**7. Conclusions**

The comparative overview of cell response to alphavirus infection, in mammals and mosquitoes, underlines the complexity of cell death regulation among different species facing the same pathogen. In both, host and vector, the first cells in contact with the virus will influence the progression of the infection, through immune response and cell death.

In mammals, alphavirus-induced apoptosis is also linked to pathogenesis in the organs secondarily infected. Some discrepancies between intrinsic and extrinsic apoptotic pathways in mammals could be explained by a secondary amplification loop through CASP6 activation or by a newly described CASP8 activation platform which directly links viral RNA sensors and apoptosis. However, the precise mechanisms need to be studied further, in other cell types and for different alphaviruses.

Experimentally interfering with apoptosis in vitro does not seem to influence the viral replication rate but can lead to persistence. It is possible that autophagy may be a way for alphaviruses to delay cell death, allowing replication over a longer period of time. Alphavirus non-structural proteins 2 and 3 appear to be mostly responsible for mammal cell death, which is not the case for mosquito cells from sensitive strains. Mammals are often considered to be an "accidental host" in arboviral infections, suggesting that nsp-induced cell death may be also "accidental" and in some way deleterious for alphaviruses. Some alphaviruses have indeed evolved to be restricted to mosquitos and do not rely on transmission to mammals any longer [197–199].

How tolerant mosquito cells survive to arbovirus infection remains unknown. In addition to a strong action of insect IAPs, a higher control of oxidative stress due to the fact of infection through p53 isoforms and autophagy may be an answer, but supplementary studies are needed for alphaviruses. Moreover, in the case of arthritogenic alphaviruses in mammals, clarification of the processes leading to chronic infection and a possible survival of infected cells is needed. The differences in cell types may explain these discrepancies and further studies would help to decipher how these cells overcome cell death.

Finally, even if it is generally admitted that alphavirus infection is silent in competent mosquitoes, a certain level of tissue destruction is observed and needed in gu<sup>t</sup> epithelia and salivary glands to allow viral propagation and transmission. As alphaviruses are still poorly studied to understand the link between cell death and vector competence, we can only extrapolate from recent DENV studies. Indeed, in addition to immune response, the mosquito's ability to rapidly eliminate infected epithelial cells through apoptosis, instead of a delayed cell death and secondary necrosis, may explain the difference between a resistant mosquito and a tolerant one. A better understanding and subsequent manipulation of vector tolerance could help to control arboviral propagation, as has recently been suggested [15,18].

**Funding:** This research received no external funding. **Acknowledgments:** The authors would like to thank Aurélie Paillet for constructive proofreading of the manuscript.

**Conflicts of Interest:** The authors declare no conflict of interest.
