CHIKV is well known to infect both non hematopoietic and hematopoietic cells
[5–10]. CHIKV not only infects macrophages but also human fibroblasts from cognitive tissues of different origins (skin, synovium)
[5, 10]. Couderc et al. demonstrated that in neonate mice with a mild infection, CHIKV primarily targets muscles, joints and skin fibroblasts, a cellular and tissue tropism similar to that reported in humans
. In a seminal study, Sourisseau and colleagues have shown that skin- and lung-derived fibroblasts (Hs 789.Sk and MRC5 respectively) were differentially infected by CHIKV
 but through mechanisms ill-characterized.
In this paper we demonstrated that HS 633T cells behave as a susceptible fibroblast cell line to CHIKV infection in contrast to the other human fibroblast cell line HT-1080 where only a smaller percentage of cells were infected and released CHIKV progenies at lower levels. We hypothesized that this difference could be due to differential expression of TLR7 and/or RIG-I which are key sensors to control CHIKV infection at least in mouse embryonic fibroblasts
. Against our expectations, our results didn’t support this hypothesis and arguing for the role of additional antiviral mechanisms mobilized differentially by fibroblast cell lines.
The IFN system is a powerful antiviral mechanism capable of controlling most, if not all, virus infections in the absence of a functional adaptative immunity
. However, our analysis did not reveal a higher expression of IFN-β in HT-1080 and, in contrast, the expression was significantly more robust in HS 633T cells at 48 h PI probably as a consequence of higher levels of viral RNA within the cells. This result is consistent with a recent study on primary human foreskin fibroblasts (HFs)
. White and colleagues demonstrated that infection of HFs by CHIKV triggered the transcription of IFN-β at 24 h PI.
Viruses have also developed several strategies to control the downstream IFN response to replicate, persist and cause chronic diseases. Here, we showed that CHIKV clinical isolate interfered equally well with the nuclear translocation of activated STAT1 in HS 633T and HT-1080 fibroblast cell models even in the presence of exogenous recombinant IFN-α. This observation is consistent with recent data studying CHIKV infection in Vero cells using virus recombinant replicons
. In their paper, Fros et al. found that CHIKV infection efficiently blocked nuclear translocation of phosphorylated STAT1 in response to either type I or II IFNs. Other Alphaviruses like Semliki forest virus (SFV) and RRV were also reported to suppress the type I IFN response
We cannot exclude the possibility that HT-1080 cells express only low levels of a functional receptor mediating CHIKV entry, yet to be characterized, but it should be stressed that the main differences in terms of susceptibility was not observed at early time point (8 h) but was evidenced at 24 h and 48 h. Counter-intuitively, the more resistant HT-1080 was producing lower levels of three main ISGs when compared to HS 633T cells at 48 h PI. We should further explore the possible contributions of other antiviral genes such as RNAse-L or PKR to explain differences between HS 633T and HT-1080 fibroblasts.
The analyses of the primary IFN and ISG responses to CHIKV infection did not explain the differences of susceptibility of the two fibroblast cell lines and experiments are now highly warranted to explore further possible additional mechanisms. We and others have recently shown that virus can hide into vesicles (blebs) to enter cells and escape classical recognition and antiviral mechanisms
 which is likely to allow secondary infection of surrounding cells. It will be interesting to analyze the differential capacity of HT-1080 and HS 633T not only to generate and shed these blebs but also to engage macropinocytosis or phagocytosis through specific receptors.