CCL5 Modulates Pneumococcal Immunity and Carriage

Abstract

Understanding the requirements for protection against pneumococcal carriage and pneumonia will greatly benefit efforts in controlling these diseases. Recently, it has been shown that genetic polymorphisms can result in diminished expression of CCL5, which results in increased susceptibility to and progression of infectious diseases. We show that CCL5, together with Th cytokine mRNA expression, is temporally up-regulated during pneumococcal carriage. To determine the contribution of CCL5 to pneumococcal surface antigen A-specific humoral and cellular pneumococcal immunity, mice were treated with anti-CCL5 or control Abs before and during Streptococcus pneumoniae strain EF3030-challenge for the initiation of carriage. CCL5 blockade resulted in a decrease of CD4+ and CD8+ T cells as well as CD11b+ cells in the spleen, cervical lymph node, lung, and nasopharyngeal associated lymphoid tissue during the recognition phase of the pneumococcal adaptive immune response. CCL5 blockade significantly reduced the Ag-specific IgG2a and IgG1 Abs in serum and IgA Ab levels in nasal washes. These decreases also corresponded to reductions in Ag-specific T cell (mucosal and systemic) responses. CCL5 inhibition resulted in decreasing the quantity of IL-4- and IFN-γ-secreting CD4+ T cells and increasing the number of Ag-specific IL-10-producing CD4+ T cells; these changes combined also corresponded with the transition from pneumococcal carriage to lethal pneumonia. These data suggest that CCL5 is an essential factor for the induction and maintenance of protective pneumococcal immunity.

Streptococcus pneumoniaeStimulates a STING- and IFN Regulatory Factor 3-Dependent Type I IFN Production in Macrophages, which Regulates RANTES Production in Macrophages, Cocultured Alveolar Epithelial Cells, and Mouse Lungs

“…Our data indicate that the type I IFNs produced by pneumococciinfected macrophages affect macrophages and neighboring AECs in an autocrine and paracrine manner, leading to an enhanced production of RANTES, which is involved in the host defense to pneumococcal pneumonia (54). We speculate that IFN a/b released by S. pneumoniae-infected macrophages binds to IFNAR and activates STAT transcription factors, which in turn enhance transcription of the RANTES promoter (56).…”

“…RANTES is a key chemokine involved in the host defense to pneumococcal pneumonia (54). We infected BMMs from wt or IFNAR-deficient mice with S. pneumoniae D39.…”

Pulmonary cytokine composition differs in the setting of alcohol use disorders and cigarette smoking

“…In our subjects with AUDs, RANTES levels correlated with levels of IP-10, a CXC chemokine secreted by cells in response to IFN-␥. In the setting of experimental pneumococcal pneumonia, pulmonary levels of RANTES and IP-10 may be increased (21,40) and, along with other proinflammatory cytokines, appear to play a role in the pneumococcal immune response. In animal experiments using an EF3030 pneumococcal strain, RANTES also influenced the production of antibodies that limited the progression of nasopharyngeal pneumococcal carriage to frank pneumonia and influenced survival (40).…”

“…In the setting of experimental pneumococcal pneumonia, pulmonary levels of RANTES and IP-10 may be increased (21,40) and, along with other proinflammatory cytokines, appear to play a role in the pneumococcal immune response. In animal experiments using an EF3030 pneumococcal strain, RANTES also influenced the production of antibodies that limited the progression of nasopharyngeal pneumococcal carriage to frank pneumonia and influenced survival (40). Our observation that BAL RANTES was increased in a dosedependent fashion among subjects with AUDs suggests a potential protective role of alcohol in pneumococcal infection.…”

Lethal Coinfection of Influenza Virus and Streptococcus pneumoniae Lowers Antibody Response to Influenza Virus in Lung and Reduces Numbers of Germinal Center B Cells, T Follicular Helper Cells, and Plasma Cells in Mediastinal Lymph Node

“…002D5 was cultured in ToddHewitt broth with 17% fetal calf serum to mid-logarithmic phase, snapfrozen in liquid nitrogen, and stored at Ϫ70°C (24). Viability of the inoculum was checked by counting colonies from serial dilutions plated on blood agar, which remained stable for at least 1 year.…”