title: Target cell limitation constrains chlamydial load in persistent infections: results from mathematical modelling applied to mouse genital tract infection data.
abstract: The interactions between chlamydial pathogens and their host contribute to the outcome of infection. Nonresolving infections in immunodeficient mice can provide insights into these mechanisms by allowing observation of a form of persistent infection. Using a mathematical model, we predict that in a nonresolving infection, the number of chlamydiae in the host will attain a stable equilibrium and that this equilibrium will be independent of the inoculum size. We test this hypothesis by infecting RAG(-/-) mice with 10(4)-10(7) inclusion-forming units (IFU) of Chlamydia muridarum and comparing the IFU levels at equilibrium. There were no statistically significant differences in equilibrium IFU levels between the reference group and other inoculation groups, supporting the hypothesis. Using the mathematical model, we estimated that at equilibrium just 3% of the chlamydiae infect a target cell. We predict that the equilibrium IFU level is highly sensitive to the rate of replenishment of healthy cells. The limitation of target cells is a key driver of infection dynamics, affecting both the peak of infection and the equilibrium level of persistent infections. Target cell limitation likely plays an important role in the dynamics of human infections as well.
authors.affiliation: The Kirby Institute, UNSW Australia, Sydney, NSW, Australia.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Craig
authors.affiliation: Arkansas Children's Hospital Research Institute, Little Rock, AR, USA.
authors.forename: Roger G
authors.initials: RG
authors.lastname: Rank
authors.affiliation: Arkansas Children's Hospital Research Institute, Little Rock, AR, USA.
authors.forename: Anne K
authors.initials: AK
authors.lastname: Bowlin
authors.affiliation: The Kirby Institute, UNSW Australia, Sydney, NSW, Australia.
authors.forename: Handan
authors.initials: H
authors.lastname: Wand
authors.affiliation: The Kirby Institute, UNSW Australia, Sydney, NSW, Australia dwilson@unsw.edu.au.
authors.forename: David P
authors.initials: DP
authors.lastname: Wilson
mesh_terms: D000818:Animals; D058491:Bacterial Load; D002689:Chlamydia / Q000302:isolation & purification*; D002690:Chlamydia Infections / Q000382:microbiology*; D004195:Disease Models, Animal; D054884:Host-Pathogen Interactions; D051379:Mice; D018345:Mice, Knockout; D008962:Models, Theoretical; D060737:Reproductive Tract Infections / Q000382:microbiology*
keywords: Chlamydia; immunodeficient; mathematical model; mouse; persistence