# New Insights into the Biology of the Emerging Tembusu Virus
## 4 Clinical Features and Pathogenicity  
### Symptomology/Disease Presentations  
TMUV is a mosquito-borne epormitic flavivirus, as with WNV and Usutu virus (USUV), with its natural maintenance cycle involving birds and mosquitoes [6]. The etiology of the infection in birds is characterized by sudden acute signs including rhinorrhea, diarrhea, anorexia and perturbation of social behavior. Infected animals also show severe neurological disorders including encephalitis, difficulty to move or imbalanced movement, ataxia and paralysis [30]. The infection rate can reach 90% in a farm, depending on husbandry conditions, whereas the mortality rate is variable, ranging from 5% to 30% of the infected flocks, and is increased by secondary infections [23]. The spleen, liver, kidney and brain usually present gross lesions. Histologic analysis shows multiple microscopic changes in infected organs with hemorrhage, inflammation, hyperplasia and macrophage and lymphocyte infiltration [3,63]. The common clinical presentation of the disease observed in infected female ducks is a generalized damage to the ovaries with large inflammation, hemorrhage and hyperemia associated with organ degeneration [4,30,77]. TMUV infection is associated with a degeneration of embryos and a dramatic decrease in egg production coined \"egg drop syndrome\", leading to important economic losses both in traditional or industrial poultry production in Asia [54]. A recent study reported that ducks of all ages are potentially susceptible to infection with TMUV--Cluster 2. Although a greater severity was reported in younger animals in some duck populations [78], a higher susceptibility to the infection was reported in old breeding ducks [77]. Moreover, older infected ducks present a longer shedding period with a high viral load, without clinical signs, suggesting the potential role of these animals in the spread of the virus during outbreaks [76]. It is now clearly established that TMUV is a neurotrophic virus for birds, although the mechanisms of diffusion at the neuronal level are still poorly understood. However, a recent study on a duckling model shed light on the modalities of passage from the blood-brain barrier (BBB) to the central nervous system [79]. Thus, in the early stages, there are few clinical symptoms, and, although there is a propagation of the virus in the brain with a corollary induction of inflammatory cytokines, the BBB seems to remain relatively impermeable to the virus. It is therefore necessary to wait for a more advanced stage of the infection to see the first neurological symptoms associated with a disruption of the BBB and a diffusion in the microvascular endothelial cells causing an inflammatory storm and fatal encephalitis in the infected animal. While symptoms due to TMUV infection are remarkably well described in birds, disease presentations in other vertebrate hosts are sparse. In 2020, [PERSON] et al. reported neuropathogenesis and global dissemination in mice intracherebrally infected with TMUV. The animals exhibited a wide range of clinical signs with additional severe internal organ lesions that led to death [80]. [PERSON] et al. investigated the presence of TMUV infection in avian farm workers [46]. Oral swab and serum samples were collected for molecular and serological screening for the presence of TMUV. Semi-nested RT-PCR was used as a molecular method, whereas IgG ELISA and a virus neutralization test were performed for serological assays. More than 70% of serum samples contained detectable levels of anti-TMUV antibodies, whereas TMUV could be isolated from 48% of oral swabs. Asymptomatic presentation was observed in infected workers as well. Moreover, the authors reported, for the first time, a potential spillover of TMUV to humans and suggested considering TMUV as an emergent zoonotic pathogen, although, as with other avian flavivirus members, human spillover events may represent self-limited, dead-end cases with no further human-to-human transmission.