Zika virus (ZIKV), a re-emerging flavivirus associated with neurological disorders, has spread rapidly to more than 70 countries and territories. However, no specific vaccines or antiviral drugs are currently available to prevent or treat ZIKV infection. Here we report that a synthetic peptide derived from the stem region of ZIKV envelope protein, designated Z2, potently inhibits infection of ZIKV and other flaviviruses in vitro. We show that Z2 interacts with ZIKV surface protein and disrupts the integrity of the viral membrane. Z2 can penetrate the placental barrier to enter fetal tissues and is safe for use in pregnant mice. Intraperitoneal administration of Z2 inhibits vertical transmission of ZIKV in pregnant C57BL/6 mice and protects type I or type I/II interferon receptor-deficient mice against lethal ZIKV challenge. Thus, Z2 has potential to be further developed as an antiviral treatment against ZIKV infection in high-risk populations, particularly pregnant women.

The ongoing Zika virus (ZIKV) outbreaks have raised global concerns due to its unexpected clinical manifestations. Antiviral development is of high priority in response to the ZIKV emergency. In this study, we report that an adenosine analog NITD008 has potent in vitro and in vivo antiviral activity against ZIKV. The compound can effectively inhibit the historical and contemporary ZIKV strains in cultures as well as significantly reduce viremia and prevent mortality in A129 mice. Our results have demonstrated that NITD008 is potent inhibitor of ZIKV and can be used as reference inhibitor for future ZIKV antiviral drug screen and discovery.

Zika virus (ZIKV) is primarily transmitted to humans through mosquito bites or sexual contact. The excretion and persistence of contagious ZIKV in various body fluids have been well documented in ZIKV patients; however, the risk of direct contact exposure remains unclear. Here, we show that guinea pigs are susceptible to ZIKV infection via subcutaneous inoculation route; infected guinea pigs exhibit seroconversion and significant viral secretion in sera, saliva, and tears. Notably, ZIKV is efficiently transmitted from infected guinea pigs to naïve co-caged animals. In particular, intranasal inoculation of ZIKV is fully capable of establishing infection in guinea pigs, and viral antigens are detected in multiple tissues including brain and parotid glands. Cynomolgus macaques also efficiently acquire ZIKV infection via intranasal and intragastric inoculation routes. These collective results from animal models highlight the risk of exposure to ZIKV contaminants and raise the possibility of close contact transmission of ZIKV in humans.

Antibiotic resistance is a serious global problem. Antibiotic resistance genes (ARG), which are widespread in environmental bacteria, can be transferred to pathogenic bacteria via horizontal gene transfer (HGT). Gut microbiomes are especially apt for the emergence and dissemination of ARG. Conjugation is the HGT route that is predominantly responsible for the spread of ARG. Little is known about conjugative elements of Gram-positive bacteria, including those of the phylum Firmicutes, which are abundantly present in gut microbiomes. A critical step in the conjugation process is the relaxase-mediated site- and strand-specific nick in the oriT region of the conjugative element. This generates a single-stranded DNA molecule that is transferred from the donor to the recipient cell via a connecting channel. Here we identified and characterized the relaxosome components oriT and the relaxase of the conjugative plasmid pLS20 of the Firmicute Bacillus subtilis. We show that the relaxase gene, named relLS20, is essential for conjugation, that it can function in trans and provide evidence that Tyr26 constitutes the active site residue. In vivo and in vitro analyses revealed that the oriT is located far upstream of the relaxase gene and that the nick site within oriT is located on the template strand of the conjugation genes. Surprisingly, the RelLS20 shows very limited similarity to known relaxases. However, more than 800 genes to which no function had been attributed so far are predicted to encode proteins showing significant similarity to RelLS20. Interestingly, these putative relaxases are encoded almost exclusively in Firmicutes bacteria. Thus, RelLS20 constitutes the prototype of a new family of relaxases. The identification of this novel relaxase family will have an important impact in different aspects of future research in the field of HGT in Gram-positive bacteria in general, and specifically in the phylum of Firmicutes, and in gut microbiome research.

Monocyte chemoattractant protein-1 (MCP1) polymorphism has been reported to be associated with systemic lupus erythematosus (SLE). However, the correlation between the polymorphism and SLE is poorly understood. In this study we investigated the role of this polymorphism together with that of chemokine SDF1-3'A and chemokine receptor CCR2-V64I. The association between gene polymorphism and SLE was explored by way of a case-control study. In 143 patients with SLE and 157 healthy controls, the polymorphisms of SDF1-3'A, -2518MCP-1 and CCR2-V64I were determined using PCR-RFLP and an amplification-refractory mutation system, respectively. No significant difference was found in allelic and genotype frequency of SDF1-3'A, CCR2-V64I and -2518MCP-1 between SLE patients and controls. However, a significant increase in the frequency of the AG genotype of MCP-1 was found among patients with arthritis (P(c)=0.003, OR 3.08, 95%CI 1.27-7.57). The frequency of individuals having G at position -2518 of the MCP-1 gene was also increased among patients with arthritis (P(c)=0.028, OR 2.99, 95%CI 1.13-8.08). It is noteworthy that the frequency of -2518MCP-1G in the Chinese Han population was 64%. The results indicate an association between the presence of G at position -2518 in the MCP-1 promoter region and the presence of arthritis in patients with SLE.

