## 4 Discussion  
The ECM receptor DG is the main receptor for the OW mmarenaviruses LASV and LCMV [14; 15] and virus binding occurs through the matriglycan chains exposed on the cellular membrane [24]. \begin{table}
\begin{tabular}{c c c c} \hline \multicolumn{4}{c}{**HT1080**} \\ \hline
**Rib Concentration (\(\mu\)M)** & **R428 + EMD (5 uM) Concentration (\(\mu\)M)** & **Effect** & **CI Value** \\ \hline
2.5 & 0.125 & 0.85 & 0.61251 \\ \hline
2.5 & 0.25 & 0.85 & 1.12848 \\ \hline
2.5 & 0.5 & 0.95 & 0.66368 \\ \hline
2.5 & 1.0 & 0.96 & 1.01803 \\ \hline
5.0 & 0.125 & 0.91 & 0.42575 \\ \hline
5.0 & 0.25 & 0.91 & 0.71527 \\ \hline
5.0 & 0.5 & 0.96 & 0.56971 \\ \hline
5.0 & 1.0 & 0.98 & 0.53217 \\ \hline
10.0 & 0.125 & 0.9 & 0.61743 \\ \hline
10.0 & 0.25 & 0.91 & 0.85150 \\ \hline
10.0 & 0.5 & 0.96 & 0.65063 \\ \hline
10.0 & 1.0 & 0.99 & 0.30661 \\ \hline
20.0 & 0.125 & 0.88 & 1.06018 \\ \hline
20.0 & 0.25 & 0.92 & 1.01350 \\ \hline
20.0 & 0.5 & 0.96 & 0.81248 \\ \hline
20.0 & 1.0 & 0.99 & 0.37553 \\ \hline \end{tabular}
\end{table} 
Table 4: Drug interaction (R428 + EMD/Rib) analysis in HT-1080 cells. Analysis performed with CompuSyn [95]. CI values \(<\) 1 means synergistic interaction, approximately 1 additive effect, and \(>\)1 antagonistic interaction. \begin{table}
\begin{tabular}{c c c c} \hline \multicolumn{4}{c}{**A549 Cells**} \\ \hline
**Rib Concentration (\(\mu\)M)** & **R428 + EMD (5 uM) Concentration (\(\mu\)M)** & **Effect** & **CI Value** \\ \hline
5.0 & 0.25 & 0.57 & 0.18109 \\ \hline
5.0 & 0.5 & 0.64 & 0.26473 \\ \hline
5.0 & 1.0 & 0.67 & 0.46052 \\ \hline
10.0 & 0.125 & 0.65 & 0.06400 \\ \hline
10.0 & 0.25 & 0.62 & 0.14596 \\ \hline
10.0 & 0.5 & 0.67 & 0.23072 \\ \hline
10.0 & 1.0 & 0.7 & 0.39856 \\ \hline
20.0 & 0.125 & 0.64 & 0.06818 \\ \hline
20.0 & 0.25 & 0.7 & 0.19979 \\ \hline
20.0 & 1.0 & 0.72 & 0.36039 \\ \hline \end{tabular}
\end{table} 
Table 3: _Cont._Although expressed in most cell types, DG is subjected to complex, tightly regulated post-translational glycosylation modifications, including extensive O-mannosyl-linked carbohydrate addition [104], which critically determines DG functionality [19]. High affinity virus-receptor binding occurs rapidly via long matriglycan chains linked to the N-terminus of the mature DG protein, and virus-receptor dissociation occurs only under low pH, pointing to internalization of the virus-DG complex [29; 30; 31]. Nevertheless, identified infected tissues do not strictly correlate with expression levels of functional DG [7; 33], suggesting that LASV entry does not depend only on DG but also on additional cellular factors, which can act in a coordinated manner depending on the specific tissue. Indeed, Axl and HGFR RTKs, which are expressed in many target cells of LASV, have been identified as additional host factors important for viral entry [27; 36; 37]. In the present study, we investigated the function of these RTKs in productive entry of LASV in the context of presence or absence of functional glycosylated DG. Axl RTK participated in the entry of several emerging viruses, such as Ebola, Zika, and dengue [50; 51; 52; 105; 106], and we have previously shown that Axl RTK contributed to LASV entry in cells lacking functional DG [37]. In the present study, we have provided evidence that, regardless of the DG glycosylation extent, Axl RTK is required for LASV entry but not for later steps of viral replication, and that Axl RTK inhibition consequently resulted in decreased rLCMV/LASV\({}_{\text{GP}}\) infectivity. Indeed, in HT-1080 cells, which do not express functional glycosylated DG, the inhibition of Axl RTK by R428 resulted in a stronger antiviral effect than in A549 and HUVEC cells, which displayed glycosylated forms of DG. Confirming our initial observations, we found that Axl RTK overexpression resulted in increased rLCMV/LASV\({}_{\text{GP}}\) infectivity, whereas in a complementary approach, Axl RTK knockdown reduced viral infectivity.