Outside-host phage therapy as a biological control against environmental infectious diseases

Background: Environmentally growing pathogens present an increasing threat for human health, wildlife and food production. Treating the hosts with antibiotics or parasitic bacteriophages fail to eliminate diseases that grow also in the outside-host environment. However, bacteriophages could be utilized to suppress the pathogen population sizes in the outside-host environment in order to prevent disease outbreaks. Here, we introduce a novel epidemiological model to assess how the phage infections of the bacterial pathogens affect epidemiological dynamics of the environmentally growing pathogens. We assess whether the phage therapy in the outside-host environment could be utilized as a biological control method against these diseases. We also consider how phage-resistant competitors affect the outcome, a common problem in phage therapy. The models give predictions for the scenarios where the outside-host phage therapy will work and where it will fail to control the disease. Parameterization of the model is based on the fish columnaris disease that causes significant economic losses to aquaculture worldwide. However, the model is also suitable for other environmentally growing bacterial diseases. Results: Transmission rates of the phage determine the success of infectious disease control, with high-transmission phage enabling the recovery of the host population that would in the absence of the phage go asymptotically extinct due to the disease. In the presence of outside-host bacterial competition between the pathogen and phage-resistant strain, the trade-off between the pathogen infectivity and the phage resistance determines phage therapy outcome from stable coexistence to local host extinction. Conclusions: We propose that the success of phage therapy strongly depends on the underlying biology, such as the strength of trade-off between the pathogen infectivity and the phage-resistance, as well as on the rate that the phages infect the bacteria. Our results indicate that phage therapy can fail if there are phage-resistant bacteria and the trade-off between pathogen infectivity and phage resistance does not completely inhibit the pathogen infectivity. Also, the rate that the phages infect the bacteria should be sufficiently high for phage-therapy to succeed.Peer reviewe

Invasion Ability and Disease Dynamics of Environmentally Growing Opportunistic Pathogens under Outside-Host Competition

Peer reviewe

Biofilm production of A) <i>Serratia marcescens</i> B) <i>Novosphingobium capsulatum</i>.

<p>Biofilm amount was measured at the end of a weeklong fitness assay. The bars show the estimated marginal mean biofilm amount based on the GLMM + SE in all treatments. Treatments are the same as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0076471#pone-0076471-g001" target="_blank">Figure 1</a>.</p

Yield of A) <i>Serratia marcescens</i> B) <i>Novosphingobium capsulatum</i>.

<p>Yield is measured as optical density, and corresponds to the total maximum biomass measured during a weeklong fitness assay. The bars show the estimated marginal mean yield based on the GLMM + SE in all treatments. Treatments are the same as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0076471#pone-0076471-g001" target="_blank">Figure 1</a>.</p

Invasion analyses of a novel environmentally growing opportunist pathogen under outside-host competition situation in different combinations of the competition coefficient (<i>f_BP</i>) parameter values and a) environmental transmission rate (<i>β</i>), b) release rate (<i>Λ</i>), c) virulence (α), d) pathogen mortality outside-host (<i>μ_P</i>), e) outside-host growth rate of pathogen (<i>r_P</i>) and f) susceptible host growth rate (<i>r_S</i>).

<p>The parameter values used are shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0113436#pone-0113436-t001" target="_blank">Table 1</a>. The black area shows the parameter combinations for which the equilibrium dynamics are locally stable preventing the invasion of the pathogen. The white area shows where the dynamics become unstable enabling invasion of the new environmentally growing opportunist pathogen (<i>P</i>).</p

Parameter values per time unit (one day) used in the stability analysis.

<p>Parameter values per time unit (one day) used in the stability analysis.</p

Bifurcation figures of the S-I-P-B dynamics, presenting maximum and minimum values (black circles), as well as equilibrium densities (red stars for when competitor (<i>B</i>) is not present, red circles when all the populations are present) of susceptible host (<i>S</i>), pathogen (<i>P</i>) and non-pathogenic (<i>B</i>) population densities in different combinations of outside-host growth rate of pathogen (<i>r_P</i>) parameter values (<i>r_P</i> = 0.001–0.5).

<p>a) When susceptible host growth rate (<i>r_S</i>) is high (<i>r_S</i> = 1), increasing <i>r_P</i> stabilizes the disease dynamics. b) Disease dynamics are cyclic when susceptible host growth rate (<i>r_S</i>) is low (<i>r_S</i> = 0.01). Used parameter values are shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0113436#pone-0113436-t002" target="_blank">Table 2</a>.</p

Parameter values per time unit (one day) used in the invasion analysis.

<p>Parameter values per time unit (one day) used in the invasion analysis.</p