Abstract
Secondary bacterial infections increase morbidity and mortality of influenza A virus (IAV) infections. Bacteria are able to invade due to virus-induced depletion of alveolar macrophages (AMs), but this is not the only contributing factor. By analyzing a kinetic model, we uncovered a nonlinear initial dose threshold that is dependent on the amount of virus-induced AM depletion. The threshold separates the growth and clearance phenotypes such that bacteria decline for dose-AM depletion combinations below the threshold, stay constant near the threshold, and increase above the threshold. In addition, the distance from the threshold correlates to the growth rate. Because AM depletion changes throughout an IAV infection, the dose requirement for bacterial invasion also changes accordingly. Using the threshold, we found that the dose requirement drops dramatically during the first 7d of IAV infection. We then validated these analytical predictions by infecting mice with doses below or above the predicted threshold over the course of IAV infection. These results identify the nonlinear way in which two independent factors work together to support successful post-influenza bacterial invasion. They provide insight into coinfection timing, the heterogeneity in outcome, the probability of acquiring a coinfection, and the use of new therapeutic strategies to combat viral-bacterial coinfections.
Highlights
Influenza A virus (IAV) poses a considerable threat to public health, resulting in 15–65 million infections and >200,000 hospitalizations each year during seasonal epidemics in the U.S.1,2
Bacterial resolution is predicted to occur with minor alveolar macrophages (AMs) depletion, but the length of time for bacterial loads to completely clear (log10P(t) < 0, where P(t) denotes the solution to Equation (6)) increases rapidly as depletion accumulates and saturates once these cells have declined by ~80% (Fig. 1B)
Not every influenza A virus (IAV) infection results in a bacterial invasion and only a proportion of successful coinfections lead to severe pneumonia[23,24]
Summary
Influenza A virus (IAV) poses a considerable threat to public health, resulting in 15–65 million infections and >200,000 hospitalizations each year during seasonal epidemics in the U.S.1,2. In the context of the coinfection, a distinct dichotomous pattern emerged with a low dose (102 CFU) compared to a higher dose (103 CFU) such that some individuals had high bacterial titers, an indication of severe pneumonia, while others had low bacterial titers and, presumably, a more mild infection[17] It is currently unclear what factors contribute to the differential dynamics, we hypothesized that this may be due to heterogeneity in the AM population because reducing the depletion parameter in our mathematical model could result in lower titers[17] and because we previously related the dose dependent effect to the AM population in a naive host[20]. Our data gives new insight into the timing of coinfections, potential therapeutic strategies, and why bacterial coinfections occur more often during influenza pandemics compared to seasonal epidemics
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