Project description:Ixodes species ticks are competent vectors of tick-borne viruses including tick-borne encephalitis and Powassan encephalitis. Tick saliva has been shown to facilitate and enhance viral infection. This likely occurs by saliva-mediated modulation of host responses into patterns favorable for viral infection and dissemination. Because of the rapid kinetics of tick-borne viral transmission, this modulation must occur as early as tick attachment and initiation of feeding. In this study, the gene expression profile of cutaneous bite-site lesions created by uninfected ticks were analyzed at 1, 3, 6, and 12 hours after Ixodes scapularis nymphal tick attachment to discover host pathways or responses potentially important in tick-borne viral establishment.
Project description:Ixodes species ticks are competent vectors of tick-borne viruses including tick-borne encephalitis and Powassan encephalitis. Tick saliva has been shown to facilitate and enhance viral infection. This likely occurs by saliva-mediated modulation of host responses into patterns favorable for viral infection and dissemination. Because of the rapid kinetics of tick-borne viral transmission, this modulation must occur as early as tick attachment and initiation of feeding. In this study, the gene expression profile of cutaneous bite-site lesions created by uninfected ticks were analyzed at 1, 3, 6, and 12 hours after Ixodes scapularis nymphal tick attachment to discover host pathways or responses potentially important in tick-borne viral establishment. Four milimeter ear biopsies from BALB/cJ mice infested with Ixodes scapularis nymphs were assayed using Affymetrix genechip 430A 2.0 arrays at 1, 3, 6, and 12 hours after infestation during a primary exposure. 3 mice were measured at each time point. Controls were 3 similarly housed but tick-free mice.
Project description:This is an open label, multicenter, non-comparative, phase IV study of panitumumab monotherapy in Indian subjects with previously treated, wild-type Kirsten rat sarcoma viral oncogene homolog (KRAS) and wild-type Neuroblastoma rat sarcoma viral (v-ras) oncogene homolog (NRAS), metastatic colorectal cancer. This study is designed to fulfil the requirement of the Indian regulatory authority to characterize the safety and tolerability of panitumumab when administered to Indian subjects with wild-type KRAS and wild-type NRAS metastatic colorectal cancer. Approximately 58 Indian subjects with previously treated wild-type KRAS and wild-type NRAS, metastatic colorectal cancer will be enrolled in order to achieve the target enrollment of 50 evaluable subjects who have received at least one dose of panitumumab. Subjects will receive panitumumab 6 milligram/kilogram (mg/kg) intravenously every 14 days until disease progression, intolerability, withdrawal of consent, or death. All subjects will be followed at 4 weeks and 8 weeks after the last administration of panitumumab, unless the treatment was discontinued due to withdrawal of consent or death of the subject.
Project description:Tick-borne diseases (TBDs) are the most common illnesses transmitted by ticks, and the annual number of reported TBD cases continues to increase. The Asian longhorned tick, a vector associated with at least 30 human pathogens, is native to eastern Asia and recently reached the USA as an emerging disease threat. Newly identified tick-transmitted pathogens continue to be reported, raising concerns about how TBDs occur. Interestingly, tick can harbor pathogens without being affected themselves. For viral infections, ticks have their own immune systems that protect them from infection. Meanwhile, tick-borne viruses have evolved to avoid these defenses as they establish themselves within the vector. Here, we show in detail that infecting longhorned ticks with distinct arthropod-borne RNA viruses through two approaches natural blood feeding and injection, all induce the production of vsiRNAs. Dicer2-like homolog plays a role in regulating antiviral RNAi responses as knocking down of this gene enhanced viral replication. Furthermore, we demonstrate that tick antiviral RNAi responses are inhibited through expression heterologous VSR proteins in recombinant SINV. We identify both the virus and tick factors are critical components to understanding TBDs. Importantly, our study introduces a novel, in vivo virus-vector-mouse model system for exploring TBDs in the future.
Project description:Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne bunyavirus that causes severe clinical symptoms and mortality in humans. Haemaphysalis longicornis tick has been identified as the competent vector for SFTSV transmission. Although antiviral RNA interference (RNAi) in insects has been well documented, the degree to which RNAi contributes to antiviral defense in ticks is still largely elusive. In this study, utilizing arthropod-borne RNA viruses, including SFTSV, we find abundant virus-derived small interfering RNAs (vsiRNAs) are induced in H. longicornis after infection through either microinjection or natural blood-feeding. Furthermore, we identify a Dicer2-like homolog, the core protein of antiviral RNAi pathway, in H. longicornis and knocking down this gene exacerbated virus amplification. To counteract this antiviral RNAi of ticks, viruses have evolved suppressors of RNAi (VSRs). Here, we show that reduced viral replication inversely correlated with the accumulation of vsiRNAs in ticks after infection with recombinant sindbis virus (SINV) expressing heterologous VSR proteins. Elucidating the antiviral RNAi pathway of ticks by model arthropod-borne RNA viruses in vivo is critical to understanding the virus-host interaction, providing a feasible intervention strategy to control tick-borne arbovirus transmission.