Evolution of the Cutaneous Immune Response to Experimental Haemophilus ducreyi Infection and Its Relevance to HIV-1 Acquisition

Abstract

Haemophilus ducreyi causes the sexually transmitted disease chancroid, which facilitates HIV-1 transmission. Skin biopsies were obtained from subjects experimentally infected with H. ducreyi to study the evolution of the immune response and immunophenotypes relevant to transmission of HIV-1. Compared with peripheral blood, there was an enrichment of T cells and macrophages after 48 h of infection in the skin. Neutrophils became the predominant cell type by 7–9 days. By immunohistochemistry, macrophage-inflammatory protein-1α was not present early in infection, but was abundant at later stages. RANTES was present throughout the papular and pustular stages of experimental infection, but not present in uninfected control skin. Stromal cell-derived factor-1 was present at low levels in all samples examined. Macrophages in lesions had significantly increased expression of CCR5 and CXCR4 compared with peripheral blood cells, and CD4 T cells had significant up-regulation of CCR5. The magnitude of increased expression of these receptors was not replicated when PBMCs were incubated with H. ducreyi or H. ducreyi lipooligosaccharide in vitro. Together with the disruption of mucosal and skin barriers, the presence of cells with up-regulated HIV-1 coreceptors in H. ducreyi-infected lesions may provide an environment that facilitates the acquisition of R5 (CCR5), X4 (CXCR4), and dual-tropic HIV-1 strains.

Combined Effect of CCR5-Δ32 Heterozygosity and the CCR5 Promoter Polymorphism −2459 A/G on CCR5 Expression and Resistance to Human Immunodeficiency Virus Type 1 Transmission

“…It is likely that in vitro hyperactivation overcame the differences that existed in CCR5 promoter activity before stimulation with the mitogen, and infectivity levels in the two groups were therefore equal. This finding also emphasizes the possibility that relative resistance to infection conferred by specific CCR5 genotype combinations can be overcome by cellular activation, as may be the case during sexually transmitted disease-triggered mucosal inflammation (15,32,42,47).…”

Haemophilus ducreyi-Induced Interleukin-10 Promotes a Mixed M1 and M2 Activation Program in Human Macrophages

“…Neutrophils are the predominant cell type in pustules (19). Phagocytosis of apoptotic neutrophils by macrophages promotes M2 polarization and the resolution of inflammation (14).…”

“…Macrophages are rapidly recruited to H. ducreyi-infected skin in human inoculation experiments (19,37). To determine the expression of surface markers associated with M1 and M2 polarization of macrophages, biopsy specimens of pustules and PBMC obtained from 10 participants who were experimentally infected were analyzed by flow cytometry.…”

Trafficking Pathways and Characterization of CD4 and CD8 Cells Recruited to the Skin of Humans Experimentally Infected withHaemophilus ducreyi

“…There is a limited amount of information about T cells that home to skin in response to infection (23,28,32). Human inoculation experiments with H. ducreyi provide a unique opportunity to study the trafficking and phenotypes of T cells recruited chiefly to the dermis in response to this pathogen (20,32). Previous work in our laboratory showed that CD4 cells isolated from H. ducreyi-infected pustules are memory cells that are enriched for the skin-homing markers CLA and CCR4.…”

“…The lesion consists of a polymorphonuclear leukocyte infiltrate that forms an epidermal abscess and a deep dermal perivascular infiltrate of T cells and macrophages that resembles a poorly formed granuloma that extends interstitially to just below the epidermis (26,36). By 48 h of infection, T cells make up about 50% of the leukocyte infiltrate and remain abundant throughout the course of experimental infection (20).…”