus, contain a single-stranded positive sense RNA genome that encodes viral proteins essential for replication also serves as the template new synthesis. As these processes move in opposite directions along genome, translation must be inhibited at defined point following infection to clear of ribosomes allow efficient replication. Here, we demonstrate vitro cell-based assays polymerase, NS5, inhibits genome. By reconstituting using highly...
Vaccinia virus (VACV) is the prototypic orthopoxvirus and vaccine used to eradicate smallpox. Here we show that VACV strain Western Reserve protein 169 a cytoplasmic polypeptide expressed early during infection excluded from factories inhibits initiation of cap-dependent cap-independent translation. Ectopic expression causes accumulation 80S ribosomes, reduction polysomes, inhibition deriving activation multiple innate immune signaling pathways. A lacking (vΔ169) replicates spreads normally...
One of the fundamental features that make viruses intracellular parasites is necessity to use cellular translational machinery. Hence, this a crucial checkpoint for controlling infections. Here, we show dengue and Zika viruses, responsible nearly 400 million infections every year worldwide, explore such control optimal replication. Using immunocompetent cells, demonstrate arrest protein translations happens after sensing dsRNA information required avoid blocking contained in viral 5'-UTR....
Zika virus (ZIKV) can infect human developing brain (HDB) progenitors resulting in epidemic microcephaly, whereas analogous cellular tropism offers treatment potential for the adult cancer, glioblastoma (GBM). We compared productive ZIKV infection HDB and GBM primary tissue explants that both contain SOX2+ neural progenitors. Strikingly, although proved uniformly vulnerable to infection, was more refractory, this correlated with an innate immune expression signature. Indeed, GBM-derived...
During the third trimester of pregnancy, there is an increase in serum triglyceride and cholesterol levels. The mechanisms accounting for these changes lipid metabolism during pregnancy are unknown. We hypothesized that, expression nuclear hormone receptors involved regulating would decrease. In 19-day pregnant mice, non-HDL levels were significantly increased, whereas total was slightly decreased, because a decrease HDL fraction. Peroxisome proliferator-activated receptor (PPAR)alpha,...
<ns3:p><ns3:bold>Background:</ns3:bold> Norovirus, also known as the winter vomiting bug, is predominant cause of non-bacterial gastroenteritis worldwide. Disease control predicated on a robust innate immune response during early stages infection. Double-stranded RNA intermediates generated viral genome replication are recognised by host sensors in cytoplasm, activating strongly antiviral interferon gene programme. Ifit proteins (interferon induced with tetratricopeptide repeats), which...
Translation initiation on structured mammalian mRNAs requires DHX29, a DExH protein that comprises unique 534-aa-long N-terminal region (NTR) and common catalytic core. DHX29 binds to 40S subunits possesses 40S-stimulated NTPase activity essential for its function. In the cryo-EM structure of DHX29-bound 43S preinitiation complexes, main density resides around tip helix 16 18S rRNA, from which it extends through linker subunit interface forming an intersubunit domain next eIF1A binding site....