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Paragraph: Because constitutive immune assumptions can prohibit pathogen invasion (R 0 <1), model fits to this time series under constitutive assumptions were handicapped by overestimations of ", which prohibited pathogen invasion. Only by incorporating an exceedingly rapid rate of induced antiviral acquisition could the model guarantee that initial infection would be permitted and then rapidly controlled. In all panel (A) plots, the rate of induced immune antiviral acquisition (r) was fixed at 0.01. Panel (B) depicts dynamics under variably induced immunity, ranging from absent (left: r=0) to high (right: r=1). In all panel (B) plots, the rate of constitutive antiviral acquisition (") was fixed at 0.0001 Branch point curves are represented as solid lines and Hopf curves as dashed lines. White space indicates endemic equilibrium (persistence), gray space indicates limit cycles, and black space indicates no infection (extinction). Other parameter values for equilibrium analysis were fixed at: b = .025, m = .001, s = 1/6, c = 0. Special points from bifurcations analyses are listed in Supplementary file 3. In fitting our theoretical model to in vitro data, we estimated the within-host virus transmission rate (b) and the rate(s) of cellular acquisition to antiviral status (r or r + ") ( Table 1 ; Supplementary file 4). Under absent immune assumptions, r and " were fixed at 0 while b was estimated; under induced immune assumptions, " was fixed at 0 while r and b were estimated; and under constitutive immune assumptions, all three parameters (r, ", and b) were simultaneously estimated for each cell-virus combination. Best fit parameter estimates for MOI=0.001 data are visualized in conjunction with br and b -" bifurcations in (r) and (B) the constitutive immunity rate of antiviral acquisition ("). Panels show variation in the extent of immunity, from absent (left) to high (right). Branch point curves are represented as solid lines and Hopf curves as dashed lines. White space indicates endemic equilibrium (persistence), gray space indicates limit cycling, and black space indicates no infection (extinction). Other parameter values for equilibrium analysis were fixed at: b = .025, m = .001, s = 1/6, a = 1/6, c = 0. Special points from bifurcations analyses are listed in Supplementary file 3. space corresponding to theoretical limit cycles, consistent with observed virus-induced epidemic extinctions in stochastic tissue cultures. In contrast to Vero cells, the induced immunity model offered the best fit to all RoNi/7.1 data, consistent with reported patterns in the literature and our own validation by qPCR ( Table 1; Arnold et al., 2018; Kuzmin et al., 2017; Biesold et al., 2011; Pavlovich et al., 2018) . As in Vero cell trials, we estimated highest b values for rVSV-G infections on RoNi/7.1 cell lines but here recovered higher b estimates for rVSV-MARV than for rVSV-EBOV. This reversal was balanced by a higher estimated rate of acquisition to antiviral status (r) for rVSV-EBOV versus rVSV-MARV. In general, we observed that more rapid rates of antiviral acquisition (either induced, r, constitutive, ", or both) correlated with higher transmission rates (b). When offset by r, b values estimated for RoNi/7.1 infections maintained the same amplitude as those estimated for immune-absent Vero cell lines but caused gentler epidemics and reduced cellular mortality (Figure 1) . RoNi/7.1 parameter estimates localized in the region corresponding to endemic equilibrium for the deterministic, theoretical model (Figure 4) , yielding less acute epidemics which nonetheless went extinct in stochastic experiments. Finally, rVSV-G and rVSV-EBOV trials on PaKiT01 cells were best fit by models assuming constitutive immunity, while rVSV-MARV infections on PaKiT01 were matched equivalently by models assuming either induced or constitutive immunity-with induced models favored over constitutive in AIC comparisons because one fewer parameter was estimated (Figure 1-figure supplements 4-5; Supplementary file 4). For all virus infections, PaKiT01 cell lines yielded b estimates a full order of magnitude higher than Vero or RoNi/7.1 cells, with each b balanced by an immune response (either r, or r combined with ") also an order of magnitude higher than that recovered for the other cell lines ( Figure 4 ; Table 1 ). As in RoNi/7.1 cells, PaKiT01 parameter fits localized in the region corresponding to endemic equilibrium for the deterministic theoretical model. Because constitutive immune processes can actually prohibit initial pathogen invasion, constitutive immune fits to rVSV-MARV infections on PaKiT01 cell lines consistently localized at or below the Branch point threshold for virus invasion (R 0 ¼ 1). During model fitting for optimization of ", any parameter tests of " values producing R 0 <1 resulted in no infection and, consequently, produced an exceedingly poor fit to infectious time series data. In all model fits assuming constitutive immunity, across all cell lines, antiviral contributions from " prohibited virus from invading at all. The induced immune model thus produced a more parsimonious recapitulation of these data because virus invasion was always permitted, then rapidly controlled. In order to compare the relative contributions of each cell line's disparate immune processes to epidemic dynamics, we next used our mean field parameter estimates to calculate the initial 'antiviral rate'-the initial accumulation rate of antiviral cells upon virus invasion for each cell-virus-MOI combination-based on the following equation:

