Autophagic Killing Effects against Mycobacterium tuberculosis by Alveolar Macrophages from Young and Aged Rhesus Macaques

Abstract

Non-human primates, notably rhesus macaques (Macaca mulatta, RM), provide a robust experimental model to investigate the immune response to and effective control of Mycobacterium tuberculosis infections. Changes in the function of immune cells and immunosenescence may contribute to the increased susceptibility of the elderly to tuberculosis. The goal of this study was to examine the impact of age on M. tuberculosis host-pathogen interactions following infection of primary alveolar macrophages derived from young and aged rhesus macaques. Of specific interest to us was whether the mycobactericidal capacity of autophagic macrophages was reduced in older animals since decreased autophagosome formation and autophagolysosomal fusion has been observed in other cells types of aged animals. Our data demonstrate that alveolar macrophages from old RM are as competent as those from young animals for autophagic clearance of M. tuberculosis infection and controlling mycobacterial replication. While our data do not reveal significant differences between alveolar macrophage responses to M. tuberculosis by young and old animals, these studies are the first to functionally characterize autophagic clearance of M. tuberculosis by alveolar macrophages from RM.

KillingMycobacterium tuberculosis In Vitro: What Model Systems Can Teach Us

“…While these data suggest that investigators should not extrapolate upon mouse data too heavily, other studies have shown that certain aspects of immune control are conserved. We showed that autophagic killing of M. tuberculosis occurs in alveolar macrophages from rhesus macaques, recapitulating our previous experiments performed using murine BMDMs (36, 52). In addition, we used alveolar macrophages to ask whether this autophagic killing was impaired upon aging, since this pathway is thought to be diminished with age.…”

Lymphatic endothelial cells are a replicative niche for Mycobacterium tuberculosis

“…For semiquantitative analysis, at least 100 cells were response in myelocytic cells (30). However, our results provide an explanation for the observation that clinical isolates of M. tuberculosis manipulate autophagy for their survival (40) and mirror those seen in M. tuberculosis infection of human primary dendritic cells (41), human type II alveolar epithelial cells (42), and some primary alveolar macrophages from adult macaques (43). Consistent with our observations, in Listeria-infected macrophages, bacteria are localized to both the cytosol and LC3 + compartments in which bacteria grow (44), and long-term infection of macrophages with M. bovis BCG also leads to growth of the bacteria in LC3 + compartments (45).…”

Aging associated altered response to intracellular bacterial infections and its implication on the host

“…Many other studies on bacterial infection have focussed on how changes in the immune system during ageing can influence infection. However, contradicting evidence regarding immune-senescence indicates the presence of other confounding factors (Esposito and Pennington, 1983; Cooper et al ., 1995; Pacheco et al ., 2013), which may decide the final outcome of infection in the aged.…”