Background and main textMyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex and controversial clinical condition without having established causative factors. Increasing numbers of cases during past decade have created awareness among patients as well as healthcare professionals. Chronic viral infection as a cause of ME/CFS has long been debated. However, lack of large studies involving well-designed patient groups and validated experimental set ups have hindered our knowledge about this disease. Moreover, recent developments regarding molecular mechanism of pathogenesis of various infectious agents cast doubts over validity of several of the past studies.ConclusionsThis review aims to compile all the studies done so far to investigate various viral agents that could be associated with ME/CFS. Furthermore, we suggest strategies to better design future studies on the role of viral infections in ME/CFS.

The transcription factor AP-1 plays a central role in the transcriptional regulation of specific types of high-risk human papillomaviruses (HPVs) such as HPV16 and HPV18, which are etiologically associated with the development of cancer of the uterine cervix in women. In our study, we investigated the AP-1 binding activity and the expression pattern of different members of the AP-1 transcription factor family (c-Jun, JunB, JunD, c-Fos, FosB, Fra-1 and Fra-2) in different grades of cervical lesions starting from mild dysplasia to invasive cervical tumors, including normal control tissues, using specific antibodies raised against each of the AP-1 members. Results indicate that though AP-1 showed high binding activity and the majority of its members were highly expressed in tumor tissues, there is a distinct pattern of gradual increase of c-fos and a concomitant decrease of fra-1 expression that perfectly match the progression of cervical lesions. While c-fos is highly expressed in invasive cervical tumor, the expression of fra-1 becomes almost nil or absent, but the reverse is true in both controls and early precancerous lesions. These findings corroborate the results obtained in the cervical cancer cell line, HeLa.

The predicted 80 open reading frames (ORFs) of herpes simplex virus 1 (HSV-1) have been intensively studied for decades. Here, we unravel the complete viral transcriptome and translatome during lytic infection with base-pair resolution by computational integration of multi-omics data. We identify a total of 201 transcripts and 284 ORFs including all known and 46 novel large ORFs. This includes a so far unknown ORF in the locus deleted in the FDAapproved oncolytic virus Imlygic. Multiple transcript isoforms expressed from individual gene loci explain translation of the vast majority of ORFs as well as N-terminal extensions (NTEs) and truncations. We show that NTEs with non-canonical start codons govern the subcellular protein localization and packaging of key viral regulators and structural proteins. We extend the current nomenclature to include all viral gene products and provide a genome browser that visualizes all the obtained data from whole genome to single-nucleotide resolution.

Cervical cancer is the major cancer in Indian women and a leading cause of cancer deaths. Every year, more than 130,000 new cases and about 70,000 deaths are recorded. The persistent infection by specific types of high-risk human papillomaviruses (HR-HPVs) is essential for the progression of cervical lesions (6,11,31,60), and women who are infected with HRHPVs are likely to develop cancer (3,4,27,40). Various studies have demonstrated that more than 70% of invasive cervical cancers harbor HPV type 16 (HPV-16) and 31), and the products of viral transforming E6 and E7 genes have been shown to contribute to tumorigenesis by functionally inactivating two important cellular tumor suppressor proteins, p53 and retinoblastoma (5,14,30,55).More than 100 types of HPV are known, but only about 30 types are associated with anogenital cancer. According to the Papillomavirus Nomenclature Committee, a new HPV type is defined by a nucleotide sequence variation of more than 10% compared to that of other known HPV types in the E6, E7, and L1 open reading frames. Those differing by 2 to 10% are referred to as subtypes, whereas intratype variants may vary by up to 2% in the coding region and 5% in the noncoding region compared to that of the prototype (2, 10).On the basis of sequence variations in E6, L1, L2, and the long control region (LCR), HPV-16 variants have been identified and grouped into six distinct phylogenetic branches: E (European), AA (Asian-American), Af1 (African 1), Af2 (African 2), As (Asian), and NA (North American) (54, 56, 57). These variants have been found to show different geographic distributions, with various oncogenic potentials. A number of sequence variations have been reported for HPV-16 E6, E7, and L1 genes as well as in the LCR in cervical cancer (33,39,48,55,56). Studies also have shown that specific intratype variants may influence the persistence of HPV infection and the progression of precursor lesions to cancer (27,58,59). HPV variants also may affect virus assembly, immunologic responses, pathogenicity, p53 degradation, immortalization activity, and the regulation of transcription (15,18,24,25,37,51). These variations immediately affect the sensitivity and specificity of different PCR-based genotype diagnostic methods.Of the two HPV-16 oncogenes E6 and E7, E6 has been found to show more variations than E7, which is relatively conserved (48,50,56,58,59). The analysis of the L1 gene, which codes for the viral major capsid protein, is of immense importance because of its high diagnostic value. The range of intratype variation observed in this region allows the distinction and assessment of known and novel HPV types (46). This is also an important target for the development of HPV vaccines.