where P E was calculated from the initial infectious dose (MOI) of each infection experiment and P S was estimated at disease-free equilibrium:

Because and " both contribute to this initial antiviral rate, induced and constitutive immune assumptions are capable of yielding equally rapid rates, depending on parameter fits. Indeed, under fully induced immune assumptions, the induced antiviral acquisition rate (r) estimated for rVSV-MARV infection on PaKiT01 cells was so high that the initial antiviral rate exceeded even that estimated under constitutive assumptions for this cell-virus combination (Supplementary file 4) . In reality, we know that NPC1 receptor incompatibilities make PaKiT01 cell lines constitutively refractory to rVSV-MARV infection (Ng and Chandrab, 2018, Unpublished results) and that PaKiT01 cells also constitutively express the antiviral cytokine, IFN-a. Model fitting results suggest that this constitutive expression of IFN-a may act more as a rapidly inducible immune response following virus invasion than as a constitutive secretion of functional IFN-a protein. Nonetheless, as hypothesized, PaKiT01 cell lines were by far the most antiviral of any in our study-with initial antiviral rates estimated several orders of magnitude higher than any others in our study, under either induced or constitutive assumptions ( Table 1 ; Supplementary file 4). RoNi/7.1 cells displayed the second-most-pronounced signature of immunity, followed by Vero cells, for which the initial antiviral rate was essentially zero even under forced assumptions of induced or constitutive immunity ( Table 1 ; Supplementary file 4). Using fitted parameters for b and ", we additionally calculated R 0 , the basic reproduction number for the virus, for each cell line-virus-MOI combination ( Table 1 ; Supplementary file 4). We found that R 0 was essentially unchanged across differing immune assumptions for RoNi/7.1 and Vero cells, for which the initial antiviral rate was low. In the case of PaKiT01 cells, a high initial antiviral rate under either induced or constitutive immunity resulted in a correspondingly high estimation of b (and, consequently, R 0 ) which still produced the same epidemic curve that resulted from the much lower estimates for b and R 0 paired with absent immunity. These findings suggest that antiviral immune responses protect host tissues against virus-induced cell mortality and may facilitate the establishment of more rapid within-host transmission rates. Total monolayer destruction occurred in all cell-virus combinations excepting rVSV-EBOV infections on RoNi/7.1 cells and rVSV-EBOV and rVSV-MARV infections on PaKiT01 cells. Monolayer destruction corresponded to susceptible cell depletion and epidemic turnover where R-effective (the product of R 0 and the proportion susceptible) was reduced below one ( Figure 5) . For rVSV-EBOV infections on RoNi/7.1, induced antiviral cells safeguarded remnant live cells, which birthed new susceptible cells late in the time series. In rVSV-EBOV and rVSV-MARV infections on PaKiT01 cells, this antiviral protection halted the epidemic ( Figure 5 ; R-effective <1) before susceptibles fully declined. In the case of rVSV-EBOV on PaKiT01, the birth of new susceptibles from remnant live cells protected by antiviral status maintained late-stage transmission to facilitate long-term epidemic persistence. Importantly, under fixed parameter values for the infection incubation rate (s) and infectioninduced mortality rate (a), models were unable to reproduce the longer-term infectious time series captured in data from rVSV-EBOV infections on PaKiT01 cell lines without incorporation of cell births, an assumption adopted in previous modeling representations of IFN-mediated viral dynamics in tissue culture (Howat et al., 2006) . In our experiments, we observed that cellular reproduction took place as plaque assays achieved confluency. Finally, because the protective effect of antiviral cells is more clearly observable spatially, we confirmed our results by simulating fitted time series in a spatially-explicit, stochastic reconstruction of our mean field model. In spatial simulations, rates of antiviral acquisition were fixed at fitted values for r and " derived from mean field estimates, while transmission rates (b) were fixed at values ten times greater than those estimated under mean field conditions, accounting for the intensification of parameter thresholds permitting pathogen invasion in local spatial interactions (see Materials and methods; Videos 1-3; Figure 5-figure supplement 3; Supplementary file 5; Webb et al., 2007) . In immune capable time series, spatial antiviral cells acted as 'refugia' which protected live cells from infection as each initial epidemic wave 'washed' across a cell monolayer. Eventual birth of new susceptibles from these living refugia allowed for sustained