No abstract

Bacterial conjugation is the process by which a conjugative element (CE) is transferred horizontally from a donor to a recipient cell via a connecting pore. One of the first steps in the conjugation process is the formation of a nucleoprotein complex at the origin of transfer (oriT), where one of the components of the nucleoprotein complex, the relaxase, introduces a site- and strand specific nick to initiate the transfer of a single DNA strand into the recipient cell. In most cases, the nucleoprotein complex involves, besides the relaxase, one or more additional proteins, named auxiliary proteins, which are encoded by the CE and/or the host. The conjugative plasmid pLS20 replicates in the Gram-positive Firmicute bacterium Bacillus subtilis. We have recently identified the relaxase gene and the oriT of pLS20, which are separated by a region of almost 1 kb. Here we show that this region contains two auxiliary genes that we name aux1LS20 and aux2LS20, and which we show are essential for conjugation. Both Aux1LS20 and Aux2LS20 are predicted to contain a Ribbon-Helix-Helix DNA binding motif near their N-terminus. Analyses of the purified proteins show that Aux1LS20 and Aux2LS20 form tetramers and hexamers in solution, respectively, and that they both bind preferentially to oriTLS20, although with different characteristics and specificities. In silico analyses revealed that genes encoding homologs of Aux1LS20 and/or Aux2LS20 are located upstream of almost 400 relaxase genes of the RelLS20 family (MOBL) of relaxases. Thus, Aux1LS20 and Aux2LS20 of pLS20 constitute the founding member of the first two families of auxiliary proteins described for CEs of Gram-positive origin.

Zika virus (ZIKV) has raised global public health concerns due to its rapid transmission and unexpected clinical manifestations. 1 No vaccine or antiviral treatment is currently available, and the development of animal model of ZIKV infection is of priority. 2,3 The mouse model of ZIKV infection was recently developed using A129 and AG129 mice. [4][5][6][7] However, both mice are deficient in critical innate immune signaling, and more importantly, these animals are limited resource, and are not available for most labs in ZIKVendemic areas. Thus, a more relevant animal mode in immunocompetent animals is urgently needed. 8 Here, we establish an immunocompetent murine model using a contemporary American ZIKV strain GZ01 (GenBank nos. KU740184) that was isolated from a patient returned from Venezuela in 2016.9 ZIKV stocks were propagated in mosquito C6/36 cells and titrated by plaque forming assay on BHK-21 cells. 10We firstly inoculated 4-week-old 129Sv/Ev male mice with 10 5 PFU of ZIKV by the intraperitoneal (ip) route. Upon infection, no animal showed any clinical signs and all survived with a gradual increase on body weight (Fig. 1A). Transient viremia were observed by RT-qPCR assay, peaked at day 1 post infection (pi) and decreased below detection limit at day 3 pi (Fig. 1B). At days 1, 2 and 3 pi, mice were anesthetized and selected organs were dissected for RT-qPCR assay. The results showed that viral RNAs were disseminated into all tested organs at day 1 pi and the highest viral RNA loads were detected in testis, which was similar to that in A129 mice. 4 At day 3 pi, viral RNAs were cleared in most tissues except for spleen and testis (Fig. 1C). Additionally, hematoxylin and eosin staining showed that no obvious histological lesions were observed in brain, heart, kidney and testis tissues at day 1 pi. Slight loose deformation of liver cells with focal necrosis and partial central venous dilatation were found in liver, and multinucleated giant cells were observed within the membrane and red pulp of spleen (Fig. 1D). Similar viremia and viral RNA kinetics were also observed in ZIKV-infected Balb/C mice (data not shown).Further, to utilize the animal model described here for potential antiviral tests, the therapeutic effects of human convalescent phase serum 9 with the neutralization antibody titer of 1/80 were assayed. Briefly, group of 129Sv/Ev mice infected with 10 5 PFU of ZIKV were administrated ip with 150 ml of antibody at 4 and 24 h pi, and mock group were treated with PBS control. Blood was collected for viremia and autopsy were performed for viral dissemination. The result showed that passive transfer of convalescent phase serum completely eliminated viremia at day 1 and 2 in all ZIKV-infected mice compared with mock treatment (Fig. 1E). Importantly, viral RNAs were undetectable in the indicated organs (spleen and testis) in mice treated with convalescent phase serum (Fig. 1F).Finally, we tested the infectivity of ZIKV in 8-week-old 129 Sv/Ev mice. The result showed that that ZIKV could also cause sh...