Intracellular Survival and Persistence of <i>Chlamydia muridarum</i> Is Determined by Macrophage Polarization

Abstract

<div><p>Macrophages can display a number of distinct phenotypes, known collectively as polarized macrophages. The best defined of these phenotypes are the classically-activated, interferon gamma (IFNγ)/LPS induced (M1) and alternatively-activated, IL-4 induced (M2) macrophages. The goal of this study is to characterize macrophage-<i>Chlamydia</i> interactions in the context of macrophage polarization. Here we use <i>Chlamydia muridarum</i> and murine bone-marrow derived macrophages to show <i>Chlamydia</i> does not induce M2 polarization in macrophages as a survival strategy. Unexpectedly, the infection of macrophages was silent with no upregulation of M1 macrophage-associated genes. We further demonstrate that macrophages polarized prior to infection have a differential capacity to control <i>Chlamydia</i>. M1 macrophages harbor up to 40-fold lower inclusion forming units (IFU) than non-polarized or M2 polarized macrophages. Gene expression analysis showed an increase in <i>16sRNA</i> in M2 macrophages with no change in M1 macrophages. Suppressed <i>Chlamydia</i> growth in M1 macrophages correlated with the induction of a bacterial gene expression profile typical of persistence as evident by increased <i>Euo</i> expression and decreased <i>Omp1</i> and <i>Tal</i> expression. Observations of permissive <i>Chlamydia</i> growth in non-polarized and M2 macrophages and persistence in M1 macrophages were supported through electron microscopy. This work supports the importance of IFNγ in the innate immune response to <i>Chlamydia</i>. However, demonstration that the M1 macrophages, despite an antimicrobial signature, fail to eliminate intracellular <i>Chlamydia</i> supports the notion that host–pathogen co-evolution has yielded a pathogen that can evade cellular defenses against this pathogen, and persist for prolonged periods of time in the host.</p> </div