Obligate intracellular bacteria depend entirely on nutrients from the host cell for their reproduction. Here, we show that obligate intracellular Chlamydia downregulate the central tumor suppressor p53 in human cells. This reduction of p53 levels is mediated by the PI3K-Akt signaling pathway, activation of HDM2, and subsequent proteasomal degradation of p53. The stabilization of p53 in human cells severely impaired chlamydial development and caused the loss of infectious particle formation. DNA-damage-induced p53 interfered with chlamydial development through downregulation of the pentose phosphate pathway (PPP). Increased expression of the PPP key enzyme glucose-6-phosphate dehydrogenase rescued the inhibition of chlamydial growth induced by DNA damage or stabilized p53. Thus, downregulation of p53 is a key event in the chlamydial life cycle that reprograms the host cell to create a metabolic environment supportive of chlamydial growth.

Infection by viruses, including herpes simplex virus-1 (HSV-1), and cellular stresses cause widespread disruption of transcription termination (DoTT) of RNA polymerase II (RNAPII) in host genes. However, the underlying mechanisms remain unclear. Here, we demonstrate that the HSV-1 immediate early protein ICP27 induces DoTT by directly binding to the essential mRNA 3' processing factor CPSF. It thereby induces the assembly of a dead-end 3' processing complex, blocking mRNA 3' cleavage. Remarkably, ICP27 also acts as a sequencedependent activator of mRNA 3' processing for viral and a subset of host transcripts. Our results unravel a bimodal activity of ICP27 that plays a key role in HSV-1-induced host shutoff and identify CPSF as an important factor that mediates regulation of transcription termination. These findings have broad implications for understanding the regulation of transcription termination by other viruses, cellular stress and cancer.

Obligate intracellular Chlamydia trachomatis replicate in a membrane-bound vacuole called inclusion, which serves as a signaling interface with the host cell. Here, we show that the chlamydial deubiquitinating enzyme (Cdu) 1 localizes in the inclusion membrane and faces the cytosol with the active deubiquitinating enzyme domain. The structure of this domain revealed high similarity to mammalian deubiquitinases with a unique α-helix close to the substrate-binding pocket. We identified the apoptosis regulator Mcl-1 as a target that interacts with Cdu1 and is stabilized by deubiquitination at the chlamydial inclusion. A chlamydial transposon insertion mutant in the Cdu1-encoding gene exhibited increased Mcl-1 and inclusion ubiquitination and reduced Mcl-1 stabilization. Additionally, inactivation of Cdu1 led to increased sensitivity of C. trachomatis for IFNγ and impaired infection in mice. Thus, the chlamydial inclusion serves as an enriched site for a deubiquitinating activity exerting a function in selective stabilization of host proteins and protection from host defense.DOI: http://dx.doi.org/10.7554/eLife.21465.001

Chlamydiae are intracellular pathogens that depend on the host for their survival and development. Chowdhury et al. demonstrate that Chlamydia trachomatis infection can prevent mitochondrial fission in primary cells by reducing DRP1 abundance via miR-30c–dependent inhibition of p53.