epidemic transmission in cases where some infectious cells persisted at later timepoints in simulation (Videos 1-3; Figure 5-figure supplement  3 ). Bats are reservoirs for several important emerging zoonoses but appear not to experience disease from otherwise virulent viral pathogens. Though the molecular biological literature has made great progress in elucidating the mechanisms by which bats tolerate viral infections (Zhou et al., 2016; Ahn et al., 2019; Xie et al., 2018; Pavlovich et al., 2018; Zhang et al., 2013) , the impact of unique bat immunity on virus dynamics within-host has not been well-elucidated. We used an innovative combination of in vitro experimentation and within-host modeling to explore the impact of unique bat immunity on virus dynamics. Critically, we found that bat cell lines demonstrated a signature of enhanced interferon-mediated immune response, of either constitutive or induced form, which allowed for establishment of rapid within-host, cell-to-cell virus transmission rates (b). These results were supported by both data-independent bifurcation analysis of our mean field theoretical model, as well as fitting of this model to viral infection time series established in bat cell culture. Additionally, we demonstrated that the antiviral state induced by the interferon pathway protects live cells from mortality in tissue culture, resulting in in vitro epidemics of extended duration that enhance the probability of establishing a long-term persistent infection. Our findings suggest that viruses evolved in bat reservoirs possessing enhanced IFN capabilities could achieve more rapid within-host transmission rates without causing pathology to their hosts. Such rapidly-reproducing viruses would likely generate extreme virulence upon spillover to hosts lacking similar immune capacities to bats. To achieve these results, we first developed a novel, within-host, theoretical model elucidating the effects of unique bat immunity, then undertook bifurcation analysis of the model's equilibrium properties under immune absent, induced, and constitutive assumptions. We considered a cell line to be constitutively immune if possessing any number of antiviral cells at disease-free equilibrium but allowed the extent of constitutive immunity to vary across the parameter range for ", the constitutive rate of antiviral acquisition. In deriving the equation for R 0 , the basic reproduction number, which defines threshold conditions for virus invasion of a tissue (R 0 >1), we demonstrated how the invasion threshold is elevated at high values of constitutive antiviral acquisition, ". Constitutive immune processes can thus prohibit pathogen invasion, while induced responses, by definition, can only control infections post-hoc. Once thresholds for pathogen invasion have been met, assumptions of constitutive immunity will limit the cellular mortality (virulence) incurred at high transmission rates. Regardless of mechanism (induced or constitutive), interferon-stimulated antiviral cells appear to play a key role in maintaining longer term or persistent infections by safeguarding susceptible cells from rapid infection and concomitant cell death. Fitting of our model to in vitro data supported expected immune phenotypes for different bat cell lines as described in the literature. Simple target cell models that ignore the effects of immunity best recapitulated infectious time series derived from IFN-deficient Vero cells, while models assuming induced immune processes most accurately reproduced trials derived from RoNi/7.1 (Rousettus aegyptiacus) cells, which possess a standard virusinduced IFN-response. In most cases, models assuming constitutive immune processes best recreated virus epidemics produced on PaKiT01 (Pteropus alecto) cells, which are known to constitutively express the antiviral cytokine, IFN-a (Zhou et al., 2016) . Model support for induced immune assumptions in fits to rVSV-MARV infections on PaKiT01 cells suggests that the constitutive IFN-a expression characteristic of P. alecto cells may represent more of a constitutive immune priming process than a perpetual, functional, antiviral defense. Results from mean field model fitting were additionally confirmed in spatially explicit stochastic simulations of each time series. As previously demonstrated in within-host models for HIV (Coffin, 1995; Perelson et al., 1996; Nowak et al., 1995; Bonhoeffer et al., 1997; Ho et al., 1995) , assumptions of simple target-cell depletion can often provide satisfactory approximations of viral dynamics, especially those reproduced in simple in vitro systems. Critically, our model fitting emphasizes the need for incorporation of top-down effects of immune control in order to accurately reproduce infectious time series derived from bat cell tissue cultures, especially those resulting from the robustly antiviral PaKiT01 P. alecto cell line. These findings indicate that enhanced IFN-mediated immune pathways in bat reservoirs may promote elevated within-host virus replication rates prior to cross-species emergence.

Question: What do the findings indicate?
enhanced IFN-mediated immune pathways in bat reservoirs may promote elevated within-host virus replication rates prior to cross-species emergence.