Variant analysis of the sporozoite surface antigen gene reveals that asymptomatic cattle from wildlife-livestock interface areas in northern Tanzania harbour buffalo-derived T. parva.

Buffalo-derived Theileria parva can 'break through' the immunity induced by the infection and treatment vaccination method (ITM) in cattle. However, no such 'breakthroughs' have been reported in northern Tanzania where there has been long and widespread ITM use in pastoralist cattle, and the Cape buffalo (Syncerus caffer) is also present. We studied the exposure of vaccinated and unvaccinated cattle in northern Tanzania to buffalo-derived T. parva using p67 gene polymorphisms and compared this to its distribution in vaccinated cattle exposed to buffalo-derived T. parva in central Kenya, where vaccine 'breakthroughs' have been reported. Additionally, we analysed the CD8+ T cell target antigen Tp2 for positive selection. Our results showed that 10% of the p67 sequences from Tanzanian cattle (n = 39) had a buffalo type p67 (allele 4), an allele that is rare among East African isolates studied so far. The percentage of buffalo-derived p67 alleles observed in Kenyan cattle comprised 19% of the parasites (n = 36), with two different p67 alleles (2 and 3) of presumptive buffalo origin. The Tp2 protein was generally conserved with only three Tp2 variants from Tanzania (n = 33) and five from Kenya (n = 40). Two Tanzanian Tp2 variants and two Kenyan Tp2 variants were identical to variants present in the trivalent Muguga vaccine. Tp2 evolutionary analysis did not show evidence for positive selection within previously mapped epitope coding sites. The p67 data indicates that some ITM-vaccinated cattle are protected against disease induced by a buffalo-derived T. parva challenge in northern Tanzania and suggests that the parasite genotype may represent one factor explaining this.

Inhibitors of Protein Glycosylation Are Active against the Coronavirus Severe Acute Respiratory Syndrome Coronavirus SARS-CoV-2.

Repurposing clinically available drugs to treat the new coronavirus disease 2019 (COVID-19) is an urgent need in the course of the Severe Acute Respiratory Syndrome coronavirus (SARS-CoV-2) pandemic, as very few treatment options are available. The iminosugar Miglustat is a well-characterized drug for the treatment of rare genetic lysosome storage diseases, such as Gaucher and Niemann-Pick type C, and has also been described to be active against a variety of enveloped viruses. The activity of Miglustat is here demonstrated in the micromolar range for SARS-CoV-2 in vitro. The drug acts at the post-entry level and leads to a marked decrease of viral proteins and release of infectious viruses. The mechanism resides in the inhibitory activity toward α-glucosidases that are involved in the early stages of glycoprotein N-linked oligosaccharide processing in the endoplasmic reticulum, leading to a marked decrease of the viral Spike protein. Indeed, the antiviral potential of protein glycosylation inhibitors against SARS-CoV-2 is further highlighted by the low-micromolar activity of the investigational drug Celgosivir. These data point to a relevant role of this approach for the treatment of COVID-19.

Viral priming of cell intrinsic innate antiviral signaling by the unfolded protein response.

The innate response to a pathogen is critical in determining the outcome of the infection. However, the interplay of different cellular responses that are activated following viral infection and their contribution to innate antiviral signalling has not been clearly established. This work shows that flaviviruses, including Dengue, Zika, West Nile and Tick-borne encephalitis viruses, activate the unfolded protein response before transcription of interferon regulatory factor 3 induced genes. Infection in conditions of unfolded protein response priming leads to early activation of innate antiviral responses and cell intrinsic inhibition of viral replication, which is interferon regulatory factor 3 dependent. These results demonstrate that the unfolded protein response is not only a physiological reaction of the cell to viral infection, but also synergizes with pattern recognition sensing to mount a potent antiviral response.

Incremental effect of natural tick challenge on the infection and treatment method-induced immunity against T. parva in cattle under agro-pastoral systems in Northern Tanzania.

This study was conducted to assess the incremental effect of natural tick challenge on the infection and treatment method-induced immunity against T. parva under agro-pastoral systems in Simanjiro district, Northern Tanzania. T. parva specific antibody percent positivity and prevalence of T. parva parasites were studied in relation to duration post vaccination and proximity to Tarangire National park. A total of 381 cattle were included in this study, of which 127 were unvaccinated and 254 had been vaccinated at different time points between 2008 and 2014. Antibody percent positivity (PP) determined by the PIM-based T. parva ELISA and the prevalence of T. parva parasites detected by a nested PCR based on the p104 gene were used to compare vaccinated and unvaccinated cattle. Results showed that seroprevalence was significantly higher in vaccinated than unvaccinated cattle (OR 10.89, p = 0.0341). Only 1.6% (6/381) of all cattle were seronegative and 5/6 of these were unvaccinated. Prevalence of T. parva parasites was significantly higher in vaccinated (50.39%) than unvaccinated (19.69%) cattle (OR 2.03, p = 0.0144). While there was a positive association between PP and duration post vaccination but the latter was inversely associated with T. parva parasite prevalence. This study also showed that cattle which were closer to the park had higher antibody PP and T. parva prevalence. It is concluded that duration post vaccination as well as proximity from the wildlife in Tarangire National park together may exert an incremental effect on the outcome of ECF vaccination by influencing stronger antibody immunity of cattle and ability to withhold high T. parva infection pressure under constant field tick challenge. Further, the high seroprevalence in vaccinated and unvaccinated cattle suggests a likely state of endemic stability to T. parva in the study area.