SUMMARYAlthough the outcome of flavivirus infection can vary from asymptomatic to lethal, environmental factors modulating disease severity are poorly defined. Here, we observed increased susceptibility of mice to severe West Nile (WNV), Dengue, and Zika virus infections after treatment with oral antibiotics (Abx) that depleted the gut microbiota. Abx treatment impaired the development of optimal T cell responses, with decreased levels of WNV-specific CD8+ T cells associated with increased infection and immunopathology. Abx treatments that resulted in enhanced WNV susceptibility generated changes in the overall structure of the gut bacterial community and in the abundance of specific bacterial taxa. As little as 3 days of treatment with ampicillin was sufficient to alter host immunity and WNV outcome. Our results identify oral Abx therapy as a potential environmental determinant of systemic viral disease, and they raise the possibility that perturbation of the gut microbiota may have deleterious consequences for subsequent flavivirus infections.
The Env protein from gibbon ape leukemia virus (GaLV) has been shown to be incompatible with human immunodeficiency virus type 1 (HIV-1) in the production of infectious pseudotyped particles. This incompatibility has been mapped to the C-terminal cytoplasmic tail of GaLV Env. Surprisingly, we found that the HIV-1 accessory protein Vpu modulates this incompatibility. The infectivity of HIV-1 pseudotyped with murine leukemia virus (MLV) Env was not affected by Vpu. However, the infectivity of HIV-1 pseudotyped with an MLV Env with the cytoplasmic tail from GaLV Env (MLV/GaLV Env) was restricted 50-to 100-fold by Vpu. A Vpu mutant containing a scrambled membrane-spanning domain, Vpu RD , was still able to restrict MLV/GaLV Env, but mutation of the serine residues at positions 52 and 56 completely alleviated the restriction. Loss of infectivity appeared to be caused by reduced MLV/GaLV Env incorporation into viral particles. The mechanism of this downmodulation appears to be distinct from Vpu-mediated CD4 downmodulation because Vpu-expressing cells that failed to produce infectious HIV-1 particles nonetheless continued to display robust surface MLV/GaLV Env expression. In addition, if MLV and HIV-1 were simultaneously introduced into the same cells, only the HIV-1 particle infectivity was restricted by Vpu. Collectively, these data suggest that Vpu modulates the cellular distribution of MLV/GaLV Env, preventing its recruitment to HIV-1 budding sites.
The host immune responses to infection lead to the production of type I interferon (IFN), and the upregulation of interferon-stimulated genes (ISGs) reduces virus replication and virus dissemination within a host. Ectopic expression of the interferon-induced 20-kDa exonuclease ISG20 suppressed replication of chikungunya virus and Venezuelan equine encephalitis virus, two mosquito-vectored RNA alphaviruses. Since the replication of alphavirus genomes occurs exclusively in the cytoplasm, the mechanism of nucleus-localized ISG20 inhibition of replication is unclear. In this study, we determined that ISG20 acts as a master regulator of over 100 genes, many of which are ISGs. Specifically, ISG20 upregulated IFIT1 genes and inhibited translation of the alphavirus genome. Furthermore, IFIT1-sensitive alphavirus replication was increased in Isg20−/− mice compared to the replication of wild-type viruses but not in cells ectopically expressing ISG20. We propose that ISG20 acts as an indirect regulator of RNA virus replication in the cytoplasm through the upregulation of many other ISGs.
Oropouche virus (OROV) is a member of the Orthobunyavirus genus in theO ropouche virus (OROV) is an arthropod-transmitted virus of the family Bunyaviridae, genus Orthobunyavirus, and serogroup Simbu. OROV has a trisegmented genome, comprised of three single-stranded negative-sense RNA segments: large (L), medium (M), and small (S). L encodes the viral RNA polymerase, M encodes the viral surface glycoproteins (Gc and Gn) and a nonstructural protein (NSm), and S encodes the nucleocapsid (N) protein and a small nonstructural protein (NSs) in overlapping reading frames (1). Although details about its cellular life cycle remain poorly characterized, OROV entry is associated with clathrin-coated pits, endosomal acidification, and membrane fusion, which facilitates nucleocapsid release into the cytoplasm (2). The receptors of OROV remain uncharacterized, although Gc is implicated in host cell attachment (3). While the precise replication strategy used by OROV has not been described, it likely occurs in the cytoplasm, similar to other bunyaviruses. Bunyavirus mRNA transcription is primed by "cap-snatching" from cytoplasmic host cellular mRNAs through activities of the viral L and N proteins (4, 5). Genome replication follows via a positive-sense strand intermediate (6). Translation of the L and S segment-encoded proteins occurs on free ribosomes in the cytoplasm, and translation of M polypeptides occurs on endoplasmic reticulum (ER)-bound ribosomes, resulting in a nascent polypeptide that is cleaved cotranslationally to generate Gn and Gc (7). Virus assembly and maturation take place in association with ER and Golgi
The mammalian host responds to viral infections by inducing expression of hundreds of interferon-stimulated genes (ISGs).While the functional significance of many ISGs has yet to be determined, their cell type and temporal nature of expression suggest unique activities against specific pathogens. Using a combination of ectopic expression and gene silencing approaches in cell culture, we previously identified Ifi27l2a as a candidate antiviral ISG within neuronal subsets of the central nervous system (CNS) that restricts infection by West Nile virus (WNV), an encephalitic flavivirus of global concern. To investigate the physiological relevance of Ifi27l2a in the context of viral infection, we generated Ifi27l2a ؊/؊ mice. Although adult mice lacking Ifi27l2a were more vulnerable to lethal WNV infection, the viral burden was greater only within the CNS, particularly in the brain stem, cerebellum, and spinal cord. Within neurons of the cerebellum and brain stem, in the context of WNV infection, a deficiency of Ifi27l2a was associated with less cell death, which likely contributed to sustained viral replication and higher titers in these regions. Infection studies in a primary cell culture revealed that Ifi27l2a ؊/؊ cerebellar granule cell neurons and macrophages but not cerebral cortical neurons, embryonic fibroblasts, or dendritic cells sustained higher levels of WNV infection than wild-type cells and that this difference was greater under conditions of beta interferon (IFN-) pretreatment. Collectively, these findings suggest that Ifi27l2a has an antiviral phenotype in subsets of cells and that at least some ISGs have specific inhibitory functions in restricted tissues. IMPORTANCEThe interferon-stimulated Ifi27l2a gene is expressed differentially within the central nervous system upon interferon stimulation or viral infection. Prior studies in cell culture suggested an antiviral role for Ifi27l2a during infection by West Nile virus (WNV). To characterize its antiviral activity in vivo, we generated mice with a targeted gene deletion of Ifi27l2a. Based on extensive virological analyses, we determined that Ifi27l2a protects mice from WNV-induced mortality by contributing to the control of infection of the hindbrain and spinal cord, possibly by regulating cell death of neurons. This antiviral activity was validated in granule cell neurons derived from the cerebellum and in macrophages but was not observed in other cell types. Collectively, these data suggest that Ifi27l2a contributes to innate immune restriction of WNV in a cell-type-and tissue-specific manner. , dengue virus [DENV] and yellow fever virus [YFV]). WNV transmission occurs betweenCulex species mosquitoes and selected avian hosts, with incidental, dead-end infection of horses, humans, and other vertebrate animals. Humans can develop severe disease following WNV infection, as the virus can invade the central nervous system (CNS) and cause flaccid paralysis, meningitis, or encephalitis, often leading to long-term neurological sequelae or death (1)...
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